Microbial Escape Mechanisms

1.         Failure of Host defense mechanisms

a.         In the normal course of an infection, disease is followed by an adaptive immune response that clears the infection and establishes a state of protective immunity.

b.            However, there are circumstances in which there are failures of host defense against infection:

i.            avoidance or subversion of a normal immune response by the pathogen.

ii.            inherited failures of defense because of gene defects.

iii.            acquired immune deficiency syndromes, a generalized susceptibility to infection which is itself due to the failure of the host to control and destroy HIV.

c.         The propagation of a pathogen depends on its ability to replicate in a host and to spread to new hosts.

d.            Common pathogens must therefore grow without activating too vigorous an immune response, and conversely, must not kill the host too quickly.

e.         The most successful pathogens persist either because they do not elicit an immune response, or by evading the response once it has occurred.

2.            Antigenic Variation

a.         One way in which an infectious agent can evade immune surveillance is by altering its antigens.

b.         This is particularly important for extracellular pathogens, against which the principal defense is production of antibody to their surface structures.

c.         Wide variety of Antigenic types:

i.          many infectious agents exist in a wide variety of antigenic types.

ii.          for example, there are 84 known types of Streptococcus pneumoniae, an important cause of bacterial pneumonia.

iii.         each type differs from the others in the structure of its polysaccharide capsule.

iv.         the different types are distinguished by serological tests and are known as serotypes.

v.            infection with one serotype of such an organism can lead to type-specific immunity, which protects against re-infection with that type but not with a different serotype.

vi.         the result is that essentially the same pathogen can cause disease many times in the same individual.

d.            Antigenic drift: point mutations in the genes encoding the surface antigens such that individuals previously infected with old variant are now susceptible to the new strain

as antibodies cannot recognize the mutant antigen.

e.            Antigenic shift: reassortment of the virus and related viruses in an animal host, leading to major changes in the viral surface antigen.

3.            Latency of some viral infections

a.         Viruses betray their presence to the immune system once they have entered cells by directing the synthesis of viral proteins, fragments of which are displayed on the surface MHC molecules of the infected cells.

b.         To replicate, a virus must make viral proteins, and rapidly replicating viruses which produce acute viral illnesses, are therefore readily detected by T cells.

c.         Some viruses enter a state of latency in which the virus is not transcriptionally active.

d.         In the latent state, the virus does not cause disease, but, because there are no viral peptides to flag its presence, it cannot be eliminated.

e.         Such latent infections can later be reactivated and this results in recurrent illness.

f.          Herpes simplex viruses persist in a latent state in the sensory neurons until factors such as sunlight, bacterial infection and immune suppression reactivates it.

g.         There are two reasons why the sensory neuron remains infected:

i.          the virus is quiescent in the nerve and therefore few viral proteins are produced, generating few virus-derived peptides to present on MHC class I.

ii.          neurons carry very low levels of MHC class I molecules, which makes it harder for CD8 T cells to recognize infected cells and attack them.

h.         Acute infection of B lymphocytes by Epstein-Barr virus:

i.          EBV infects B cells, causing them to proliferate and produce virus.

ii.          this leads to proliferation of antigen-specific T cells which kill the infected B cells.

iii.            however, a fraction of B cells become latently infected.

iv.         these cells express a viral protein, EBNA-1, which is needed to maintain the viral genome, but interacts with the proteasome to prevent its own degradation into peptides that would elicit a T-cell response.

4.            Resistance of Defense mechanisms

a.         Some pathogens induce a normal immune response but have evolved specialized mechanisms for resisting its effects.

b.         For instance, some bacteria that are engulfed in the normal way by macrophages have evolved ways of avoiding destruction by these phagocytes; indeed they use macrophages as their primary host.

c.            Mycobacterium tuberculosis, for example, is taken up by macrophages, but prevents the fusion of the phagosome with the lysosome, protecting itself from the bactericidal actions of the lysosomal contents.

d.         Other microorganisms, such as Listeria monocytogenes, escape from the phagosome into the cytoplasm of the macrophage, where they can multiply readily, and then spread to adjacent cells in tissues.

e.         The protozoan parasite Toxoplasma gondii can generate its own vesicle, which isolates it from the rest of the cell because it does not fuse with any cellular vesicle.

f.          Many viruses have evolved mechanisms to subvert various arms of the immune system, ranging from capturing cellular genes for cytokines to synthesizing complement regulatory molecules or inhibiting MHC class I synthesis or assembly.

5.            Immunosuppression

a.         Many pathogens suppress immune responses in general.

b.         For example, staphylococcal bacteria produce toxins, such as the staphylococcal enterotoxins and toxic shock syndrome toxin-1, that act as superantigens.

c.            Superantigens are proteins that bind the antigen receptor of very large numbers of T cells, stimulating them to produce cytokines that cause significant suppression of all immune responses.

d.         The stimulated T cells proliferate and then rapidly undergo apoptosis, leaving a generalized suppression with peripheral deletion of many T cells.

6.            Mechanisms of subversion of host immune system