Immune Response to Infectious Diseases

1. Immune Response to
Infectious Diseases Viral Infections Bacterial Infections Protozoan Diseases Diseases Caused by Parasitic Worms (Helminths) Emerging Infectious Diseases

2. Viruses are obligatory intracellular microorganisms • They live inside cells, using components of the nucleic acid and protein synthetic machinery of the host to replicate and spread • Viruses typically infect various cell types by using normal cell surface molecules as receptors to enter the cells • After entering cells, viruses can cause tissue injury and disease by any of several mechanisms. • cytopathic effect of viruses • Latent infections • Lytic infection: Viral replication interferes with normal cellular protein synthesis and function and leads to injury and ultimately death of the infected cell • HIV life cycle

3. Viral Infections • Virus attempts to subvert immune defence mechanisms • nonspecific and specific defense mechanisms

4. The innate immune response to viral infection is primarily through the induction of type I interferons (IFN- and
IFN-) and the activation of NK cells

5. Innate immunity to viruses • Interferon are produced by infected cells especially plasmacytoid DCs through various pathways • Pathways converge on the activation of protein kinases that activates IRF transcription factors stimulating interferon transcription • Biochemical pathways are triggered by: • Endosomal TLR reecognizing viral RNA and DNA • Activation of cytoplasmic RIG like receptors by viral RNA • NK cells recognize and kill the infected cells without MHC I expression • Protection • Eradication

8. Interferon's • Interferon gamma is secreted from • CD4+ Th1 cells • CD8 cells, gamma/delta T cells • activated NK cells • Macrophage, monocyte, fibroblasts • Interferons plays a role in activating lymphocytes to enhance anti-microbial and anti-tumor effects • In addition it plays a role • in regulating the proliferation • differentiation • response of lymphocyte subsets • Signaling takes place through a IFN Receptor complex consisting of two alpha chains (Type I receptor) and two beta chains (Type 2 receptor) • Upon phosphorylation by Jak1, Stat1(alpha) transduces the signal into transcriptional events • Induction of antiviral activity by IFN- and -. These • interferons bind to the IFN receptor, which in turn induces the synthesis of both 2-5(A) synthetase and protein kinase (PKR). • The action of 2-5(A) synthetase results in the activation of RNAse L, which can degrade mRNA. PKR inactivates the translation initiation factor eIF-2 by phosphorylating it. Both pathways thus result in the inhibition of protein synthesis and thereby effectively block viral replication.

9. Adaptive immunity to viruses • Adaptive immunity mediates through: • Antibodies: • Blocking virus binding and entry sites • Neutralizing antibodies e.g. IgA against respiratory and intestinal infections • Opsonization • Complement- effective against viruses with lipid envelopes • Limitations: • Effective only in extracellular (early phase, released from infected cells) • Humoral immunity due to previous infection or immunization can protect from infection • But not eradicate an established infection • For that only CTLs are effective

10. Many Viruses are Neutralized by Antibodies • Antibodies specific for viral surface antigens are often crucial in containing the spread of a virus during acute infection and in protecting against reinfection • Antibodies are particularly effective in protecting against infection if they are localized at the site of viral entry into the body. • For example, influenza virus binds to sialic acid residues in cellmembrane glycoproteins and glycolipids; • rhinovirus binds to intercellular adhesion molecules (ICAMs) • and Epstein-Barr virus binds to type 2 complement receptors on B cells • If antibody to the viral receptor is produced, it can block infection altogether by preventing the binding of viral particles to host cells. • Secretory IgA in mucous secretions plays an important role in host defense against viruses by blocking viral attachment to mucosal epithelial cells • The advantage of the attenuated oral polio vaccine, is that it induces production of secretory IgA which effectively blocks attachment of poliovirus along the gastrointestinal tract • Viral neutralization • In some cases, antibodies may block viral penetration by binding to epitopes that are necessary to mediate fusion of the viral envelope with the plasma membrane. • If the induced antibody is of a complement-activating isotype, lysis of enveloped virions can ensue. • Antibody or complement can also agglutinate viral particles and function as an opsonizing agent to facilitate Fc- or C3b-receptor–mediated phagocytosis of the viral particles

11. Adaptive immunity to viruses • Adaptive immunity mediates through: • CTLs: • CD8+ T cells recognize cytosolic, endogenously synthesized viral peptides through MHC I • Cross presentation makes it possible that infected non-APCs can also be presented to the CTLs • Complete activation of CTLs requires • Cytokines produced by various immune cells e.g. CD4+ T helper cells • Danger signal /Co-stimulation from infected cells • Antiviral effects of CTLs include: • Granzyme mediated killing activity • Activation of nucleases • Secretion of IFN-Ƴ

12. Viruses may thwart humoral responses by changing their antigens(serotypes) however some conserved/invariant proteins may be produced which may activate CTL responses and therefore lead to eradication of infections

13. Immunopathology due to CTLs • LCMV infection in mice causes spinal cord meninges inflammation • LCMV is a non-cytopathic virus • CTLs from diseased mouse can also cause the same effect in healthy mice • Livers of acute and chronic hepatitis also contain large number of CD8+ T cells

14. Immune evasion strategies adapted by viruses

15. Immune evasion by viruses • Various immune evasion mechanisms adapted by the viruses include: • Antigenic variation • Immunoregulatory proteins • Decoy proteins • Homolog proteins

16. Immune evasion by viruses • Viruses can alter their antigens, thus hide away from immune Surveillance • Mostly the B cell epitopes undergo change more than the T cell epitope • Mechanisms are mostly: • Point mutation • Reassortment of RNA genome • Influenza virus is a good example of a virus that undergoes changes, two important proteins are: • Hemagglutinin • Neuraminidase • Influenza pandemics in 1918, 1957 and 1968, n 2009 • Other examples include, rhinovirus and HIV

17. Many viruses subvert particular parts of the immune system • synthesis of complement-regulatory molecules • capture of cellular genes for cytokines or chemokines and their receptors • the production of decoy proteins that mimic the host proteins involved in inflammation and immunosuppression • E.g. Decoy proteins for TIR domains that are part of the TLR/IL-1 receptor signaling pathway • The human cytomegalovirus (CMV ), another herpesvirus, produces a protein called UL18, which is homologous to an HLA class I molecule • CMV also impairs antiviral responses by producing a homolog of the cytokine IL-10, called cmviL-10, which down regulates the production of several pro-inflammatory cytokines by immune cells, including IFN, IL-12 and IL-23, IL-l, IL-6, and TNF-a, to promote tolerogenic rather than immunogenic adaptive responses to viral antigens • Several viruses also produce molecules that interfere with chemokine responses, either by producing decoy chemokine receptors or chemokine homologs that interfere with natural ligand-induced signaling through chemokine receptors

18. c

19. IMMUNO
EVASINS • Immunoevasins produced by • viruses interfere with the processing • of antigens that bind to MHC class I • molecules