VIRAL INFECTION

Host - virus interactions and relationships and the pathogenesis of virus disease
Host-virus interactions
 Acquisition of viral infections
o direct infection (of respiratory, alimentary, and genital tracts; skin; oropharyngeal mucosa; or
conjunctiva)
o insect vectors e.g. arboviruses
o animal bites (i.e., rabies)
o blood or blood products/blood transfusions (i.e., hepatitis)
o some viruses (i.e., rubella, cytomegalovirus) can traverse the chorionic barrier (mother to
neonate)
 Virus spread in the host
o cell to cell via cell-free virus (local infections)
o release into bloodstream (systemic infections)
o cell-cell fusion without touching extracellular matrix (difficult to attack these viruses)
o travel through axons
o for enveloped viruses, site of budding determines how virus spreads: e.g., apical vs local.
 Common outcomes
o inapparent or asymptomatic infection i.e., no clinical symptoms
o disease i.e., viral damage to tissues/organs; loss of function; tissue damage due to host
immune responses
 Host antiviral responses
o humoral and cellular immune responses
o Antibody neutralize the virus
o virally derived peptides trigger cytotoxic T-cell response
o Interferon production by infected cell – early, nonspecific antiviral defense triggered by ds-
RNA i.e., blocks viral replication by either blocking protein synthesis (i.e., PKR) or by
chewing up mRNA.
Phosphorylated PKR phosphorylates and inactivates EIF-2a which is needed for protein
synthesis. Interferon activates dependent RNAase which chews up mRNA
o Infected cells display virally-derived peptides on their cell surface becoming targets for
complement-fixing antibody and cytotoxic T-cells.
o Neutralizing antibody prevent virus attachment or uncoating. Usually directed against
envelope or capsid proteins; protect against repeated cycles or virus infection.
Virus-Host relationships
Virus-host relationships include the following:
1. Lytic.
Viruses that exhibit this type of relationship are said to be virulent or vegetative. They cause
alterations of the host cytoplasmic membrane. This is followed by the action of viral lyzosome
that causes formation of holes in the cell leading to cell death (lysis) and release of infective
viruses.
2. Lysogenic.
Viral nucleic acid becomes integrated in the host cell genome. When the host cell multiplies it
helps the infective viral genome to replicate. Each daughter cell will possess part of the
integrated nucleic acid material so that replication is continuous.
3. Viral release without lysis.
Viruses with this type of cycle extrude or bud from the host cell without rupturing or lysing the
host cell. Particles in this case are usually helical or filamentous in shape and most of them
possess single stranded nucleic acid materials. Most animal and human viruses do not lyse host
cells on release.
PATHOGENESIS OF VIRAL DISEASES
To produce disease, viruses must enter a host, come in contact with susceptible cells, replicate,
and produce cell injury. Understanding mechanisms of viral pathogenesis at the molecular level
is necessary to design effective and specific antiviral strategies. Much of our knowledge of viral
pathogenesis is based on animal models, because such systems can be readily manipulated and
studied.
Steps in Viral Pathogenesis
Specific steps involved in viral pathogenesis are the following: viral entry into the host, primary
viral replication, viral spread, cellular injury, host immune response, viral clearance or
establishment of persistent infection, and viral shedding.
A. ENTRY AND PRIMARY REPLICATION
In order for host infection to occur, a virus must first attach to and enter cells of one of the body
surfaces — skin, respiratory tract, gastrointestinal tract, urogenital tract, or conjunctiva. Most
viruses enter their hosts through the mucosa of the respiratory or gastrointestinal tract. Major
exceptions are those viruses that are introduced directly into the blood-stream by needles
(hepatitis B, human immunodeficiency virus [HIV]), by blood transfusions, or by insect vectors
(arboviruses).
Viruses usually replicate at the primary site of entry. Some, such as influenza viruses (respiratory
infections) and rotaviruses (gastrointestinal infections), produce disease at the portal of entry and
have no necessity for further systemic spread. They spread locally over the epithelial surfaces,
but there is no invasion of underlying tissues or spread to distant sites.
B. VIRAL SPREAD AND CELL TROPISM
Many viruses produce disease at sites distant from their point of entry (e.g., enteroviruses, which
enter through the gastrointestinal tract but may produce central nervous system disease). After
primary replication at the site of entry, these viruses then spread within the host. Mechanisms of
viral spread vary, but the most common route is via the bloodstream or lymphatics. The presence
of virus in the blood is called viremia.
Virions may be free in the plasma (e.g., enteroviruses, togaviruses) or associated with particular
cell types (e.g., measles virus). Some viruses even multiply within those cells. The viremic phase
is short in many viral infections. In some instances, neuronal spread is involved; this is
apparently how rabies virus reaches the brain to cause disease and how herpes simplex virus
moves to the ganglia to initiate latent infections.
Viruses tend to exhibit organ and cell specificities. Thus, tropism determines the pattern of
systemic illness produced during a viral infection. As an example, hepatitis B virus has a tropism
for liver hepatocytes, and hepatitis is the primary disease caused by the virus.
Tissue and cell tropism by a given virus usually reflect the presence of specific cell surface
receptors for that virus. Receptors are components of the cell surface with which a region of the
viral surface (capsid or envelope) can specifically interact and initiate infection. Receptors are
cell constituents that function in normal cellular metabolism but also happen to have an affinity
for a particular virus. The identity of the specific cellular receptor is known for some viruses but
is unknown in many cases.
Factors affecting viral gene expression are important determinants of cell tropism. Enhancer
regions that show some cell-type specificity may regulate transcription of viral genes. For
example, the JC polyomavirus enhancer is much more active in glial cells than in other cell
types.
Another mechanism dictating tissue tropism involves proteolytic enzymes. Certain
paramyxoviruses are not infectious until an envelope glycoprotein undergoes proteolytic
cleavage. Multiple rounds of viral replication will not occur in tissues that do not express the
appropriate activating enzymes.
Viral spread may be determined in part by specific viral genes. Studies with reovirus have
demonstrated that the extent of spread from the gastrointestinal tract is determined by one of the
outer capsid proteins.
C. CELL INJURY AND CLINICAL ILLNESS
Destruction of virus-infected cells in the target tissues and physiologic alterations produced in
the host by the tissue injury are partly responsible for the development of disease. Some tissues,
such as intestinal epithelium, can rapidly regenerate and withstand extensive damage better than
others, such as the brain. Some physiologic effects may result from nonlethal impairment of
specialized functions of cells, such as loss of hormone production. Clinical illness from viral
infection is the result of a complex series of events, and many of the factors that determine
degree of illness are unknown. General symptoms associated with many viral infections, such as
malaise and anorexia, may result from host response functions such as cytokine production.
D. RECOVERY FROM INFECTION
The host either succumbs or recovers from viral infection. Recovery mechanisms include both
innate and adaptive immune responses. Interferon and other cytokines, humoral and cell-
mediated immunity, and possibly other host defense factors are involved. The relative
importance of each component differs with the virus and the disease.
In acute infections, recovery is associated with viral clearance.
E. VIRUS SHEDDING
The last stage in pathogenesis is the shedding of infectious virus into the environment. This is a
necessary step to maintain a viral infection in populations of hosts. Shedding usually occurs from
the body surfaces involved in viral entry. Shedding occurs at different stages of disease
depending on the particular agent involved. It represents the time at which an infected individual
is infectious to contacts. In some viral infections, such as rabies, humans represent dead-end
infections, and shedding does not occur.