Failures of Host Defense Mechanisms

Report
Failures of Host Defense
Mechanisms
Dr. Sheeba Murad Mall
• In the normal course of an infection, the infectious agent first
triggers an innate immune response
• The foreign antigens of the infectious agent, enhanced by signals
from innate immune cells, then induce an adaptive immune
response that clears the infection and establishes a state of
protective immunity
• This does not always happen
• There are possibilities in which there are failures of host defense
against pathogens:
– the avoidance or subversion of a normal immune response by the
pathogen
– inherited failures of immune defenses because of gene defects
– acquired immune deficiency syndrome (AIDS), a generalized
susceptibility to infection that is itself due to the failure of the host to
control and eliminate the human immunodeficiency virus (HIV)
The most successful pathogens persist either
because they do not elicit an immune
response or because they evade the response
once it has occurred
Over millions of years of co-evolution with their
hosts, pathogens have adapted various strategies
for avoiding destruction by the immune system
Evasion and subversion of immune
defenses
• Just as vertebrates have developed many
different defenses against pathogens, so
pathogens have evolved numerous ways of
overcoming them
• some pathogens have adapted mechanisms to
keep one step ahead of the adaptive immune
response like:
– resisting phagocytosis
– avoiding recognition by the adaptive immune system
– actively suppressing immune responses
Antigenic variation allows pathogens
(bacteria) to escape from immunity
• antigenic variation (extracellular pathogensgenerally eliminated by antibodies against
their surface structures):
– Streptococcus pneumoniae (bacterial
pneumonia)- 84 types/ serotypes differ in their
structure of polysaccharide capsules
– Different serotypes result in to a situation that
essentially the same pathogen can cause disease
many times in the same individual
Fig. 13.1 Host defense against
Streptococcus pneumoniae is type
specific. The different strains of
S. pneumoniae have antigenically distinct
capsular polysaccharides. The capsule
prevents effective phagocytosis until
the bacterium is opsonized by specific
antibody and complement, allowing
phagocytes to destroy it. Antibody
against one type of S. pneumoniae
does not cross-react with the other
types, so an individual immune to one
type has no protective immunity to a
subsequent infection with a different
type. An individual must generate a new
adaptive immune response each time he
or she is infected with a different type of
S. pneumoniae.
Antigenic variation allows pathogens
(viruses) to escape from immunity
• Two important mechanisms adapted by viruses include:
– Antigenic drift is mechanism of immune evasion by viruses
especially in case of influenza virus
• point mutations in the genes encoding hemagglutinin and a second surface protein,
neuraminidase
• Every 2-3 years a variant flu virus arises with mutations that allow it to evade
neutralization by the antibodies present in the population
• Other mutations affect epitopes in the proteins that are recognized by T cells particular CD8 cytotoxic
T cells
• An epidemic resulting from antigenic drift is usually relatively mild
– Antigenic shift and is due to major changes in the hemagglutinin
of the virus
• Antigenic shift is due to reassortment of the segmented RNA genome of the human virus
and animal influenza viruses in an animal host, in which the hemagglutinin gene from the
animal virus replaces the hemagglutinin gene in the human virus
• Antigenic shifts cause global pandemics of severe disease, often with substantial
mortality, because the new hemagglutinin is recognized poorly, if at all, by
antibodies and T cells directed against the previous variant
Fig. Two types of variation allow repeated infection with
type A influenza virus. Neutralizing antibody that
mediates protective immunity is directed at the viral
surface protein hemagglutinin (H), which is responsible
for viral binding to and entry into cells. Antigenic drift
(left panels) involves the emergence of point mutants
with altered binding sites for protective antibodies on
the hemagglutinin. The new virus can grow in a host
that is immune to the previous strain of virus, but as T
cells and some antibodies can still recognize epitopes
that have not been altered, the new variants cause only
mild disease in previously infected individuals. Antigenic
shift (right panels) is a rare event involving the
reassortment of the segmented RNA viral genomes of
two different influenza viruses, probably in a bird or a
pig. These antigen-shifted viruses have large changes in
their hemagglutinin, and therefore T cells and
antibodies produced in earlier infections are not
protective. These shifted strains cause severe infection
that spreads widely, causing the influenza pandemics
that occur every 1 0-50 years. There are eight RNA
molecules in each viral genome, but for simplicity only
three are shown.
Antigenic variation allows pathogens
(parasite) to escape from immunity
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antigenic variation in pathogens involves programmed gene rearrangements major health
problem in Africa is the sleeping sickness
Malaria is another serious and widespread disease caused by a protozoan parasite that
varies its antigens to avoid elimination by the immune system
African trypanosomes are insect-borne protozoan parasites that replicate in the extracellular
spaces of tissues and cause the disease known as trypanosomiasis or sleeping sickness
In African trypanosomes changes in the major surface antigen occur repeatedly within the
same infected host
The trypanosome is coated with a single type of glycoprotein, the variant-specific
glycoprotein (VSG), which elicits a potent protective antibody response that rapidly clears
most of the parasites
The trypanosome genome, however, contains about 1000 VSG genes, each encoding a
protein with distinct antigenic properties
A VSG gene is expressed by being placed into the active expression site in the parasite
genome
Only one VSG is expressed at a time, and it can be changed by a gene rearrangement that
places a new VSG gene into the expression site
T he few trypanosomes with changed surface glycoproteins are not affected by the
antibodies previously made by the host, and these variants multiply and cause a recurrence
of disease
Antibodies are then made against the new VSG, and the whole cycle is repeated
• The chronic cycles of
antigen clearance lead
to immune-complex
damage and
inflammation, and
eventually to
neurological damage,
resulting finally in the
coma that gives
sleeping sickness its
name
Antigenic variation by DNA
rearrangement in bacteria
• Salmonella enterica serotype Typhimurium, a common cause of
salmonella food poisoning
• Salmonella Typhimurium regularly alternates two versions of its surface
flagellin protein
• Inversion of a segment of DNA containing the promoter for one flagellin
gene turns off expression of the gene and allows the expression of a
second flagellin gene that encodes an antigenically distinct protein
• Neisseria gonorrhoeae, which causes gonorrhea, a major sexually
transmitted disease and an increasing public-health problem in the
United States
• N. gonorrhoeae has several variable antigens, the most important of
which is the pilin protein, which is responsible for adherence of the
bacterium to a mucosal surface
• Like the VSGs of the African trypanosome, there is more than one pilin
gene variant, only one of which is active at any given time
• From time to time, a different pilin gene replaces the active gene under
the control of the pilin promoter
Some viruses persist in vivo by ceasing to
replicate
• To replicate, a virus must make viral proteins, and
rapidly replicating viruses that produce acute illnesses
are readily detected by T cells, which normally control
them
• Some viruses, however, can enter a state known as
latency, in which the virus is not being replicated
• In the latent state, the virus does not cause disease;
however, because there are no viral peptides to signal
its presence it cannot be eliminated
• Latent infections can be reactivated, and this results in
recurrent illness
• herpesviruses, which are characterized by their ability to
establish lifelong infections
• An example is herpes simplex virus (HSV), the cause of
cold sores, which infects epithelial cells and spreads to
sensory neurons serving the infected area
• local epithelial infection is resolved by an effective
immune response
• However the virus persists in a latent state in the sensory
neurons
• Factors such as sunlight, bacterial infection, or hormonal
changes reactivate the virus, which then travels down the
axons of the sensory neuron and re-infects the epithelial
tissues
• This cycle can be repeated many times
Persistence and reactivation of
herpes simplex virus infection.
The initial infection in the skin is
cleared by an effective immune
response, but residual infection
persists in sensory neurons such as
those of the trigeminal ganglion,
whose axons innervate the lips.
When the virus is reactivated,
usually by some environmental
stress and/or alteration in immune
status, the skin in the area served
by the nerve is reinfected from
virus in the ganglion and a new
cold sore results. This process can
be repeated many times
why the sensory neuron
remains infected?
• first, the virus is quiescent and generates few
virus-derived peptides to present on MHC
class I molecules
• second, neurons carry very low levels of MHC
class I molecules, which makes it harder for
CD8 cytotoxic T cells to recognize infected
neurons and attack them
Why low MHC I expression
on neurons?
Why low MHC I expression on
neurons?
• The low level of MHC class I expression might be
beneficial for neuronal survival, in order to avoid
the inappropriate attack of cytotoxic T cells on
neurons
• however, the low MHC I expression make
neurons vulnerable to persistent infections
• Brain is an immunocompromised organ due to
the Low MHC I expression-
herpes zoster usually reactivates only once in a
lifetime in an immunocompetent host
• Herpes zoster (varicella zoster), which causes
chickenpox remains latent in one or a few dorsal
root ganglia after the acute illness is over, and can
be reactivated by stress or immunosuppression
• It then spreads down the nerve and reinfects the
skin to cause the disease shingles, which is
marked by the reappearance of the classic
varicella rash in the area of skin served by the
infected dorsal root
Shingles- marked by the reappearance of
the classic varicella rash

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