Immunology

Host pathogen interaction and immune evasion mechanisms

Any microorganism which is able to cause disease in a host organism is termed a pathogen. When
a pathogenic microorganism (bacterium, virus or protozoal parasite) infects the human body, a
battle ensues between the host’s innate & adaptive immune systems and the pathogen’s
assorted virulence mechanisms and factors. The outcome of this battle determines whether, and
how well, the host survives and recovers. Full recovery entails the achievement of physiological
(and immunological) homeostasis in the host, and the length of time this takes will depend on the
nature and severity of the infection and whether there has been any prophylactic or therapeutic
intervention. Many pathogens also deploy diverse immune evasion tactics in the host to achieve
host cell invasion and colonisation and may successfully exploit host cells to access target tissues.
Immune evasion strategies are those strategies that bacterial pathogens use to avoid or inactivate
host defenses and ensure their own survival within a host. Immunology

Virulence and immune evasion strategies, the latter of which may involve: (1) hiding from the
immune system (e.g. within cells); (2) interfering with the function of the immune system (e.g.
blocking signals); (3) destroying elements of the immune system (e.g. the structures which present
microbial antigens to immune effectors to initiate a response in the host). Virulence generally
involves the employment of various mechanisms to destroy, or cause the malfunction of, host cells.
The host may also employ counterstrategies in response to these.

Viruses such as Varicella zoster (chickenpox) and Herpesviridae (herpes simplex viruses,
Varicella-Zoster virus, cytomegalovirus etc) can hide from the immune system in neurons and
non-neuronal cells where they may persist for many years, before emerging in pathogenic form
when the host has a lowered resistance. This is the case also for bacteria such as Borrelia
burgdorferi and Burkholderia pseudomallei (causative of Lyme disease and melioidosis,
respectively) where there are reports that symptoms of infection have re-emerged months to years
(B.burgdorferi), and even up to 60 years (B.pseudomallei), after the initial infection. In terms of
immune interference, more overt strategies may be deployed, e.g. Leishmania protozoal parasites
belonging to Leishmania spp. can selectively inhibit the transcription of the pro-inflammatory
cytokine interleukin 12 (IL12p40) in the host, thus suppressing the host’s immune response.

To sustain their virulence mechanisms, many bacteria can sequester free iron in the mammalian
host, through the elaboration of iron-binding siderophores. Iron is an essential component of

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metabolism in both the host and the micro-organism. Thus to protect itself from such virulence
mechanisms, the host cell fights back by synthesising siderocalin receptors which competitively
bind iron. Mammalian host cells have also evolved an array of pattern recognition receptors for
microbes or microbial factors, such as the Toll-like receptors (TLRs), which when bound, trigger
intracellular signalling cascade(s) with antimicrobial effects.

Whilst many bacterial pathogens are intracellular in nature, others do not need to invade the host
cell, but instead use various secretion processes which effect the delivery of toxins and other
virulence factors into the host cell. Examples of bacteria which have developed the ablity to make
a hollow projection (a so-called translocon) which on contact with the host cell can deliver anti-
host factors into it, often resulting in host cell apoptosis (so-called Type III secretion),
include Escherichia coli, Shigella flexnerii, Yersinia pestis and Chlamydia trachomatis which
cause diverse syndromes of food poisoning, dysentery, bubonic plague and genito-urinary tract
infection, respectively (see Figure 1). However, some bacteria such as Francisella
tularensis (causative of tularemia) and Burkholderia spp. (causative of melioidosis or glanders)
have multiple secretion processes through which they deliver virulence factors into the host cell.

Bacteria are multifaceted in their methods used to escape immune detection. They employ tactics
such as modulating their cell surfaces, releasing proteins to inhibit or degrade host immune factors,
or even mimicking host molecules. Mastery of these camouflaging and precise weaponry
techniques by bacterial pathogens significantly complicates efforts to develop new vaccines and
innovative treatments.

Hidden in Plain Sight: Cell Wall Modification, Capsule Production, and Mimicry

The cell wall of a bacterial pathogen is often the first target of the human immune system, which
uses tools such as antibodies and antimicrobial peptides (AMPs) to kill and neutralize the bacteria.
Because the cell wall is also a bacterium’s first line of defense, it is not surprising that modulation
of this outermost layer is an evasive technique used widely across bacterial species.

E. coli, S. enterica, and various other gram-negative organisms acylate the lipid A component of
the lipopolysaccharide in their cell walls (see Figures 1 and 2), thereby changing their negatively
charged surface to a positive charge. This alteration allows the bacterial cells to repel positively
charged AMPs produced by host immune cells. Masking negatively charged cell surfaces is not

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unique to gram-negative bacteria: several gram-positive pathogens, such as Staphylococcus

Figure 1: Orientation of LipidA within the gram-negative cell wall.

Neisseria meningitidis, which lives in the human upper respiratory tract as a commensal organism,
causes systemic infection if the bacteria begin replicating in the bloodstream. A major contributor
to the success of N. meningitidis as a pathogen is its its physical “cloak,” or polysaccharide
capsule, which helps protect the bacteria from many of our body’s defenses by hiding it from the
immune system. The genes necessary for capsule synthesis are downregulated during early
infection to allow for invasion of host cells. However, the bacteria produce capsule once again
upon entering the bloodstream in order to survive in the presence of immune factors, such as
complement, that are found there. Researchers have found that the capsular polysaccharide
even provides protection of N. meningitidis against AMPs found inside of host cells.

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Figure 2: LPS acetylation, with lipid A acyl groups shown in black.

In some bacterial species, polysaccharide capsules serve not only a physical barrier, but also as a
an advanced camouflaging system. For instance, the capsule of certain strains of E. coli and that
of N. meningitidis serotype B contains polysaccharides that are structurally similar to
polysaccharide found on the surface of some mammalian cells. In fact, the similarity of these
capsular polysaccharides to those found on certain cells within infant brains has been implicated in
the success of these pathogens in causing severe neural disease.

Another mechanism of immune evasion is the ability of some helminths to induce host cell
apoptosis. Apoptosis has been described as a host regulatory mechanism in various helminth
infections, including schistosomiasis, lymphatic filariasis, and onchocerciasis.