Failures of Host Defense Mechanisms · Failures of Host Defense Mechanisms Evasion and subversion of immune defenses •Antigenic variation allows pathogens to escape from immunity

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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.