Tissue Repair: Regeneration, Healing & Fibrosis

Outcomes of acute inflammation.

Resolution: (the ideal outcome) refers to the return to normal which will follow an
uncomplicated acute inflammation. The tissue is restored to its original state, prior to the
injury.
If tissue damage was more extensive, some degree (or a combination of the two may result
from acute inflammation.):
1. regeneration (the replacement of necrotic parenchymal cells by new parenchymal cells of the same type),
2. scarring
In chronic inflammation, there has been considerably more tissue injury, so true resolution
cannot occur. More parenchymal cells have been lost (the functional cells of a tissue or
organ; eg., the myocardial cells in the heart, the hepatocytes in the liver); again, either
regeneration or scarring (or a combination of the two) can take place. Concurrently, the
necrotic cells and inflammatory debris must be removed.
Read the Overview of Tissue Repair in your textbook, found on p. 58.

Regeneration
When parenchymal cells are lost, the adjacent surviving cells may undergo division to
replace them. The extent of regeneration depends:
(1) ability of that cell type to divide
(2) numbers of surviving cells,
(3) surviving connective tissue framework to allow the normal tissue structure.
Read the discussion on The Control of Cell Proliferation, found on pp. 59-61 of your text.
The regenerative capacity of different cell types vary:
a) Labile cells are those which normally divide actively through life, to replace cells which
are normally being lost. These cells have a short intermitotic (resting) phase. Familiar
examples include the epithelial cells of the skin and mucosal surfaces (eg., those cells lining
the alimentary and respiratory tracts). The hematopoietic cells of the bone marrow are also
labile populations. Injury to these tissues will be rapidly followed by regeneration, which
occurs from the basal germinative layers in the case of epithelial cells, and from stem cells
in the case of the bone marrow. An obvious prerequisite for regeneration is that
sufficient numbers of the labile cells have survived the initial injury.

b) Stable cells are long-lived and have a low rate of division. They are reversibly
postmitotic, remaining in the intermitotic phase for years, but can divide if necessary.
Examples of stable cells include the parenchymal cells of solid organs such as the liver,
kidney and pancreas (hepatocytes, renal tubular epithelial cells and pancreatic acinar cells,
respectively), as well as fibroblasts and endothelial cells. Thus, cells of organs such as the
liver can regenerate after necrosis, provided that some cells have survived and there is a
connective tissue framework to support the regeneration.
c) Permanent cells are those which cannot divide after fetal life. Examples of permanent
cells are those of the nervous system (both central and peripheral) and cardiac muscle
cells. Injury to these cells can only heal by scarring of the tissue - the functional cells of
these tissues cannot be replaced. Extensive injury to nervous or cardiac muscle tissue will
thus lead to a functional deficit.
Modern Scope of Permanent Cell Populations
Recent research indicates that these may be an oversimplification, but much of this is
beyond the scope of this course. Recently research reported in the media has provided us
with a few interesting examples. The Brain That Changes Itself, a book by Norman Doig
MD, demonstrates that nervous tissues are capable of overcoming some of the results of
irreversible injury through a process referred to as plasticity. You are currently exploring
the plasticity of your brains as you study this material, as this is the principle by which we
adopt new skills and knowledge! However, this principle may explain how some individuals
surviving with brain and spinal injuries are eventually capable of adapting the functional
deficits that arise.
Additionally, current research into stem cell transplantation suggests that such injuries might
eventually be reversible through transplantation!

What determines the rate of cell proliferation?

The primary motivators for cell replication are proteins called cyclins, which interact with
cyclin-dependent kinases within the nucleus and control the entry and progression of cells
through the cell cycle. Fig. 5-20 (textbook p.181) is a diagram illustrating the cell cycle, and
indicates the effects of cyclins and cyclin-dependent kinases on the cycle.
The rate of cyclin activity can be further modified by a variety of factors:
1. A variety of external growth factors have been identified, and include epidermal
growth factor, platelet-derived growth factor, insulin-like growth factors, fibroblast
growth factor, and interleukins. A variety of systemic hormones also promote cell
replication, including thyroid hormone and growth hormone. These factors most

commonly act through interactions with cell surface or nuclear surface antigens to
indirectly upregulate cyclin activity.
2. Cell proliferation is in part regulated by inhibitory signals, and include those who
normally regulate cell proliferation healthy cells (including those involved in
contact inhibition, which regulates cell proliferation in the context of the cells
relationship with its neighbouring cells), and those that monitor cells for
abnormalities and have a variety of effects, including impaired proliferation and
induction of apoptosis.
The net rate of cell proliferation is dependent on:
1. The ability to replicate; postmitotic cells and those that have reached a state of
senescence (have previously proliferated to a point that they are no longer
capable).
2.

The balance between proliferative and inhibitory signals (cyclin activity).

3. The balance between the rate of cell proliferation and cell loss secondary to
apoptosis.

Scarring (Fibrosis)
What exactly is scarring? Scarring can be defined by replacement of normal tissue by
dense collagenous connective tissue after injury, the result of healing by fibrosis. This
contrasts with regeneration as scarring results in local loss of normal tissue parenchymal
cells and architecture.
Scarring occurs:

when regeneration is not possible, either because the injured cells are permanent
cells, or because the injurious process caused sufficiently widespread necrosis to
affect both the supportive connective tissue framework, as well as the numbers of
viable labile or stable cells surviving

when an acute inflammatory process is not resolved, or there is ongoing tissue

necrosis in chronic inflammation

Healing and the Labile Cell Population

CASE STUDY
A veterinary pathologist is sent several 3-day-old piglets that the farmer says are ADR
(Aint Doin Right); most of his recent piglets have been similar, but only a few have died.
She also says that many of them have been Scouring (have diarrhea). The piglets are
alive on submission, euthanized and necropsied immediately. The piglets are all moderately

dehydrated, all have staining of their tails and legs with feces, have soft or fluid feces within
their intestines and colons, but otherwise no discriminating lesions in the intestine or colon.
The pathologist provides a tentative diagnosis of Undifferentiated Diarrhea (despite the
presence of diarrhea, there are no grossly obvious lesions to indicate what pathogen might
be responsible). The pathologist submits tissues for histopathology as well as for evaluation
for the presence of viruses, microscopic parasites, and pathogenic bacteria.
You might ask yourself Why would the farmer submit live sick animals to be euthanized for
necropsy. Well, autolysis(decomposition of tissues after death) can rapidly obscure subtle
histologic lesions in some tissues, particularly in the gastrointestinal tract. As such, farmers
will often sacrifice few sick but live animals in order to better determine the cause of
an epidemic illness that threatens all of the animals.

The pathologist reviews the histology and demonstrates a cause of diarrhea there has
been loss of the mature intestinal mucosal cells (enterocytes) lining the villi, resulting in
collapse of the villi (a lesion termed villus atrophy), but sparing the crypt cells, which form
the proliferative stem cell compartment of the mucosal epithelium.

Answer the following questions:

1. How is this lesion likely to heal?
2. Why might this animal have diarrhea?
Viral testing demonstrates a Type A rotavirus, a common cause of epidemic villus atrophy
and diarrhea in very young piglets. This disease is often associated with high morbidity but
low mortality/case fatality in well-managed pig herds. Diarrhea occurs because the mature
villous enterocytes are necessary to absorb nutrients and water from the food entering the
intestinal tract; the nutrients that are not absorbed produce an osmotic effect that draws
fluid from the body into the feces, producing diarrhea and dehydration. However, the
intestinal tract is likely to heal well via regeneration, as the crypt stem cells and normal
tissue framework are preserved, as long as the piglets do not succumb to dehydration and
associated complications.

Rotaviruses are a common cause of diarrhea in a variety of species, including humans: an

estimated 130 million cases of human rotavirus occur annually, mostly in children aged 0.52 years, and causes nearly a million deaths annually.

The veterinary pathologist reports these findings, and the farmer and her veterinarian
develop a plan to get this epidemic under control and prevent further losses, both now and
in the future, including:
In truth, I have used the term epidemic improperly here: in animal populations, the
appropriate term is Epizootic.

1. Looking for predisposing causes of this epidemic; rotaviral enteritis is often

associated with abnormally cool temperatures in the barns, so insulation and
heating systems are evaluated. Diseases may also be introduced to barns with
poor Biosecurity (protective steps and protocols designed to actively exclude
disease, such as exclusion of wildlife/vermin, shower-in/shower-out procedures,
and flow of animals within the barns).
2. Looking at options for optimizing piglet immunity, such as the availability of
vaccines against Type A rotaviruses.
3. Developing plans for surveillance for future disease outbreaks.

Take a second and look up the following definitions:

(answers at the end of the chapter)
1. Morbidity: rate of incidence of a disease
2. Mortality: death rate
3. Case Fatality: is the proportion of deaths within a designated population of "cases"
(people with a medical condition), over the course of the disease

4. Epidemic: is the rapid spread of infectious disease to a large number of people in a

given population within a short period of time, usually two weeks or less.

As stated, injury to the villous enterocytes produces an injury that can often be recovered
from, with time and treatment for/prevention of diarrhea and associated complications.
However, not all injury to such a labile population is going to end well.
Some pathogens will either specifically target the fast-dividing crypt stem cells (such
as Canine Parvovirus), or will cause severe nonspecific injury to all levels of the intestinal
mucosa (such as might have occurred as a result of ischemia in the Case Study of small
intestinal torsion in Unit 02, or with the profound necrosis associated with Salmonella spp).

Answer the following question: How might this type of lesion heal, as compared to the
villus atrophy lesion?

Healing and the Stable Cell Population

CASE STUDY
In late fall, a young dog begins vomiting, seems dopey, and becomes very lethargic. He is
taken to a veterinarian. The owners report that he has been in the house for the past two
days while he has been sick. He is no longer vomiting, but seems very weak and will not eat
or drink. He usually runs freely on the owners property, with access to both the yard and
garage. He is up to date on all vaccinations. Physical abnormalities include severe
dehydration and depression, and an elevated pulse and respiratory rate. The owners report
that the dog has not urinated for at least one day.
Because of the extent of the dogs dehydration, he is hospitalized and started on
intravenous fluids. Blood samples are taken for serum chemistries, blood gases and a CBC,
and a urine sample is collected for urinalysis. Laboratory abnormalities include:

elevated BUN (blood urea nitrogen) and creatinine, indicating impaired renal
function

metabolic acidosis (decreased blood pH)

neutrophilia (increased total numbers of neutrophils in the blood), indicating

stress

urine casts (cylindrical clumps of necrotic renal tubular epithelial cells their
shape represents an actual cast of the tubular lumen), indicating severe tubular
injury, and calcium oxalate crystals, suggesting toxicity

A tentative diagnosis of acute renal tubular necrosis is made. On further questioning, the
owners report that the dog may have had access to antifreeze (ethylene glycol) in the
garage - the car engine antifreeze had recently been changed. Ethylene glycol is readily

consumed by dogs (and cats), and rapidly absorbed from the gastrointestinal tract. Most is
secreted unchanged in the urine, but some is metabolized in the liver to a variety of toxic
metabolites, including glycolic acid. Renal tubular damage is caused by these metabolites.

Renal tubule epithelial cells are stable cells. Describe possible outcomes for this dog
what factors will influence healing of the tubular injury?
Management of ethylene glycol toxicity involves increasing renal blood flow, enhancing the
excretion of ethylene glycol, managing the acidosis, and giving time to allow possible
regeneration of the renal tubular epithelium.
The extent of injury to the tubular epithelium will vary, depending on the amount of ethylene
glycol ingested and the amount metabolized in the liver. If injury was mild, then renal tubular
epithelial cells will begin to regenerate and normal renal function will gradually return.With
moderate injury, fewer epithelial cells may remain, and there may be injury to the connective
tissue which supports the tubular epithelium - repair may thus occur more slowly, with some
regeneration occurring, but also scarring resulting.
If injury was severe and extensive, then no regeneration of tubular epithelial cells can occur,
and too little functional renal epithelium may remain to support normal renal function. The
animal will die from the complications of acute renal failure.
Some stable cell populations are more capable of regeneration than others. The above
Case Study deals with kidney; renal tubular epithelial cells are slow to proliferate, so the
progression to chronicity and scarring with a single insult is more likely. However, some
other stable cell populations are quicker to respond to insult! Hepatocytes (parenchymal
liver cells) begin to proliferate rapidly after insult and are less likely to enter a chronic
healing phase with a single insult.

Healing and the Permanent Cell Population

CASE STUDY
A 42 year old man develops acute chest pain and difficulty breathing. He is admitted to
hospital through emergency, and a myocardial infarction is diagnosed.

Answer the following questions:

1. If the patient survives the attack, how will the myocardium heal?
In addition to the aforementioned scarring, the remaining viable myocardium
attempts to compensate for the loss of contractile mass. Noninfarcted regions
undergo hypertrophy and dilation; in combination with the scarring and thinning of
the infarcted zones, the changes are collectively termed ventricular remodeling.
2. What factors will influence the prognosis for this patient?
Long-term prognosis after MI depends on many factors, the most important of
which are left ventricular function and the severity of atherosclerotic narrowing of
vessels perfusing the remaining viable myocardium. The overall mortality rate
within the first year is about 30%, including deaths occurring before the patient
reaches the hospital. Thereafter, the annual mortality rate is 3% to 4%.
(You can refer to the discussion of Ischemic Heart Disease Myocardial Infarction on pp.
377-385 of your textbook to check your answers).

How does scarring develop?

Repair by scarring involves several different processes. Note that although these have
been separated into different categories, in reality they are to some degree occurring
concurrently.
a. Debridement is the removal of debris (inflammatory exudate, blood, necrotic
tissue) from the area the clean-up which allows scar formation to occur.
Neutrophils release lysosomal enzymes which liquefy the debris, so it can be
more readily removed by the lymphatics and by macrophages. (Debridement also
occurs with resolution and regeneration.)
b. Granulation tissue formation is an important component of scar formation,
acting to fill the injured area until more mature scar tissue can develop.
Granulation tissue is highly vascular immature connective tissue it consists of
proliferating fibroblasts, newly formed capillaries, and some inflammatory cells.
Grossly, it appears as pink, soft and granular, because of the many new
capillaries. Granulation tissue formation is the result of two concurrent processes,
angiogensis and the migration and proliferation of fibroblasts:
c. Angiogenesis - the formation of new blood vessels.

Read the discussion of angiogenesis found on pp. 66-67 of your textbook.

Complete the following:
1. Besides having a critical role in wound in healing, angiogenesis is also
important in: (2 points)
2. What are the five general steps in the process of angiogenesis?

Note that the newly formed vessels are leaky, which contributes to the edema of
healing wounds. A variety of growth factors stimulate both fibroblasts and
endothelial cells; integrins (structural proteins in the extracellular matrix) also
influence vessel growth.
d. Collagenization refers to the process by which collagen is laid down in the area.
Collagen is synthesized by fibroblasts, via the production of the precursor,
procollagen. Collagen is an insoluble fibrillary (consisting of fibrils or strands)
protein, which gives much of the tensile strength to scar tissue. With a
microscope, collagen appears as pink, fibrillar material (with H&E stain); grossly,
collagen appears as the white firm material which gives scar tissue its
characteristic appearance.
e. Maturation (Remodeling) refers to the process by which granulation tissue is
gradually replaced by mature connective tissue. The content of collagen increases
and the numbers of capillaries and inflammatory cells decreases. A mature scar is
a poorly cellular mass of collagen. The strength of the scar increases as the
amount of collagen increases, as the type of collagen changes (collagen types are
recognized on the basis of the structure of their polypeptide chains), and there is
increased cross-linking between collagen molecules.
The glycoprotein fibronectin has an important role in the formation of granulation tissue.
Synthesized by the endothelial cells, fibroblasts and macrophages, it is chemotactic for
fibroblasts, and helps organize endothelial cells into new capillaries.
Granulation tissue is NOT the same thing as granulomatous inflammation -be careful with
these terms as they sound somewhat similar, but mean quite different things!

f.

Contraction of the scar occurs as it matures, decreasing its size. Actomyosin

filaments in certain fibroblasts (myofibroblasts) cause early contraction. Later
contraction is due to the increased presence of collagen.

Horses (and some people!) have a tendency to form exuberant granulation tissue (proud
flesh) following skin wounds. This can delay the rate of healing, as the excessive
granulation tissue-which often extends above the wound surface prevents epithelium from
bridging over the wound. This is especially a problem with wounds of the lower limbs, where
there is little loose soft tissue, as well as a tendency for excessive movement.
Proud flesh appears as a tumour-like mass of reddish tissue, and must be differentiated
from tumours and infections. Proper wound management, especially with wounds of the
lower limbs, is of importance in helping to prevent the development of this excessive
granulation tissue.

How healing occurs will depend on the nature and extent of the injury and the type of tissue
affected. Lets spend some time describing skin injuries, the most visible types of injury.

Healing of Skin Injuries

How healing occurs will depend on the nature and extent of the injury and the type of tissue
affected. Lets spend some time describing skin injuries, the most visible types of injury.
To digress for a moment, Ill briefly review the structure of the skin. The skin is composed
of the epidermis and the dermis. The more superficial epidermis, the part you see, is made
up of stratified squamous epithelium. The cornified (keratinized) layers of cells in the
superficial epidermis are continually being lost, and are replaced by cells moving upward
from the basal layer (which consists of labile cells). The deeper dermis consists of
supportive connective tissue (collagen), blood vessels, and the adnexa the hair follicles,
sebaceous glands, apocrine glands and sweat glands which are associated with the skin.
Skin injuries or wounds can be classified as follows you have probably heard some of
these terms used before:
Types of skin injury:
Abrasion commonly called a graze or scrape - when epidermal cells of the skin are
removed, the mildest form of skin injury. This is the type of injury which occurs when you fall
on cement or asphalt and skin your knee; mechanical force is involved. As the basal layers
of epidermal cells are not affected, regeneration occurs from below.

Laceration the result of tearing of tissues, especially over bony surfaces. They affect both
the epidermis and dermis.
Incision a cut the cutting of tissues by a sharp-edged object. As with a laceration, both
the epidermis and dermis are affected. Both lacerations and cuts cause little loss of basal
epidermal (germinative) cells.
Contusion a bruise produced by blunt trauma; there is blood vessel damage and
hemorrhage into tissue.
Avulsion the tearing away of a part due to severe trauma
Crush injuries, burns and large lacerations all cause extensive loss of the epidermis.
Puncture wound a stab the result of penetration by an object, usually of relatively
small diameter, into the skin or other tissues. Such penetrating wounds cause deep injury to
tissues. Perforating wounds go right through the tissue, so both entry and exit wounds are
present.
Injury due to mechanical trauma is discussed on pp. 287-288 of your textbook. The
processes involved in scar formation are the same processes involved in the healing of skin
wounds, with the exception that epithelialization also must occur. Skin healing can be
considered either healing by first intention or healing by second intention, depending on
the extent of the injury and whether or not the wound edges are brought together.
Read the discussion on Cutaneous Wound Healing on pages 70-72 of your textbook, and
complete the following:
A. Healing by First Intention

Using the example of a simple skin incision (as might occur while you were chopping
vegetables), describe in point form the steps involved in the complete healing of the
wound by first intention: (nine points)
(You can check at the end of this unit (Self-assessment) for a suitable answer to
this question.)

What is a scab?
The reddish brown scab which develops over a wound is composed of clotted blood
and some inflammatory cells. It acts as a bandage to protect the wound from
infectious agents. In small wounds which are healing by first intention, the epidermal
cells rapidly grow under the scab to re-establish the integrity of the skin. The scab
will separate when the new epidermis matures and starts shedding its superficial
keratinized layers.

It is important that wound edges are approximated (brought close together) to allow
healing by first intention. This is usually accomplished in large wounds by using
sutures (stitches).
The benefits of healing by first intention are that healing occurs more quickly and
scarring is minimized. Sutures are commonly removed after 7-10 days. Although at
this time the tissue has not regained all of its normal strength, if the sutures are left
longer the risk of wound infection and scarring is increased.
B. Healing by Second Intention

Complete the following: Healing by second intention occurs when: (4 points)

Healing by second intention is necessarily slower than healing by first intention, as
the defect which must be healed is much larger, as would occur with lacerations or
cuts which are not sutured, and any wound causing a large epidermal defect.

Describe in point form how the process of healing by second intention differs from
healing by first intention (primary healing): (three points)

Ill emphasize here that granulation tissue (that is, proliferating capillaries and
fibroblasts), so important in healing by second intention, also has a role in healing by
first intention - proliferating capillaries and fibroblasts are seen in the dermis as it

heals. The difference is that in healing by first intention, it is much less prominent,
and is covered by regenerating epidermis much earlier (usually by about two days).

What are some possible complications of healing by second intention? (four points)

(Refer to the discussion, Factors that Influence Tissue Repair on pp. 69-70 of your
textbook).
Keloid formation, consisting of abnormal nodular masses of collagen, can result
from even minor skin wounds. Keloid formation demonstrates a familial tendency.
View Fig 2-32 (p. 69, text), which illustrates the appearance of keloid tissue. Similar
lesions are relatively common in horses.
View Fig. 2-33 (text, p. 70), which compares healing by first intention and second
intention.
Ultimately, many factors can influence the extent and effectiveness of wound
healing. These include:
o Nutritional factors vitamin C, protein or zinc deficiency may lead to
defective collagen synthesis
o Drugs patients on corticosteroids (often used to suppress immunemediated diseases) will show delayed wound healing
o Foreign material material such as fragments of wood, dirt etc. in wounds,
as well as the presence of necrotic tissue or large clots will delay the rate of
healing.The presence of foreign material in tissue will lead to chronic
inflammation.
o Blood supply if blood supply to the area is compromised, healing will be
delayed. This can occur in diabetes mellitus, due to the presence of
microvascular disease which impairs blood flow to tissues.
o Age advanced age may lead to less effective wound healing
The size and shape of the wound, the nature of the injured tissue, the degree of
immobilization, as well as the presence of infection are all factors which will also
influence the rate of healing.

Create a flow diagram of your own to summarize these responses.

Returning to the first Case Study (Healing and the Labile Cell Population), if injury to
the intestinal tract occurs by scarring rather than regeneration, what major
complication might arise?

Unit 06:
Introduction
Much of the history of the world has been influenced by infectious disease. Until the last
century, many children did not survive past infancy, and many adults died before reaching
old age. Improvements in sanitation and the development of vaccines have made huge
changes in the way we view infectious disease - in North America, we expect to survive to
old age but for the modern scourges of cancer and cardiovascular disease. However, in
many parts of the world, sickness and death due to infectious disease are still very real
concerns.
This is not to say that we can be complacent. The emergence of AIDS (acquired
immunodeficiency syndrome) in the early 1980s made it apparent that infectious diseases
are still risks in our lives. New disease concerns are emerging - increased travel between
continents has done much to erase the previous geographic boundaries for a variety of
infectious diseases. A number of drug-resistant strains of bacteria have emerged antibiotics are no longer the panacea we had hoped. On an almost daily basis we read
headlines in the newspapers about new concerns - mad cow disease, flesh-eating
disease, drug-resistant strains of tuberculosis, West Nile virus, avian influenza, and

contaminated food and water supplies. An awareness of how infectious organisms cause
disease is as important now as ever.

Introduction
Infectious agents are often the cause of both the inflammatory and the immune responses.
In this unit, we will discuss the major types of infectious organisms (viruses, bacteria, fungi,
and parasites), with respect to the effect they have on the bodys cells and tissues. In many
cases, the clinical signs associated with infections are due to the inflammatory and immune
responses mounted against these organisms by the host.
Yes, this is a large-unit, and there is a lot of material, but we are going to focus on how
these organisms cause disease, rather than emphasizing the characteristics of the
organisms themselves (the realm of microbiology). Ill make reference to specific reading, or
figures which I want you to view in the textbook. We will consider some specific disease
entities, where they illustrate principles of pathogenesis, or are of current interest.

Overview of Infectious Agents General Principles

(Text, pp. 309-315)
The major groups of organisms which we will consider are the prions, viruses, bacteria,
fungi, and parasites. The term parasite can be somewhat confusing. In the broadest sense,
a parasite refers to a plant or animal, which lives upon, or within another living organism, at
whose expense it obtains some advantage. By this definition, many of the groups of
organisms (infectious agents) named above are parasites. By popular usage, however,
parasite has come to refer more specifically to protozoan, metazoan (helminths and flukes)
and arthropod organisms that cause disease. The term parasite will be used both ways in
this unit.
The above classifications relate to the structural complexity of the organism. In order of
increasing complexity, from simplest to most complex, we would consider first the prions
(the agent causing Mad Cow Disease is a prion), viruses, the intracellular bacteria
(rickettsia and chlamydia), the mycoplasma (a simple form of bacteria), the bacteria, fungi,
protozoa, and finally, the metazoa (helminths, flukes) and arthropods.
The viruses can be further classified as RNA or DNA viruses, on the basis of the type of
nucleic acid in their genomes. Bacteria are further classified by shape - cocci, rods (bacilli),
spirochetes - by their reaction on Gram staining (gram-positive or gram-negative), and by
their oxygen requirement for growth (aerobic or anaerobic). Fungi can be classified as either
yeasts or molds (mycelial fungi), or as dimorphic (having both yeast and mold forms). Both

the protozoa and metazoa are further classified into genera and species on the basis of
structural characteristics.
To help put this in perspective, Ive summarized these classifications in an Appendix at the
end of this unit, Classification of Infectious Organisms. DONT TRY TO MEMORIZE
THIS !! It is included only to help you organize information which will be presented in this
unit.
Infectivity and pathogenicity...and opportunistic and virulent pathogens
Infectivity refers to the ability of an organism to colonize tissues,
whereas pathogenicity refers to the ability of an organism to cause disease. Pathogenic
organisms can be classified as either low-grade or high-grade, on the basis of their ability to
cause disease. Low-grade pathogens will only cause disease in immunocompromised
hosts these are termed opportunistic infections. High-grade
pathogens (virulent pathogens) may cause disease even in healthy hosts.

Finally, infectious agents can also be considered on the basis of their site of multiplication:
The viruses are obligate intracellular organisms, as are the prions and two types of bacteria,
the rickettsia and the chlamydia. Obligate intracellular parasites require host cells to grow
and multiply, using the hosts metabolic machinery for growth. They tend to infect
parenchymal cells. Culture of such organisms thus requires living cell systems, such as
tissue cell culture or embryonated eggs.
Extracellular organisms multiply outside of cells these include most of the other
pathogens. These can be cultured on artificial media (with the exception of the protozoa and
metazoa).
Facultative intracellular organisms (such as the mycobacteria and some fungi) can grow
both inside (usually in macrophages) and outside of cells they can be cultured either on
specialized artificial media or in cell culture.
This classification system (by site of multiplication) is useful to keep in mind, as the way in
which the organism affects the host and, in turn, the type of inflammatory and immune
response mounted by the host are largely determined by the organisms site of
multiplication.
Intracellular Organisms
Prions

Viruses

DNA Viruses
RNA Viruses
Rickettsia and Chlamydia
Extracellular Organisms
Mycobacteria
Bacteria
Gram-positive/Gram-negative?
Aerobic/Anaerobic?
Morphology?
Rod-shaped (bacilli) Round (cocci) Spirochetes
Fungi
Yeasts
Filamentous
Dimorphic (both Yeast and Filamentous forms)
Protozoa
Metazoa
Arthropods

How can an organism gain entry to the body?

For an organism to be successful as a parasite, it must be able to be transmitted from one
host to another. The organism must enter the hosts tissues and multiply there to cause
disease. (There is an exception to this organisms which produce exotoxins outside of the
body but we will discuss these later.)
Read pages 315-319 of your textbook, which give a brief historical perspective on infectious
diseases, an introduction to new and emerging diseases, and an overview of the categories
of infectious agents.
Most organisms gain entry to the body via natural passages that is, any tissue of the body
that is exposed to the external environment. These are termed the primary portals of entry.

Read the section titled Release from the Body and Transmission of Microbes (p.315-319,
text). Spend a minute listing and briefly describing these barriers:

the skin
o Outer keratinized skin layers are constantly shed and renewed; low pH
and fatty acids inhibit microbial growth

o Organisms can penetrate through breaks in skin (wounds, insect bites,

needles, etc)
o Heat and humidity/wetness favour organisms entering through skin

the respiratory tract

the intestinal tract

the urogenital tract

Organisms can also gain entry to the tissues via trauma and direct inoculation. Other than
by trauma, the tissues of internal organs such as the heart, bones, brain and muscles can
only be infected via the blood (recall hematogenous osteomyelitis, described in the previous
unit) or the lymphatics organisms arriving via these routes will have gained access at one
of the primary portals of entry.
Using this knowledge of the primary portals of entry, we can summarize the four principal
methods of spread of infection:
a. Physical contact
o Either Direct or via Fomites (intermediate objects, such as utensils,
clothing, doorknobs, etc.)
b. Airborne infection
o Transmission through the air via dust or droplets (an estimated 20,000
droplets containing potential pathogens can be expelled by one
sneeze)
c. Food-borne infection
o Contamination of food or water is a primary mode of spread of enteric
disease
d. Insect-borne infection
o Insects can transmit viral, bacterial, and protozoal disease

Read the section, Release from the Body and Transmission of Microbes, found on p. 318
of your text, to add details to the above list.

The Result of Infection

When a micro-organism invades a tissue, one of three things may happen:

1. The invader dies (most likely!), due to the actions of both nonspecific defences
(including inflammation) and more specific immune responses
2. The invader may survive without giving rise to obvious clinical disease, but
causing an immune response
3. The invader survives, multiplies, and produces clinical disease
Many factors will influence the outcome of host exposure to a pathogen; three primary
components that may contribute are the pathogen itself, the host, and the environment.
The Pathogen
1. The virulence of the pathogen (what does this mean?).
2. The dose of pathogen exposure.
The Host/Environment
1. The status of the primary defences of the host (nonspecific protective
mechanisms).
2. The immune status of the host (ability to mount an appropriate immune response,
ability to recognize the pathogen from previous exposure).
The Host and Environment are often lumped together, as ultimately the effects of
environmental conditions manifest as changes in the factors above (such as the effects of
cold on the immune system, the effects of air quality on lung and mucus membrane
defences).
Infection is said to occur when an infectious agent has entered and multiplied in a host.
Infection does not necessarily imply disease - some infections can remain latent for long
periods.
When the infectious agent has lead to the development of an immune response (ie., the
development of antibodies and/or cellular immunity) but disease is not clinically apparent,
subclinical infection is said to occur.
When the infectious agent has survived and multiplied in the host, producing tissue
damage, then clinically apparent infectious disease occurs.
In most infectious diseases, infection is localized to the site of entry of the pathogen for
example, the gastrointestinal tract in the case of enteric bacteria. On occasion, the
organism may enter the bloodstream or the lymphatics and spread more widely. In some

cases, disease may not be apparent at the site of entry of the organism. (In poliomyelitis, for
example, the causal enterovirus enters via the intestinal tract, but there is usually no sign of
intestinal infection.)
Once the organism has infected the host tissue, disease may result from both the effects of
the organism on the host tissue and the effects of the host response to the organism (both
the inflammatory response and the immune response).
Read Spread and Dissemination of Microbes Within the Body, found on pp. 317-318 of
your text.

Infection of the bloodstream

The presence of micro-organisms in the blood is of clinical significance. Depending on the
type of organism, this finding is termed viremia, bacteremia, fungemia or parasitemia (emia meaning of the blood). The first three conditions are diagnosed using blood cultures,
whereas parasitemia can be diagnosed by identifying the parasite in blood smears. In the
blood, organisms may be carried free in the plasma, or attached to or within blood cells or
leukocytes.
Bacteremia refers to the presence of viable bacteria within the bloodstream, and ranges
from transient bacteremia, in which small numbers of bacteria in the bloodstream are
removed by the body, preventing their multiplication, to severe bacteremia where large
numbers of bacteria in the bloodstream are capable of overwhelming the bodys defences.
Toxemia refers to the presence of bacterial toxins within the bloodstream.
Septicemia refers to the disease state that arises from the presence of large numbers of
bacteria, or their toxic byproducts, within the bloodstream, resulting in a clinical syndrome
characterized by high fever and a precipitous drop in blood pressure. In these cases, shock
and DIC may result in death.
Transient bacteremia may be of significance in immunocompromised hosts, and in those
with chronic cardiac valve disease or with valve prostheses (the bacteria may grow in the
damaged valves).
Well now go through each of the major classifications of organisms, the viruses, bacteria,
fungi and parasites, and discuss how each type of organism injures its host, and how the
host responds to the organism.
Read the brief introductions to How microorganisms cause disease, on p.319 of your text.

Viruses and other Intracellular Parasites

Obligate intracellular organisms include the prions, viruses, rickettsia and chlamydia.
Viruses can cause a variety of changes when they infect cells; intracellular bacteria, the
rickettsia and chlamydia, can cause many of the same changes. The effects of prions on
host cells are not yet well understood.
We should spend a few minutes going over some basic information about viruses those of
you with a background in microbiology can probably whiz through this. Viruses, being
obligate intracellular parasites, are dependent on a phase of intracellular growth. Between
cycles of intracellular replication, viruses exist as free viral particles, or virions. Viruses
share a common general structure, which includes:
1. A central core of nucleic acids which encode the genome of the virus. In a
proportion of viruses, this genome is encoded with DNA, the remainder are
encoded with RNA.
2. A well-structured protein coat,
3. An outer lipid envelope, only found in a limited proportion of viruses
The host cell supplies the energy, substrates and synthetic machinery for viral
growth. The viral life cycle can be summarized as:
o the virus must find susceptible cells, with appropriate receptors on their
cell membranes which are recognized by proteins on the virus surface
(ligands)

the virus binds to receptors on the cell via viral surface ligands

the virus penetrates the cell fusion to cell membrane, receptor

mediated endocytosis, or translocation of virus across cell
membrane

virus is uncoated inside the cell; genome separates from

structural elements

virus initiates cycle of nucleic acid transcription and translation,

using specific enzymes

new viral proteins are synthesized and new viral genomes

replicated

new virions are assembled and released directly

(unencapsulated viruses), or by budding (encapsulated viruses)

Why do viruses only infect certain cell types?

The presence of appropriate cell receptors for the virus determines the organotropism of
the virus certain viruses preferentially affect specific parenchymal cells. For example, the

poliomyelitis virus has a tropism for the motor neurons of the central nervous system; the
Hepatitis A virus has a tropism for cells of the liver. The clinical signs of different viral
infections are the result of the type of cell infected and the type of cell injury resulting from
the virus.
How do viruses cause injury to their hosts?
Once viruses have infected target cells, they can mediate injury to those cells by a number
of means; often multiple mechanisms may be involved. Read Mechanisms of Viral Injury,
on pp. 319-320 of your text.
1. Virally-mediated cell necrosis
a. Virally-mediated cell injury
Upon viral infection of a target cell, the virus may impair normal cell functions
directly, resulting in sublethal or lethal cell injury, by several means:

Cell lysis may occur during virus replication and release (as a
means of dispersion of virions). Viral replication will often interfere
with normal cell functions, resulting in cell death.

Inhibition of host cell DNA, RNA or protein synthesis functions,

which may result in either subtle cell dysfunction or cell death
(particularly when critical enzyme paths are involved).

Damage to cell membranes by direct insertion of viral proteins into

the cell membrane, which can alter membrane function and/or
integrity (resulting in cell swelling and/or lysis). Some viral proteins
may promote fusion of neighbouring cells, resulting in formation of
syncytial cells or giant cells.

Inclusion Bodies
Inclusion body formation occurs in some viral and rickettsial infections.
Inclusion bodies are formed during the process of viral replication, and
consist of either assembled viral particles or parts of viral nucleic acid
synthesis.
Inclusion bodies can occur in the cytoplasm or the nucleus (or both), and
useful diagnostically in the microscopic identification of specific viral
infections. For instance, Rabies virus infection produces characteristic
eosinophilic inclusion bodies within the cytoplasm of infected neurons.

Cell death may occur rapidly causing extensive necrosis of target cells. Good
examples include the effects of influenza viruses on respiratory epithelium,
yellow fever virus on hepatocytes, and polioviruses and rabies virus on
neurons. Viruses that result in cell death are termed cytopathic viruses.
An example of a cytopathic virus is the Ebola virus.
Ebolavirus, a filovirus, has caused outbreaks of disease in Africa. The Ebola
virus is particularly virulent and often leads to the death of the host. It causes
necrosis and preferentially affects endothelial cells, resulting in widelydisseminated hemorrhage (and shock) and disseminated intravascular
coagulation (Ebola is one of several viral hemorrhagic fevers known).
Filoviruses (including Ebola and Marburg viruses) are filamentous,
enveloped, RNA viruses that are highly cytopathic and generally result in
cytolysis. The reservoir hosts for Ebola are unknown, but bats are highly
suspected. Other primate species may be infected and may be a source of
infection for humans. Spread between humans occurs via contact with
secretions or through reuse of needles without sterilization.
Filoviral disease is characterized by fever, muscle pains, anorexia, rashes,
abdominal pain, and hemorrhage.

Some viruses result in slow and progressive cell death over a protracted
period of time; such infections are termed persistent or chronic viral
infections. Good examples of these viruses include those that result in
chronic viral hepatitis, including hepatitis B and C viruses. Read the
discussion on viral hepatitis on pp. 614-620 of your textbook. Hepatitis C virus
(HCV) is particularly recognized for causing chronic hepatitis, evolving to
cirrhosis.

Answer the following:

HCV transmission can occur via:

HCV infection may lead to: (three points)

Cirrhosis refers to the loss of normal lobular architecture of the liver as a

result of necrosis followed by scarring fibrosis and nodular regeneration. It is
the result of profound or chronic injury to the liver, as may occur with chronic
intoxication (such as alcohol) or viral injury, and will lead to diminished hepatic
function. If you are interested, you can read more about cirrhosis on pp. 607608 of your textbook.

The potential outcomes of hepatitis C infection are outlined in fig.15-10 of

your text on p. 615.
b. Virally-mediated alteration of apoptosis pathways
As you will recall from Unit 01, apoptosis is a path by which cells may
undergo programmed suicide when faced with loss of integrity. With some
viral infections, host cells may undergo self-directed apoptosis as a
mechanism to control viral infection and eliminate infected cells. However,
some viruses are noted to encode genes which are capable of impairing
apoptosis, in such a way as to promote persistent viral infection (but in doing
so favouring neoplastic transformation and the development of cancers).
2. Inflammatory and immune-mediated cell death
Obligate intracellular pathogens such as viruses will induce an acute response which
is characterized by lymphocytes, plasma cells, and macrophages (and usually very
few neutrophils, probably because the immune response predominates over
inflammation, producing few neutrophil chemotaxins).
Viral infection of a host cell may result in expression of viral proteins on the surface
of the host cell, which are recognized as foreign by CD8+ (cytotoxic) T-lymphocytes,
inducing a cell-mediated immune response and cytolysis. Similar to apoptosis, this
is an important mechanism by which the body attempts to eliminate virally-infected
cells; however, the host response may also result in significant cell death and
associated illness. For instance, much of the hepatocellular loss associated with
hepatitis B virus (HBV) infection is mediated by DC8+ T-cell-mediated cytolysis.
The body also responds to virus infection by producing the glycoprotein cytokine
Interferon (IFN). IFN is produced by CD4+ T-lymphocytes in the Th3 response.
Besides being a potent macrophage activator and enhancer of NK cell activity, IFN
has antiviral effects. These antiviral effects are due to interference of viral translation.
Interferon is also secreted by other cells (fibroblasts, macrophages) following
exposure to a virus.

The lack of neutrophil response in viral infections is useful diagnostically increased

numbers of lymphocytes in tissues are suggestive of a response to a viral pathogen,
rather than a bacterial pathogen. Additionally, the peripheral blood may show an
increased number of lymphocytes (lymphocytosis), whereas neutrophils numbers are
more often normal or decreased.

3. Virally-induced cell transformation and proliferation, resulting in neoplasia

Infection with some viruses may result in transformation of those cells, causing
them to become immortal and to grow independently of growth-regulating signals,
resulting in cancer. This will be discussed in greater detail in the next unit, Neoplasia.
The Epstein-Barr Virus (EBV), also a herpesvirus, has been implicated as a cause
of several neoplasms, including nasopharyngeal carcinoma and Burkitts lymphoma.
If you are interested, you can read further about EBV on pp. 202-203, 442 and 620
of your textbook.

Latent Viral Infections

The relationship between the virus and the host are extremely variable infection is
much more common than disease. Latent infections result when viral genes remain
in surviving target cells for long periods, often for the life of the host, but are not
expressed. Latent infections may result in later reactivation, leading to disease later
in life. As well, such infections are more commonly associated with neoplastic
transformation.
A variety of factors may lead to reactivation of latent infections, including stress,
trauma, advancing age, nutritional or hormonal imbalance, and immune deficiency.
Herpesviruses frequently cause latent infections. As a group, herpesviruses are
among the most widely prevalent viruses in the population. They are large, doublestranded DNA viruses with a protein capsid and a lipid envelope. The lipid envelope
is acquired when virions bud out from an infected cell. The severity of the cytopathic
effect and the degree of interruption of cell functions varies with the different types of
herpesviruses and the type of cell infected.
The ubiquity of herpesvirus infection is related to their diversity, their inability to
remain in a latent and/or recurrent state, and the fact that they are generally highly
contagious.

Herpes simplex 1 and 2 (HSV-1 and HSV-2) are related viruses, HSV-1 primarily
causing oral lesions (coldsores), while HSV-2 primarily causes genital lesions.

Describe how a latent HSV-1 infection becomes reactivated and causes a coldsore
(refer to p. 552 of your textbook). (three points)
Refer to the Self-Assessment answers at the end of this Unit.
Note that stomatitis refers to inflammation of the oral mucosa.
Following a case of chickenpox (varicella) in childhood, the causal herpesvirus
(Varicella-zoster) may remain dormant for years, then be reactivated to cause
shingles (zoster) in later life. Shingles is a painful condition caused by the
reactivated virus travelling down sensory nerves, leading to the development of
blisters on the skin supplied by that nerve.

Outcomes of Viral Infection

As one might predict, the outcome of viral infection varies quite dramatically with the
severity of infection and the target cells affected. Acute cytolysis/necrosis of target
cells with a particularly virulent virus may result in death (such as might be seen in
the heart, brain, or liver).
The outcome of less severe infection is more likely to be survival, but the outcome
(regeneration or scarring) varies as discussed inUnit 04. Recovery from viral
infection is often associated with the development of an appropriate immune
response that is capable of neutralizing the virus.
A major complication that may occur with viral infection is secondary bacterial
infection; cell death or dysfunction results in impairment of important immune
mechanisms, providing fertile soil for other pathogens or opportunistic
microorganisms to take root. For example, viruses that injure the epithelium of the
upper airways can cause paralysis or loss of surface cilia, impairing normal ciliary
clearance mechanisms and making the host more susceptible to secondary bacterial
infections.

The Rickettsias and Chlamydias

As both the Rickettsia and Chlamydia reproduce inside cells, they produce many of the
same changes in cells as those induced by viruses. The body also responds to these
organisms in much the same way as it responds to viruses the cellular response is
typically mononuclear (lymphocytes, plasma cells, macrophages).
Chlamydia
Read pp. 311-313 of your textbook Chlamydiae, Rickettsias, and Mycoplasmas

Chlamydia trachomatis is the major cause of non-gonococcal urethritis (inflammation of the

urethra recall that -itis refers toinflammation of ...). Chlamydial cervicitis (inflammation of
the cervix) can lead to neonatal ophthalmia, a purulent inflammation of the conjunctiva of
the eyes of newborns, and is also a major infectious cause of female sterility.
Trachoma, caused by a different serotype of C. trachomatis, is endemic in tropical
countries, and on a world-wide basis, is the leading cause of blindness. A severe
conjunctivitis leads to eventual scarring and opacification of the cornea.
Chlamydophilia psittaci is the causal agent of psittacosis, a zoonotic disease which can
be passed from birds to man. Avian species which can be affected include pigeons,
chickens and turkeys, and various pet bird species, including finches and a variety of
psittacines (budgies, parrots, etc. the parrot family) thus the name of the disease. The
disease in birds varies greatly, ranging from outbreaks with high mortality to subclinical
cases. Birds can act as a reservoir of infection for man, with transmission largely by infected
droplets. Outbreaks of disease in man have lead to many of the strict importation controls
and quarantine requirements for psittacine birds.
In man, the organism causes an acute illness characterized by fever and flu-like symptoms,
and interstitial pneumonia (similar to viral pneumonias), which causes a dry, non-productive
cough. It is treatable with antibiotics, but severe cases can lead to death.
Zoonotic diseases are diseases which can be transmitted from animals to man.
The Rickettsia
The Rickettsia require arthropod vectors for transmission; these include lice, ticks, and
mites.
R. prowazeckii, the causal agent of typhus (spotted fever) is transmitted by the bites of
fleas, ticks and lice, with the rat being the primary reservoir of infection. The organism

injures the vascular endothelium, leading to thrombosis and haemorrhage (a hemorrhagic

vasculitis). Through history typhus has been a major cause of epidemics in association with
war and famine, as discussed in Hans Zinssers Rats, Lice and History.
Other rickettsial diseases include Rocky Mountain spotted fever, and Q fever.
Facultative intracellular organisms
Facultative intracellular organisms, such as mycobacteria and fungi, can also lead to
disease, but the mechanisms by which these organisms cause cell damage are not well
understood. Probably the host response to these organisms (both the inflammatory and the
immune response) leads to much of the tissue injury seen. Many mycobacteria and some
fungi can remain dormant in tissues (macrophages), due to the organisms being controlled
by the immune system. Immune suppression will lead to reactivation of these infections,
similar to the reactivation of latent viral infections.

Prions
(Text, p. 309)
Finally, the last group of obligate intracellular pathogens which we will discuss are the
prions, pathogens which relatively recently jumped into the public spotlight with the outbreak
of mad cow disease (bovine spongiform encephalopathy) (BSE) in Britain (mid 1990s),
and much more recently, with the detection of several infected cattle in Canada and the
United States. Read the section titled Prions on p. 309 of your textbook as well as Prion
Diseases, on pp. 831-832.
The prions differ from viruses, as they lack nucleic acid (RNA or DNA). Prions are the
causal agents of a variety of spongiform encephalopathies, recognized in both man and
several other mammals. The term spongiform refers to the characteristic vacuolar
degeneration seen in the brain (view Fig 22-21, p. 832). Disease may be sporadic,
inherited, or transmitted.

Complete the following: Infectious prion proteins are: (two points)

Examples of these slow neurologic diseases include scrapie of sheep, BSE of cattle,
chronic wasting disease (CWD) of elk and mule deer, and Kuru, both sporadic and newvariant cases of Creutzfeldt-Jakob disease (CJD) and the inherited Gerstmann- Straussler
syndrome (GSS) of man.

Prion associated diseases develop when normal prion protein (PrPc) undergoes a
conformational change, to form an abnormal protein (PrPsc).

Complete the following: PrPsc causes:

Disease results from the effect of accumulation of large amounts of this abnormal prion
protein, which leads to dysfunction of the affected brain tissue and neuronal loss. There is
no inflammatory response to the organism. All of these diseases are slow, degenerative
neurologic diseases, characterized by progressive loss of function ending in death.
Much of the concern over BSE (mad cow disease) stems from the possibility of its transfer
from cattle to man, by the consumption of infected beef products (particularly brain). This
concern has some basis, as Kuru (in a New Guinea cannabalistic tribe) was believed to be
transmitted by the mourning ritual of consuming the brains of the deceased. Additionally, the
outbreak of BSE in British cattle was related to the practice of using sheep offal (the
remains following routine butchering) as a protein supplement in cattle feed. Owing to the
extremely long latent period of these diseases, proving that consumption of beef products
lead to specific cases of CJD will be very difficult; however, cases of new-variant CJD
in Britain have been linked to the outbreak there of BSE in cattle in the 1990s.

Prions can be considered subviral transmissable agents, consisting of protein only. There is
much yet to be learned about the mode of transmission.

Bacterial Infections
It is important to remember that on a daily basis, we are exposed to huge numbers of microorganisms, but few go on to cause disease. In fact, there are a great number of bacteria
which are normally resident in the body these are known as the normal flora (or
commensal flora). Many of these normal flora may serve a protective role, helping to
prevent colonization of more virulent organisms by competing for growth factors.
A similar variety of organisms are found in other mammals. The microbial flora of the
ruminant forestomachs and the equine cecum are of particular importance in allowing
normal digestion of cellulose.
Opportunistic bacteria

Under normal circumstances, these bacteria (the normal flora) are beneficial, but in certain
situations, they can cause disease. They will behave in an opportunistic fashion if the host
is immunosuppressed, or if they gain access to a part of the body where they are not
normally resident.
Antibacterial agents
Bacteria outside of a host can be killed by a variety of antibacterial agents, which exert
their effect by either denaturing bacterial protein, or interferring with bacterial
metabolism. Bacteriostatic agents are those which inhibit the growth or multiplication of
bacteria.Bactericidal agents are those that kill bacteria. A broad-spectrum antibiotic is
one which is effective against a wide variety of bacteria. The indiscriminate use of broad
spectrum antibiotics has the undesired effect of also killing many desired, commensal
bacteria. Finally,once a course of antibiotics is begun, it should be continued for the full
period (usually 7-10 days). If therapy is stopped earlier, the surviving (more resistant)
organisms will lead to the growth of larger numbers of similarly resistant organisms, which
will subsequently be more difficult to treat.
Antibiotics use and misuse...
Within the body, it is more difficult to kill bacteria, as many agents toxic to bacteria are also
toxic to host cells. Antibiotics are substances which were initially prepared from fungi. They
were found to have more specific activity against bacteria, either inhibiting their growth or
killing them. The first antibiotic to be derived from fungi was penicillin (from the fungus
Penicillium notatum). Many modern second generation antibiotics have been synthetically
derived.
The development of antibiotic-resistant strains of bacteria is one of the major emerging
problems of modern medicine. Because of their mode of reproduction and their ability to
multiply extremely rapidly, bacteria have an enormous capacity to mutate and adapt to
change. Through the use of antibiotics for purposes such as promoting weight gain in
livestock, or the use of antibiotics in treating nonspecific diseases, we have selected
bacterial strains which are resistant to many of the commonly used antibiotics. Additionally,
genetic material coding for this resistance (plasmids) can be transferred between bacteria.
These resistant strains are becoming increasingly difficult to treat, and are a particular
problem in hospital acquired infection (nosocomial infections).
When using an antibiotic, it is of the utmost importance to ensure that, firstly, the disease
being treated is of bacterial origin. A great many of the sore throats, colds and similar
complaints which physicians see on a daily basis are of viral origin, and antibiotics
are not indicated. Secondly, once the disease has been identified as bacterial in origin (by
culture, preferably), the sensitivity of the organism to specific antibiotics should be
determined. This ensures that the appropriate antibiotic is used - not all organisms are

sensitive to all antibiotics; it is preferable to use the antibiotic which is most specific for the
particular organism.
The discovery of antibiotics
Antibiotics were discovered relatively recently and their increasingly widespread use has
lead to a therapeutic revolution since the second world war. Overall, however, improved
sanitation and the development of immunizations for many infectious bacterial diseases
have done more to decrease the prevalence of these diseases than the development of
antibiotics.

How do bacteria cause cell and tissue injury

Read the section, Mechanisms of Bacterial Injury (p. 320-322, text). Bacteria produce cell
and tissue injury by:
1. adhering to host cells
2. release of locally acting as well as remotely acting toxins - endotoxins,
exotoxins,enterotoxins
3. production of local vasculitis
The extent and severity of tissue injury casued by bacteria depends on their ability to attach
to and enter host cells or to produce toxins. The bacterial genes that encode adherence
proteins and toxins are often coregulated by specific environmental conditions.
1. Bacterial Adhesins

Complete the following:

1. Bacterial adhesins are:
2. Adhesin types vary between different groups of bacteria. Gram positive
cocci bind to host cells by: (two points)
3. Gram negative rods and cocci have surface fimbriae (pili), which are
filaments composed of repeating subunits. Pili function to: (two points)

Gram positive cocci also have fibrillar surface M proteins, which prevent
phagocytosis by macrophages.
Facultative intacellular bacteria have a restricted tropism, to infect epithelial cells
and/or macrophages; they generally bind to host cell plasma membrane integrins or
extracellular matrix proteins (e.g. Fibronectin, collagen),
2. Bacterial Toxins (p. 321)
Bacterial Endotoxin
Endotoxins are the lipopolysaccharide component of the cell walls of gram-negative
bacteria, and are released into the blood of the host following bacterial death and
lysis. They exert their effects on small blood vessels, causing:
1. generalized peripheral vasodilation, progressing to shock
2. endothelial injury and activation of the coagulation cascade, leading to DIC
and acute respiratory distress syndrome
3. massive cytokine release (including interleukin-1 from macrophages),
producing a systemic acute phase response and fever
Endotoxic shock may accompany severe urinary tract infection, intestinal surgery, or
any gram-negative bacterial infection.

Bacterial Exotoxins
Exotoxins are secreted proteins that directly cause cell injury. These can subdivided
into:
1. Locally-acting exotoxins
These are typically enzymes that are secreted into their immediate
environment. These enzymes have a role in breaking down complex food
materials into smaller, more assimilable units (amino acids, peptides, etc.) to
be used for bacterial metabolism. These enzymes are also useful for tissue
invasion; in a host, these enzymes can cause local tissue injury and permit
deeper entry into the host.
Staphylococcus aureus, the most pathogenic of the staphylococci, produces
the enzyme coagulase, which converts fibrinogen to fibrin. Coagulase
production is correlated with pathogenicity, with coagulase- negative

staphylococci (such as S. epidermidis) having low virulence. Coagulase is

believed to cause the bacterium to become coated with a layer of fibrin, which
helps it resist phagocytosis. The staphylococci tend to form pus in tissues
(perhaps due to this ability to resist phagocytosis), causing a wide range of
lesions (pimples, boils, styes, wound infections, osteomyelitis). It is an
important cause of secondary bacterial pneumonia (following primary viral
respiratory illness) (see pp. 489-491, text).

Clostridium perfringens, a gram-positive anaerobe, is widely found in the soil

and in the intestinal tract of both man and nearly all warm-blooded animals.
(From the intestine, it frequently invades tissues after death, causing bloating
of cadavers.) It is the most frequent isolate from cases of gas gangrene in
man.
C. perfringens ferments a wide variety of sugars, producing acid and gas.
The breakdown of sugars in muscle leads to gas formation in tissues.
In addition, C. perfringens produces a variety of enzymes, which act locally:

hyaluronidase, collagenase, and hemolysins

lecithinase (alpha toxin), which breaks down cell membrane lipid,

leading to cell necrosis

The net effect of these activities is the production of severe necrotizing

inflammation, with gas production.

2. Remotely-acting exotoxins
These are secreted by living bacteria, absorbed into the bloodstream, and
often mediate their effects at distant sites in the body. They are highlyantigenic proteins, and will induce the formation of specific antibodies (termed
antitoxins). Because of their protein nature, they are heat-labile, and can be
destroyed by cooking this can be useful knowledge, as many exotoxins are
the causes of food poisoning. Examples of bacteria that produce exotoxins
include:

Staphylococcus aureus Toxic Shock Syndrome Toxin

Streptococcus pyogenes erythrogenic toxin

Group A Streptococci (necrotizing fasciitis flesh-eating disease)

Corynebacterium diphtheriae diphtheria toxin

Clostridium tetani tetanus toxin

Clostridium botulinum botulism toxin

Group A streptococci are also the cause of strep throat, scarlet fever,
puerperal sepsis (following childbirth), erysipelas (man), and the poststreptococcal diseases glomerulonephritis and rheumatic fever.
Toxic shock syndrome is the result of the proliferation of staphylococci in the
vagina in association with the use of certain highly absorbent tampons. Toxic
shock syndrome toxin (TSST) is a bacterial super-antigen which causes
fever, shock, and multi-system organ failure.
It is described on p. 96 of your textbook.
Necrotizing Fasciitis
Also known as flesh-eating disease, necrotizing fasciitis (NF) gained public
attention when it lead to the amputation of Lucien Bouchards leg. Caused by
virulent strains of Group A streptococci, NF causes a rapidly advancing
necrotizing process which spreads in the subcutaneous tissues and may
extend to deep fascia. (Fascia refers to the meshwork of connective tissue
which lies subcutaneously and which separates muscles; hence the
name necrotizing fasciitis.). There is thrombosis of vessels and secondary
cutaneous gangrene. The causal bacteria secrete an exotoxin.
The disease affects previously normal people who may have had some minor
trauma; it may also occur as a complication of a surgical wound. The process
begins as a tender, red, swollen region, which over 24-48 hours rapidly
progresses to involve a much larger area. Systemic signs include
leucocytosis, fever, chills and prostration. The skin and underlying tissues
become discoloured and gangrenous, septicemia develops, and , without
treatment, death often follows.
Early diagnosis and therapeutic intervention are vital. Supportive care and
high doses of antibiotics are given. The extent of necrosis means that
antibiotics cannot penetrate readily into the affected tissue (recall that
antibiotics reach tissues via the bloodstream), so surgical resection of
affected tissues or amputation may be required.

Tetanus
Clostridium tetani is a gram-positive anaerobe.The C. tetani bacillus can
survive for long periods as spores. Tetanus is usually acquired by
contamination of wounds. C. tetani produces an exotoxin, tetanospasmin,
which travels along nerves from the wound to the spinal cord. This toxin
interferes with the release of inhibitory neurotransmitters, leading to violent
muscle spasms. The term lockjaw referred to this incapacitating muscle
contraction. Children and adults are routinely vaccinated against tetanus (the
T of DPT refers to tetanus toxoid), and tetanus antitoxin is given
prophylactically to patients with potentially contaminated wounds.
Botulism
Botulism is different from other bacterial diseases in that the causal organism
does not multiply inside the body disease is acquired by ingesting the preformed toxin, which is one of the most potent known toxins.
Clostridium botulinum is an anaerobic bacillus with highly resistant spores,
which is found primarily in the soil; it also is found in the intestine of domestic
mammals. It is of concern as a cause of food poisoning, as it will grow in a
variety of foods (preserved meats, canned goods), if the temperature
employed in canning is insufficiently high to kill the spores.
The toxin acts by blocking the release of cholinergic neurotransmitters,
particularly at neuromuscular junctions. This leads to a progressive, flaccid
paralysis, which affects facial and limb muscles, and ultimately the respiratory
muscles.
Botulism can also be problem in wildlife species. Large waterfowl die-offs
have occurred in the prairies when hot dry weather causes the sudden fall of
water levels in many sloughs. A variety of invertebrates are left stranded on
the newly exposed shorelines, die, and allow the multiplication of C.
botulinum, with associated toxin production. Ducks and geese which then
consume these invertebrates develop botulism, characterized first
by weakness of the neck muscles (limberneck), and leading to death.

3. Enterotoxins
Enterotoxins are exotoxins which exert their effect on intestinal mucosal cells
(termed enterocytes). They are produced by bacteria during multiplication,

either within the gut lumen (eg. Vibrio cholerae, certain E.coli strains), or
outside the body in foods (eg. Staphylococcus aureus), which are then eaten.
Enterotoxins attach to gut mucosal cell receptors, causing either structural
damage or functional alteration (increased fluid secretion by intestinal
epithelial cells). Enterotoxins thus variably cause diarrhea (sometimes
hemorrhagic), cramping, and abdominal pain.
Examples of bacteria which produce enterotoxins include:

Clostridium difficile

Vibrio cholerae

Staphylococcus aureus

Clostridium perfringens

Toxigenic Escherichia coli strains

Cholera
Cholera is a disease which has enormous historical significance. It is still
endemic in much of Asia, and has caused outbreaks in many other parts of
the world, often in association with contamination of water supplies.
Cholera is caused by Vibrio cholerae, which secretes an enterotoxin. This
enterotoxin leads to isosmotic fluid secretion by the intestinal epithelial cells
(through increased cAMP generation). Voluminous diarrhea leads to
extensive loss of water and electrolytes; death can result from dehydration,
electrolyte imbalance, and shock. The provision of a clean water supply is of
great importance in preventing cholera.

The categories exotoxin and enterotoxin are a bit fuzzy at times. We have
much yet to learn about the activities of many bacterial toxins. Although some
strains of E. coli can produce enterotoxins, which lead to fluid secretion from
the epithelial cells of the small intestine (leading to diarrhea), there are also
enteroinvasive strains which can penetrate the intestinal epithelium. Finally,
there are strains which are neither enteroinvasive nor enterotoxigenic, but are
termed enteropathogenic. (Dont worry too much about this terminology!)

The enteropathogenic E. coli O157:H7 (O157:H7 refers to the serotype) is

the agent responsible for hamburger disease, acquired through the
consumption of improperly cooked hamburger (ground beef). The organism is
carried in the intestine of cattle (especially dairy cattle), and can contaminate
the carcass at the time of slaughter. It can also be acquired from a variety of
other food sources, such as milk products or vegetables, if fecal
contamination has occurred. More recently, in Walkerton, Ont., the potential
of a contaminated water supply in causing widespread disease has become
apparent. In man, it causes abdominal cramping, diarrhea, and/or bloody
diarrhea (hemorrhagic colitis), and can lead to the development of
the hemolytic uremic syndrome.
E. coli O157:H7 secretes a verocytotoxin (VT) (ie., a compound which is
toxic to Vero cells; this finding is used diagnostically). The role of this toxin in
the initial non-specific diarrhea is not certain, but VT seems to have a toxic
effect on vascular endothelial cells, leading to thrombosis and injury to small
vessels, primarily in the gastrointestinal tract and kidneys. This results in
hemorrhagic colitis and the hemolytic uremic syndrome (HUS), the systemic
complications of infection with verocytotoxigenic E. coli (VTEC) stains. The
hemolytic uremic syndrome causes severe renal dysfunction, and is
potentially fatal; HUS is described in your text on pp. 540-541.
Outbreaks of disease in the American northwest in 1993 (related to
contaminated ground beef used by a fast-food chain), in Japan in 1996
(related to contaminated radishes and other produce used in preparing school
lunches), and in Walkerton, Ontario in the spring of 2000 illustrate the
importance of VTEC as a public health concern.
The VTEC Research Group, consisting of researchers from the University of
Guelph, Health of Animals/ Health Canada and the Hospital for Sick Children
(University of Toronto) is a multi-disciplinary group of microbiologists,
physicians, veterinarians, immunologists and epidemiologists. The group
studies verocytotoxigenic E. coli, and has done much to further describe the
reservoirs and transmission of infection as well as modes of resistance to
infection.

Food Poisoning
Food poisoning refers to acute gastroenteritis (causing severe vomiting and
diarrhea) caused by the action of bacterial toxins, due to bacterial contamination of
food or drink. Food poisoning can be caused by a variety of different bacterial
organisms.

The causes of food poisoning can be considered in two categories:

1. Infection type:

Bacteria in the contaminated food multiply, and produce their toxins

in the bowel (eg. Travellers diarrhea, casued by E. Coli; Salmonella
sp.)

Signs appear 12-24 hours following ingestion of contaminated food

Salmonella enteritidis can contaminate apparently normal-looking eggs, and

has been incriminated as the cause of numerous outbreaks of gastroenteritis.
Disease can be avoided by ensuring that eggs are cooked at a sufficiently
high temperature.

2. Toxin type:

Bacteria in the food produce toxins, which are then ingested. Signs
appear earlier (2-6 hours).

The classic example is staphylococcal food poisoning, when food

(contaminated during preparation staphylococci are commonly
found on the skin) is stored at temperatures which allow bacterial
multiplication and toxin production.

Weve been discussing the ways in which bacteria affect the host weve
talked about the production of locally acting enzymes and the production of
remotely acting toxins. Lets briefly (and finally!) turn to the third way in which
bacteria can cause injury...
3. Production of a local vasculitis
Highly virulent bacteria can invade and cause thrombosis of small blood vessels
(leading to ischemic necrosis of the area around the infection). Toxins produced by
the bacteria may also cause vascular injury.

How does the body respond to bacterial infections

Read the section, Spectrum of Inflammatory Responses to Infection (p.323-326, text).
Suppurative Inflammation
Acute inflammation (with pain, redness, heat and swelling, as well as the systemic fever
response) accompanies many acute bacterial infections. There is increased vascular

permeability, and the cell response is characterized by the presence of large numbers of
neutrophils. (There may also be an increased number of neutrophils in the blood.) The
neutrophils are attracted by chemotactic factors, many released by the bacteria at the site of
infection.
Suppurative inflammation (both acute and chronic) is thus characteristic of many bacterial
infections there is liquefactive necrosis and the formation of pus. Abscesses may form.
(Refer back to the unit on inflammation to review abscess formation). The pyogenic
bacteria evoke this response (mostly extra-cellular gram-positive-cocci, and gram-negative
rods). Suppuration is particularly likely to occur when anatomical factors inhibit drainage
and the resolution of acute inflammation.
Appendicitis is often the result of obstruction of the lumen of the appendix, with subsequent
suppurative inflammation caused by a variety of bacterial organisms (E. coli, streptococci).
What is the appendix anyway? Refer to pp. 600-601 of your textbook for a more detailed
discussion of acute appendicitis.

The inflammatory response of the host can be the cause of many of the disease signs
shown by the host. A good example of this is the effect of inflammatory exudation into the
pericardial sac:
Hardware disease of cattle
Pieces of hardware (nails, lengths of baling wire, etc.) tend to become trapped in the wall
of the reticulum (one of the forestomachs) of cattle, because of the anatomy of its lining (a
honeycomb-like mesh). From there, the piece of metal works its way through the reticulum
wall, and travels forward through the diaphragm, often penetrating into the chest cavity and
thence the pericardial sac. These metal fragments carry bacteria along with them, setting up
purulent or fibrinous inflammation along their path. Once in the pericardial sac,
severe fibrinopululent inflammation can lead to the accumulation of a large amount of
fluid, which can have a restrictive effect on cardiac function.

Likely consisting of a mixture of fibrin and pus -this is termed fibrinopurulent exudate there is thus a fibrinopurulent pericarditis, likely of bacterial origin. The lungs have a
glistening wet appearance, indicating pulmonary edema, and there is also some purulent
inflammation of parts of the pleura (pleuritis).

How are bacterial infections diagnosed

The presence of purulent inflammation (as discussed above) is suggestive of bacterial

infection. However, it is not always easy to determine whether a bacterial agent is causing a
particular disease. A bacterium can be isolated from a tissue, but not necessarily be the
cause of the disease (remember that many bacteria are normal residents). Kochs
postulates are criteria necessary to establish an etiologic association between the
presence of a microorganism and the presence of disease.
Kochs criteria are:
1. A causal organism can be found in disease lesions
2. The organism can be isolated in culture
3. Secondary inoculation of the purified organism causes lesions in experimental
animals
4. The organism can be recovered from the experimental animal
It may not always be practical or possible to fulfill these postulates, but they indicate the
ideal, and help prevent us from making assumptions with regard to causation which may not
be correct.
To identify a bacteria, smears of the affected tissue are first taken using sterile
swabs. Gram-staining and microscopic examination allows an early narrowing of the
possibilities (eg., organisms can at this stage be identified as gram-positive cocci, gramnegative rods, etc.). Smears are then cultured on appropriate media, and finally a variety of
tests to identify the biochemical characteristics of the organism will allow a final
identification.

Fungal Infections
Fungi can exist in hosts both as single cell forms (yeasts), either intracellularly or
extracellularly, or as hyphae (long filaments). Yeasts are microscopic; hyphae may also be
identified microscopically in tissues. Special stains will improve the visibility of fungi in tissue
sections. If hyphae form large enough colonies (mycelia) in or on tissues, they may be
grossly apparent. Read the introductory discussion on fungi on p. 313 of your textbook.
Fungal growth requirements include high humidity, warmth and oxygen; the requirement for
warmth and humidity mean that fungal diseases are generally more prevalent in certain
geographical regions, particularly in tropical climates.
The use (and abuse) of antibiotics has lead to an increased incidence of fungal infections,
because normal bacterial flora, which has a role in limiting fungal growth, is disrupted.

Additionally, immunosuppressive therapy and chemotherapy (for transplantation and

cancer, respectively) favour opportunistic fungal infectious, by suppressing cell-mediated
immunity. Fungal infectious can be serious in AIDS patients for the same reason. Fungi
cause tissue injury by inducing DTH hypersensitivity responses to fungal antigens. This
hypersensitivity to fungal antigens is useful diagnostically. There are a variety of skin tests
available to help identify the causal agent in a suspected case of systemic fungal disease.
Granulomatous lesions in tissue (produced by DTH) may suggest fungal disease; special
stains can the be used to demonstrate the fungal forms in the tissue.
Additionally, some fungi (such as Aspergillus and Mucor spp.)can directly invade small
blood vessels (vasculitis), leading to thrombosis and necrosis of the adjacent tissues.
Systemic fungal diseases
Generally, systemic fungal diseases those which affect the deeper tissues (Histoplasmosis, Coccidioidomycosis, and Blastomycosis; refer to pp. 499-500 of your
textbook for more detail about these diseases) are relatively rare, but they can be severe
problems in some individuals, especially in endemic areas. The fungal spores come from
soil, plant material, bird droppings, etc.
Systemic fungal diseases are a particular problem in immunosuppressed individuals, such
as AIDS patients, and in patients treated with immuno-supressive drugs (ie., cancer
patients, transplant patients, or patients with immune-mediated diseases). Many fungal
infections can thus be considered opportunistic infections.
Superficial fungal diseases
These are likely better known to most people, as they are considerably more common and
include such diseases as athletes foot, ringworm, and vaginal yeast infections.
Dermatomycoses
The dermatomycoses are highly contagious (readily passed from person to person), and
may be difficult to treat. The dermatomycoses are commonly known as ringworm. Factors
favouring transmission include crowded living conditions and poor hygiene. They are
characterized by patchy, reddened, scaling lesions, typically affecting skin between the
fingers and toes (athletes foot) or in the groin area; ringworm of the scalp causes patchy
hair loss.
Candidiasis
Candida albicans is the fungus which most often causes disease. Candida is often a
commensal organism on the mucous membranes, found in sites such as the oral cavity,
genitalia and gastrointestinal tract. It is rarely a problem, but in certain situations (such as in
immuno-suppressed individuals, or following antibiotic therapy which has disturbed the
normal bacteria flora of these sites), Candida can overgrow.

Read the section titled Candidiasis (pp. 502-503 of your textbook), and complete the
following: It then leads to conditions such as: (five points)
Although normally a superficial infection, Candida fungemia can sometimes occur; this is
termed invasive candidiasis, with bloodborne orgainisms disseminating to various tissues.

Parasites
Most parasites have complicated life cycles which involve more than one host. The
definitive host is the host of the adult (mature, reproducing) form of the parasite. The
intermediate host is the host of the immature form(s) of the parasite. Some parasites may
have more than one intermediate host.
The effect a parasite has on a host will depend on which stage of its life cycle affects the
host (ie.,whether the host is acting as the intermediate host or the definitive host of the
parasite). Read pp. 313-314 of your textbook, which is an introduction to parasites. We will
only be considering parasites as causes of disease.
Inflammatory reactions in tissues that are associated with parasitic forms are often
characterized by eosinophils and granulomatous inflammation. Recall from unit 04 the roles
of both type I hypersensitivity (IgE-mediated) and Type IV hypersensitivity (cell mediated) in
controlling parasitic infections.

The Protozoa
On a world-wide basis, protozoal parasites dominate as causes of infectious disease. The
protozoa are one-celled organisms, several of which are important pathogens in man. They
can be either intracellular of extracellular parasites. Much of the difficulty in treating
protozoal infections stems from the variety of forms which they can assume within their
host. Transmission is either via insect vectors (as with malaria and sleeping sickness) or by
ingestion (ie. of fecally-contaminated food or water as with amebiasis and toxoplasmosis).
We will discuss two of these diseases in more detail:
Malaria
Malaria, the greatest infectious public health problem in the world, is caused by the
protozoal parasite, Plasmodium. This organism uses both man and specific species of

mosquitoes to complete its life cycle. Malaria is endemic in Asia and Africa. There are four
species of Plasmodium which cause malaria: P. vivax, P. malariae, P. ovale, and P.
falciparum.
Read the discussion on malaria on pp. 418-419 of your textbook, and complete the
following: When an infected mosquito (Anopheles spp.) bites a person, infectious stages of
the parasites (sporozoites) are injected (from the mosquito saliva) into the bloodstream,
where they undergo asexual reproduction.

Complete the following:

1. Describe briefly how disease is produced. The life cycle of the parasite in man is:
(three points)
2. The distinctive clinical features of malaria relate to: (four points)

Toxoplasmosis
Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii. The definitive hosts
of Toxoplasma are members of the cat family, including domestic cats. Cats excrete oocysts
in their feces, which mature and become infectious after 1 to 21 days. Human ingestion of
infectious oocysts can lead to disease in some individuals. Those with AIDS or with deficient
cell-mediated immunity are at greatest risk. A fever and lymphadenopathy (enlarged lymph
nodes) can be followed by cerebral dysfunction. Cerebral toxoplasmosis is characterized by
many necrotic foci, with variable associated mononuclear cell infiltrates and the presence of
organisms in the brain.
Congenital infection is of great concern, as fetal infection can occur transplacentally in the
third trimester. The organism affects the fetal brain and retina, leading to extensive necrosis
with calcification and scarring. Death can occur in utero, or the fetus can be born with a
variety of defects (microcephaly, hydrocephaly, mental retardation, and visual problems).
For this reason, many cat owners become concerned about toxoplasmosis if a household
member is pregnant. However, daily cleaning of litter boxes (so any oocysts do not have
time to become infectious) and the use of gloves while gardening (to avoid exposure to

infectious oocysts in the soil) should prevent any possible exposure.

You can read about toxoplasmosis on pp. 829-830 of your text.

Helminths
Well now move on to consider the multicellular parasites the helminths include the
nematodes, cestodes and trematodes. They have well-defined life cycles with intermediate
hosts, and may infect many different animal species as well as man. Man can act either as
a natural or accidental host in which case the parasite can progress through its life cycle,
or as an aberrent host, in which case further development of the parasite in the host is
blocked, and it dies. (The term accidental refers to the parasite developing in a host which
is not its usual host.)
The type of disease which develops (pathology and symptomatology) will depend on the
stage of the life cycle of an individual parasite and the organ affected; systemic signs may
develop (fever, anemia) if the parasites invade the bloodstream or cause blood loss. In
many parasitic infections the signs of disease may be minimal. Eosinophilia (increased
numbers of eosinophils in the blood) is often seen in association with parasitic infections.
In general, these organisms do not behave as opportunistic pathogens. Read the
introductory discussion; Helminths, on pp. 313-314 of your textbook.
1. Nematodes (Roundworms)
In most cases, no intermediate hosts are required for completion of nematode life
cycles.
Pinworm disease, trichinosis and filariasis (p. 77, text: Lymphatic obstruction) are
also caused by nematodes. Pinworms are a common parasite of the intestine of
children; the primary sign of infection is anal irritation and itching. Trichinosis
(characterized by an acute myositis, inflammation of the muscles, caused by the
larval forms) is now quite rare, owing to improvements in the inspection of pork and
changes in its handling and cooking. Filariasis is a tropical disease, requiring the
Culex mosquito for transmission of infection. The adult worms live in the lymphatics
(particularly of the groin and pelvis), where they can cause obstruction. Chronic
edema and fibrosis leads to enlargement of the affected tissues, a condition referred
to as elephantiasis.

Hookworm disease (ankylostomiasis)

Hookworms (Ankylostoma hook-mouthed) are prevalent in tropical climates,
where the larval form of the worm lives in moist soil. Hookworm infection is acquired
when the larvae burrow through the skin of the bare feet, and enter veins; they are
carried in the blood to the lung, where they then cross into the small airways and
travel up the trachea. From the trachea, they enter the pharyngeal area, are
swallowed, and finally reach the small intestine. Here, in the duodenum and
jejunum, the adult worms attach to the mucosa and feed by sucking blood. Blood
loss will lead to iron-deficiency anemia, weakness and fatigue. Eggs passed in the
stool develop in the soil to infective larvae, ready to re-initiate the life-cycle.
Roundworm disease (ascariasis)
Roundworms (Ascaris spp.) are acquired when the eggs of the parasite are ingested,
for example, on uncooked vegetables. Infection is common in children, who
frequently put their fingers in their mouths. Once the eggs reach the intestine,
larval forms penetrate the intestinal wall, and they undergo travels similar to
hookworms before maturing as adult worms in the intestine once more. Clinical
effects of the adult worms include obstruction of the bowel (by large numbers of
worms), and inflammation of the bile duct and pancreatic ducts, caused by parasitic
migration. The migration of the larval forms through the lungs can lead to coughing
and wheezing.

2. Cestodes (tapeworms)
The tapeworms which cause disease in man spend part of their life cycle in man and
part in another animal. They are long, flattened, segmented worms. The beef, pork
and fish tapeworms exist as a cystic stage in their animal host; man becomes
infected by eating inadequately cooked meat. Once in the human host, the adult
matures and reproduces sexually in the intestine, from which eggs are passed to
eventually infect their animal host (ie., when human waste contaminates pasture or
water). They rarely cause disease signs in their human hosts.
Tapeworm
The dog tapeworm (Echinococcus granulosus) passes its adult stage in the
intestine of dogs and other canids. Humans become infected by eating vegetables
which have been contaminated by the excreta of dogs. Dogs, in turn, are infected
when they consume infected sheep. The disease is thus principally a problem in

sheep-producing areas. In man, the cystic stage of the parasite causes hydatid
disease. Cysts can form in a variety of tissues, and can reach alarming sizes;
hydatid disease can be fatal.

3. Trematodes (flukes)
The trematodes are flatworms which require an intermediate host (often snails).
Schistosomiasis, which occurs primarily in Egypt and northern Africa, is the most
common disease caused by flukes. The adult flukes live in the veins of the pelvis and
bladder. The spiny eggs are laid in the wall of the urinary bladder, where they
produce an intense inflammatory reaction, which leads to hematuria (blood in the
urine). (See fig. 8-12, p. 325, text, which illustrates a chronic inflammatory reaction).
There is a predisposition to cancer of the bladder wall.

External Parasites
Finally, weve nearly reached the end of this unit ! Well end with a brief discussion of
arthropod parasites, the ectoparasites: scabies, lice and fleas. These live on or in the skin,
and are introduced on page 314 of your textbook. They can cause itching, with secondary
scratching leading to traumatic injury to the skin; this may be complicated by secondary
bacterial infection. Some individuals develop hypersensitivity reactions to the bites of
arthropods (to the saliva which is deposited in the skin), and develop an extreme itching
response.
The prefix -ecto denotes situated on or on the outside. Arthropods are important as
disease carriers recall the arboviruses (arthropod-borne) discussed earlier. Arthropods are
also the vectors of a variety of bacterial, rickettsial and protozoal diseases. For this reason,
the control of vectors is of major importance in the control of many diseases. As carriers of
disease, arthropods can act in one of two ways:
Mechanical vector the arthropod picks up the infecting agent and either deposits in on
exposed foods, or passes it on via the contamination of biting mouth parts
Biologic vector the arthropod has an essential role in the completion of the life cycle of
the infecting agent.

Flea allergy dermatitis is a common cause of skin problems in dogs and cats. The bite of
even one flea can lead to a hypersensitivity response, which leads to an intense itch
sensation. The affected animal licks and chews the itchy area (often the lower back and
tailhead region), causing hair loss and an exudative dermatitis. Pustules and scabs develop
as secondary bacterial infection (Staphylococcus) occurs.