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Failures of Host Defense Mechanisms
Evasion and subversion of immune defenses
• Antigenic variation allows pathogens to escape from immunity
• three main forms of antigenic variation: 1. a wide variety of antigenic types, Streptococcus 2. mechanism of antigenic variation
a. Antigenic drift mild epidemic effect, influenza virus b. Antigenic shift global pandemics
3. Programmed gene rearrangements Changes in the major surface antigen occur repeatedly within the same infected host: • Trypanosoma variant-specific glycoprotein (VSG), which elicits a
potent protective antibody response that rapidly clears most of the parasites
• Salmonella enterica serotype Typhimurium alternates two versions of its surface flagellin protein
• Neisseria gonorrhoeae pilin protein
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a wide variety of antigenic types mechanism of antigenic variation
Programmed gene rearrangements
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13-4 Immunosuppression or inappropriate immune
responses can contribute to persistent disease.
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Stages of phagosomal maturation
Ronald S. Flannagan, Gabriela Cosío & Sergio Grinstein Nature Reviews Microbiology 7, 355-366
Some
viruses
persist in
vivo latent
infections
can be
reactivated
recurrent
illness
i. e Herpes
simplex,
Herpes
zoster –
chickenpox
Some pathogens resist destruction by host defense
mechanisms or exploit them for their own purposes.
Ronald S. Flannagan, Gabriela Cosío & Sergio Grinstein Nature Reviews Microbiology 7, 355-366 (May 2009)
Listeria
monocytogenes
escape from
phagosom and
use actin
Toxoplasma gondii generates its
own vesicle, which does not fuse
with any cellular vesicle
Mycobacterium
tuberculosis –
prevents fusion
of phagosome
with lysosome
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Immunosuppression or inappropriate
immune responses can contribute to
persistent disease
staphylococcal enterotoxins and
toxic shock syndrome toxin-1
bind the antigen receptors of very
large numbers of T cells, stimulating
them to produce cytokines that cause
a severe inflammatory illness-toxic
shock
HBV and HCV infect the liver and
cause acute and chronic hepatitis,
liver cirrhosis, and in some cases
hepatocellular carcinoma
Paraskevi A. Farazi & Ronald A. DePinho Nature Reviews Cancer 6, 674-687 (2006)
Pinchuk et al., Toxins 2010, 2, 2177-2197
Immunosuppression or inappropriate immune responses can
contribute to persistent disease
Misch E A et al. Microbiol. Mol. Biol.
Rev. 2010;74:589-620
Tuberculoid leprosy fever cytokines by macrophage
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Immune responses can contribute directly to
pathogenesis.
Respiratory syncytial virus (RSV) infection vaccination more sever illness than children without vaccination. Vaccinated children failed to induce neutralizing antibodies. Induced TH2 released IL-3, IL-4, IL5 bronchospasm Schistosome – egg in hepatic protal vein elicit a potent immune response leading to chronic inflammation, hepatic fibrosis, and eventually liver failure
Regulatory T cells can affect
the outcome of infectious
disease.
Leishmania major, Treg cells accumulate in the dermis impair the ability of effector T cells to eliminate pathogens from this site.
HBV and HCV elevated numbers of FoxP3+ Treg cells in the circulation and in the liver avoid clearance and set up a chronic infection chronic liver infections persistent disease
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Immunodeficiency disease
• Immunodeficiencies :
– Primary immunodeficiencies inherited mutation of genes involved in immune responses
• Adaptive immune defects
• Innate immune defects
– Secondary immunodeficiencies acquired as a consequence of other diseases or are secondary to environmental factors such as starvation etc.
Primary immunodeficiency diseases
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T-cell development Defects severe combined immunodeficiencies
Genetic defects in thymic function that block T-cell
development result in severe immunodeficiencies.
A DiGeorge syndrome (Bubble) baby.
Kuby Fig 19-4
A Nude mouse
Kuby
Fig 19-5
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Defects in B-cell development result in deficiencies in antibody
production that cause an inability to clear extracellular bacteria.
The absence of immunoglobulin in the serum (agammaglobulinemia) -X-linked – lack of Bruton’s tyrosine kinase Bruton's X-linked agammaglobulinemia (XLA)
Immune deficiencies can be caused by defects in B-cell
or T-cell activation and function.
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Defects in complement components and complement-regulatory proteins cause defective humoral immune function and tissue damage
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Defects in phagocytic cells permit widespread bacterial
infections.
Mutation in the molecular regulators of inflammation can cause uncontrolled inflammatory responses that result in ‘autoinflammatory disease.’
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Secondary immunodeficiencies are major predisposing
causes of infection and death
Acquired immune deficiency syndrome
Acquired immune deficiency syndrome
HIV is a retrovirus that infects CD4 T cells, dendritic cells, and macrophages
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Genetic variation in the host can alter the rate of
progression of disease.
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HIV integrates into the host-cell genome.
Replication of HIV
occurs only in activated T cells
Lymphoid tissue is
the major reservoir of HIV infection
An immune
response
controls but
does not
eliminate
HIV.
The destruction of immune function as a
result of HIV infection leads to increased susceptibility to opportunistic infection
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HIV therapy • Drugs that block HIV
replication lead to a rapid
decrease in titer of
infectious virus and an
increase in CD4 T cells
HIV accumulates many mutations in the
course of infection, and drug treatment is
soon followed by the outgrowth of drug-resistant variants
HIV accumulates many
mutations in the course of
infection, and drug
treatment is soon followed
by the outgrowth of drug-
resistant variants.