Anti-Inflammatory Responses

1
Anti-Inflammatory Responses

• Complement regulatory proteins e.g. C1
  inhibitor, C4 binding protein, Factor H, Factor
  I, complement receptor CR1, decay accelerating
  factor.
• Acute phase proteins e.g. protease inhibitors,
  ceruloplasmin.
• PGE2, TGF?, Prostaglandins
• IL-10
• sIL-1R

2
Immunopathology

• Virus-bacterium synergistic pathology
• Sepsis and Endotoxemia
• Molecular mimicry
• Superantigens

3
Virus-Bacterium Synergy

• Enhancement of inflammatory response by bacterial
  growth, IFN?, complement.
• Increased tissue damage by bacterial toxins
  (cytolysin, LPS)
• Amplification of macrophage reactivity by
  cytokines, LPS,

4
Sepsis and Endotoxemia

• Proinflammatory cytokinesTNF?, IFN?, IL-1,
  IL-6, IL-8, IFN?, IFN?
• C5a
• Neutropenia
• Soluble cytokine receptors (TNF-R, IL-1R)

5
Molecular Mimicry

• Chlamydia - heart
• Campylobacter - Guillan-Barre syndrome

6
Superantigens

• S. aureus enterotoxins causing food poisoning,
  vomiting diarrhea (SEA, SEB).
• ? Lymphocyte proliferation
• ? Cytokine production
• Toxic shock syndrome.

7
Immune Evasion

• Camouflage
• Encapsulation
• Antigenic mimicry
• Antigenic masking
• Antigenic shift
• Latency
• Intracellular replication

• Subversion
• Production of anti-Ig proteases
• Destruction of phagocyte
• Inhibition of chemotaxis
• Inhibition of phagocytosis
• Inhibition of phagolysosome fusion
• Resistance to lysosomal enzymes
• Superantigens

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Mechanisms of Immune Evasion I Camouflage

• Capsule formation
• S aureus protein A
• Sialic acid
• LPS O protein
• S aureus coagulase
• M bacterium granuloma formation

9
Mechanisms of Immune Evasion III
Anti-Phagocytosis

• Inhibit opsonization (S aureus protein A)
• Inhibit chemotaxis
• Kill phagocyte (S aureus streptolysin)
• Inhibit phagocytosis (S pneumoniae capsule, S
  pyogenes M protein)
• Inhibit lysosomal fusion (M. tuberculosis)
• Escape lysosome and grow in cytoplasm
  (Mycobacteria, Salmonella, S. aureus)
• Block activation by IFN? (Mycobacteria)
• Viral envelope glycoproteins
• LPS

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Mechanisms of Immune Evasion II Proteases

• Inhibit opsonization (N gonorrhoeae IgA protease)
• Inhibit chemotaxis
• Kill phagocyte (S aureus streptolysin)
• Inhibit phagocytosis (S pneumoniae capsule, S
  pyogenes M protein)
• Inhibit lysosomal fusion (M. tuberculosis)
• Escape lysosome and grow in cytoplasm
  (Mycobacteria, Salmonella, S. aureus)
• Block activation by IFN? (Mycobacteria)
• Viral envelope glycoproteins
• LPS

11
Viral Mechanisms of Immune Evasion I

• Humoral Response
• Latency e.g. HSV, retroviruses
• Syncytia formation e.g. HSV, VZV, HIV
• Antigenic variation e.g. HIV
• Blocking antigen e.g. HBV e Ag
• Complement decay e.g. HSV

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Viral Mechanisms of Immune Evasion II.

• Interferon
• HBV blocks transcription of IFN?
• EBV synthesizes BRC1, an analogue of IL-10.
• Adenovirus RNA - double stranded duplex blocks
  interferon antiviral action early protein binds
  cl I heavy chain preventing upregulated expression

13
Viral Mechanisms of Immune Evasion III

• Immune Cell Function
• CTL cytolysis e.g. HSV
• TH depletion e.g. HIV
• Immunosuppression e.g. measles, EBV

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Viral Mechanisms of Immune Evasion IV.

• Antigen Presentation
• Inhibition of Cl I MHC expression e.g.
  Adenovirus, CMV
• Inactivating peptides e.g. HBV
• Inhibition of Inflammation
• Blocking of inflammatory cytokines e.g.
  Poxviruses, adenovirus.

15
Infection and Pathogenesis

• Colonization (Benign or asymptomatic) ?Infectio
  n ? ? Disease (Pathogenesis) ? Clinical or
  Subclinical

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Requisites for Successful Growth

• Attachment
• Nutrition
• Survival from host defence
• Transmission

17
Virulence Factors

• Factors which promote infection and which
  contribute to disease
• Studied with mutants
• Are multifactorial
• Consist of
• Factors promoting colonization and invasion
• Factors which are pathogenic

18
Bacterial Virulence Factors I Colonization

• Adherence Capsules, Pili, adhesins
• Penetration e.g. invasins
• Host gene modification.

19
Capsules

• Present in some gram negative and positive
  bacteria.
• May be composed of protein or polysaccharide
  layers.
• Is poorly antigenic and anti-phagocytic
• Can act as a barrier to toxic hydrophobic
  molecules such as detergents.
• Can promote adherence to other bacteria or cell
  surfaces

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Pili (Fimbriae)

• Composed of subunits of pilin.
• Promote adherence to other bacteria or host.
• Synonyms adhesins, lectins, evasins, aggressins.
• Fragile, often replaced.

21
Bacterial Pathogenesis

• Toxic byproducts of bacterial growthe.g. acids,
  gas, proteases
• Toxins
• Endotoxins e.g. LPS
• Exotoxins
• Immunopathogenesis e.g. Chlamydia, treponemes
  (syphilis), Borrelia (Lyme disease)

22
Endotoxins Lipopolysaccharide

• Fever
• Leukopenia, followed by leukocytosis
• Complement activation
• Thrombocytopenia
• Coagulation
• Decreased blood circulation
• Shock
• Death

23
Exotoxins

• AB. e.g. Shigella dysenteriae, C. tetani, V.
  cholerae.
• Cell Membrane Disruption. e.g. C. perfringens
• Superantigens. e.g. S. aureus

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Exotoxins I AB (i)
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Exotoxins IAB (ii)
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Exotoxins I AB (iii)