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

Immunopathology

• Virus-bacterium synergistic pathology

• Sepsis and Endotoxemia

• Molecular mimicry

• Superantigens

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,

Sepsis and Endotoxemia

• Proinflammatory cytokines:TNF, IFN, IL-1, IL-6, IL-8, IFN, IFN

• C5a• Neutropenia

Soluble cytokine receptors (TNF-R, IL-1R)

Molecular Mimicry

• Chlamydia - heart• Campylobacter - Guillan-Barre’ syndrome

Superantigens

• S. aureus enterotoxins causing food poisoning, vomiting & diarrhea (SEA, SEB).

Lymphocyte proliferation

Cytokine production• Toxic shock syndrome.

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

Mechanisms of Immune Evasion I: Camouflage

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

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

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

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

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

Viral Mechanisms of Immune Evasion III

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

EBV

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.

Infection and Pathogenesis

Colonization (Benign or asymptomatic)

Infection Disease (Pathogenesis)

Clinical or Subclinical

Requisites for Successful Growth

• Attachment

• Nutrition

• Survival from host defence

• Transmission

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

Bacterial Virulence Factors I: Colonization

• Adherence: Capsules, Pili, adhesins

• Penetration: e.g. invasins

• Host gene modification.

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

Pili (Fimbriae)

• Composed of subunits of pilin.• Promote adherence to other bacteria or

host.• Synonyms: adhesins, lectins, evasins,

aggressins.• Fragile, often replaced.

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)

Endotoxins: Lipopolysaccharide• Fever• Leukopenia, followed by

leukocytosis• Complement activation• Thrombocytopenia• Coagulation• Decreased blood

circulation• Shock• Death

Exotoxins

• AB. e.g. Shigella dysenteriae, C. tetani, V. cholerae.

• Cell Membrane Disruption. e.g. C. perfringens

• Superantigens. e.g. S. aureus

Exotoxins I: AB (i)

Exotoxins I:AB (ii)

Exotoxins I: AB (iii)