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
a wide variety of antigenic types
Programmed gene rearrangements
13-4 Immunosuppression or inappropriate immune responses can contribute to persistent disease.
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
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
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
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
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
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.
Defects in complement components and complement-regulatory proteins cause defective humoral immune function and tissue damage
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.’
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
Genetic variation in the host can alter the rate of progression of disease.
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
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.
