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West Nile Virus: host immune response vs. viral pathogenesis

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West Nile Virus: host immune response vs. viral pathogenesis

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    1. West Nile Virus: host immune response vs. viral pathogenesis ARWA ALI FAIZO MSC MEDICAL MICROBIOLOGY MMIC 7050 MICROBIAL PATHOGENESIS DEPARTMENT OF MEDICAL MICROBIOLOGY

    2. West Nile Virus Overview. West Nile Virus structure. Replication of WNV. Common diseases associated with WNV. WNV pathogenesis. CNS invasion mechanisms. WNV models. Immunity against WNV.

    3. West Nile Virus: overview Family: Flaviviridae. Member of Japanese encephalitis (JE) antigenic complex of viruses. WNV remain in an enzootic cycle (between Mosquitos and migratory birds). route of human infection: bite of an infected mosquito (arthropod main vector). infects birds (primary reservoir). infects humans and horses (dead end host). Other transmission routes: Blood transfusion, organ transplantation and breast milk.

    4. WNV epidemiology

    5. incidence of WNV neuroinvasive disease in U.S

    6. Virus structure Enveloped. Positive ss-RNA genome (11,000 nucleotides). Structural proteins: Core protein (C) >> packaged RNA genome viral envelope protein (E) membrane protein (M) >> replication, assembly, receptor recognition and B and T cells stimulation. Non Structural proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5

    7. Cellular replication

    8. Diseases associated WNV 80% Asymptomatic infection. West Nile Fever (20%-30% of infections) Flu-like symptoms severe disease (neurological disease) (1/150) High fever and Severe headache Stiff neck and Flaccid paralysis. Disorientation or confusion Tremors or muscle jerking Signs and symptoms of Parkinson's disease People at high risk: Advanced age Immunocomprimised Medical condition (diabetes, cancer)

    9. WNV pathogenesis

    10. CNS invasion mechanisms

    11. WNV models: In vivo >> excellent model for studying WNV: MICE the same regions of the human brain were infected in WNV-infected mice suggesting a similar tropism of WNV in humans and mice. In vitro >> primary neurons. human and mouse neuroblastoma cells. cortical astrocytes (HBCA).

    12. Immunity against WNV 1- Innate immune response protecting the body from the virus. Virus clearing from the body in the case of infection. Major components of innate immune response cell components: Macrophages Dendritic cells Interferon IFN Type I (aand ß) IFN Type II (?) Toll like receptor (TLR)

    13. Innate immune response 1- Macrophages and dendritic cells (phagocytosis- Ag presentation) WNV-infected mosquitos’ bites >> WNV infects macrophages and dendritic cells >> viral replication and dissemination. first target for WNV. Critical for early WNV replication. saliva of Aedes aegypti mosquito plays an important role for the viral replication in early stages. impairs IL-12 and IFN-ß production in infected cells. enhances IL-10 production. interferes with the Ag presentation ability of the macrophages >> inactive adaptive immune response >> viral replication.

    14. Innate immune response 2- polymorphonuclear leukocytes: Neutrophil “paradoxical role” in WNV infection.

    15. Innate immune response 3- Natural killer cells Natural killer (NK) cells are important in combating WNV infection.

    16. Innate immune response: cytokines production 4- Type I Interferon activation type I interferon (IFN-a and IFN-ß) has an important role against WNV infection.

    17. Type I interferon: 5- role of IPS-1 Purpose: examined the importance of IPS-1 in protection against WNV infection. Models: Mice IPS-1-/- (C57BL/6J) wild type mice. Results: IPS-1-/- mice highly susceptible to WNV infection (100% mortality), average survival time 7.3 days wild type mice 38.5% mortality with an AST of 13.2 days.

    18. Innate immune response 5- Role of Caspase-12 Purpose: investigate the role of caspase-12 in WNV infection. Models: Wild type C57BL/6 mice. Casp12-/- mice Results: (Casp12-/- mice) significantly more susceptible to WNV-induced lethality developed severe neurological symptoms. significantly higher Viremia level at day 24 after infection (real-time qPCR) of WNV envelope (WNV-E) and lower IFN-ß response.

    19. Innate immune response 6- Interferon-? important factor >> minimizes the severity of WNV infection. >> enhances the antiviral immune response. mice which lack IFN-? >> 90% vulnerable to lethal WNV infection. >> enhanced viral replication. >> Higher level of viremia. >> early CNS infection

    20. Interferon evasion mechanisms

    21. Interferon evasion mechanisms

    22. Innate immune response 7- complement important part of host innate immunity. Essential for adaptive response. Complement cascade include: (C5b,6,7,8,9)>> Membrane attack complex. C5 deficient mice >> NO effect on mortality. C3a, C5a >> monocytes/granulocytes. C3 fragments >> opsonisation. C3 >> facilitates Ag presentation. C1q >> decreases the Ab amount needed for WNV neutralization.

    23. Complement evasion by WNV

    24. Adaptive immune response to WNV Composed of Cellular and humoral immune response. B cells produce and secrete antibodies against NS1, prM and E protein IgM and IgG. differentiate into memory B cells to help providing long-lasting immunity. T cells Helper T cells (Th cells): express CD4+ glycoprotein and secrete cytokines. Cytotoxic T cells: express CD8+ glycoprotein and induce apoptosis of infected cells.

    25. Adaptive immune response to WNV 1- B-cells Role of sIgM in controlling WNV infection: Result: The Survival of sIgM-/- Mice was decreased compared with wild type after WNV infection. sIgM is an important factor in triggering IgG response. Conclusion: sIgM is significat for fight WNV infection and triggering IgG response.

    26. Adaptive immune response to WNV 2- T-helper cells Role of CD4+ T-Cells: Result: CD4-depletetion mice are highly susceptible to WNV infection. WNV infection persist in the CNS (brain) and spleen of CD4-depleted mice. Conclusion: CD4 T-cells are essential to prevent WNV infection and persistence in CNS.

    27. Adaptive immune response to WNV 3- T-helper cells The level of WNV-specific antibody was decreased in CD4-depleted mice.

    28. Adaptive immune response to WNV 4- T-cytotoxic cells CD8+ T lymphocytes also play a significant role in preventing lethal WNV infection.

    29. Immune response against CNS infection activation of immune repose in the infected-brain is crucial for viral clearance. Glial cells are considered the immune system in the CNS, in particular in the brain. three different types of glial cells populate the CNS.

    30. Immune response against CNS infection Purpose: address the role of CD8+ cells Results: WNV-infected CD8- mice >> significantly higher viral titer in their spleens, spinal cords, and brains compared to wild type although the level of viremia was not changed. conclusion: CD8+ cells are required for viral clearance.

    31. Immune response against CNS infection Purpose: Assess the role of chemokine in controlling WNV infection and regulating immune cell trafficking. Results: chemokine CXC motif receptor 3 (CXCR3) and C-C chemokine receptor type 5 (CCR5) knock-out mice could not clear the infection and had a higher mortality rate compared to wild type. Conclusion: The presence of CXC motif receptor 3 (CXCR3) and C-C chemokine receptor type 5 (CCR5) is important in clearing WNV from CNS.

    32. Take-home massages WNV is a ssRNA virus that belong to Flaviviridae family that infect humans and horses mainly through arthropod bite. Although the majority of WNV infections are asymptomatic, severe neuroinvasive diseases can develop and lead to death. WNV starts the initial round of replication in Lymph node while the second round takes place in visceral organs. Transmigration of WNV from blood circulation through permeable blood brain barrier to CNS possibly by inducing TNF-a and MMPs leads to the most severe form of infection Mice considered as the best model to study the pathogenesis and immunity of WNV. Innate immune response is considered the first line of defence against the infection. mosquito saliva significantly decreases the expression of interferon-ß and IL-12 and enhances IL-10 expression by macrophage which is crucial for initial viral replication. PMNs and Natural killer cells have an important role in controlling WNV infection IPS-1 and caspase-12 are crucial for type I interferon production and therefore protection against WNV infection.

    33. Take-home massages IFN-? is an antiviral that has a protective role against WNV occurs in peripheral lymphoid tissues, and prevents viral dissemination to the CNS. PRR pathways can be antagonized by WNV E protein and non structural proteins Complement system is essential for both innate and adaptive immune response. However, WNV NS1 protein is responsible for antagonize the response to this system. Both Cellular and humoral immune response are important for fighting WNV. sIgM is essential in controlling WNV infection and triggering IgG response. CD4 T-cells have an important protective role against WNV persistence infection in CNS. the presence of WNV-specific Ab is important for controlling viremia and reducing the severity of the disease whereas CD8+ T cells are critical for inducing viral clearance and inhibiting viral persistence. Glial cells are considered as the immune system in the CNS against WNV infection CD8+ cells is crucial for viral clearance from CNS and infected tissues CXC motif receptor 3 (CXCR3) and C-C chemokine receptor type 5 (CCR5) both are crucial against WNV infection in CNS

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