Lecture 7: Innate defenses against viruses Time course of an innate immune response

1. Lecture 7: Innate defenses against viruses • Time course of an innate immune response • Pattern recognition/ danger • Damage caused by viruses -Cytopathic effect -CTL lysis • Cells responding to virus -neutrophils -macrophages • Effectors made by cells -Proinflammatory cytokines -interferons • Local effects of interferon -antiviral state • Systemic effects of interferon -fever, acute phase reactants, activation of Complement • Viruses that mess with the response

2. Lecture 7: Innate antiviral defenses. Innate defenses stop most infections. _________________7days_______________years____

3. Time course of an innate immune response to a virus.

4. The course of an acute infection-rapid and self limiting Brackets indicate infectious virus present Virus Time 10 days Figure 15.1 Virology Red shaded area-symptoms

5. Innate defenses are most important in an acute infection. Figure 15.8 Virology

6. Pattern recognition: Antigens are recognized by innate immune system Pattern recognition: TLRs recognize viral capsids, viral RNA (TLR3, 7), or DNA (TLR9) Innate immune system is responsible for recognizing that something poses DANGER.

7. Recognition of danger through detection of tissue damage Cytopathic effect-Cell pathology Pathogenic mechanism Viruses that lyse the cell, or cause major disruptions to the morphology of the cell cause damage by direct cytopathic effect. Infectious agent disease

8. Viruses can cause tissue damage by inducing cell mediated immunity. Pathogenic mechanism Infectious agent disease

9. Innate immune cells responding to infection: Neutrophils Neutrophils are phagocytic and are first to arrive at sites of infection About 70% of the circulating cells are neutrophils Granules contain antimicrobial peptides including defensins.

10. Effectors made by cells: defensins Neutrophils secrete many antimicrobial and antiviral compounds. Alpha defensins are potent antivirals Some are directly lytic to virus infected cells others bind to viral capsid and inhibit assembly.

11. Innate immune cells responding to infection: Macrophages Receptors on macrophages recognize patterns on viral antigens Resident antigen presenting cells recognize the pathogen TLR receptor Viruses are recognized by presence of sugars on glycoproteins and surface TLR receptors recognize viral capsid or membrane proteins

12. Macrophages bind to antigens through receptors 1. Internalize antigen 2. Detection by endosomal TLR receptors 3. Deliver signals into the cell to activate macrophages TLR3-viral dsRNA TLR9-viral DNA Tells the macrophage what type of response to make

13. Macrophages release cytokines to initiate immune responses TNF-alpha, interleukin-1 (IL-1), Il-6 and interferon (IFN) Cytokines act locally at site of infection to recruit more

14. Effectors made by cells: interferon Interferon is a “warning protein” made by leukocytes (especially dendritic cells) if they detect virus. interferons Interferon receptors Interferon-alpha and interferon-beta are made by cells after recognition of dsRNA or viral capsid proteins. It binds to receptors on other cells and turns on the antiviral program.

15. IFN-a and b are Type I interferons, IFN-g is Type II interferon Mitogens are non-specific stimulators of lymphocytes

16. Type I Interferons have local effects on other immune cells ‘Antiviral state’ induced in neighboring cells e.g. TRIM22 inhibits trafficking of HIV gag proteins.

17. Anti-viral program in neighboring cells Over 100 proteins are induced by Type I interferons: • 2’-5’ oligoadenylate synthetase is activated to make oligoadenylate (AAAAAAA) which in turn activates RNase L. • RNase L degrades cellular and viral mRNA. • dsRNA activated protein kinase (Pkr) stops new protein synthesis in infected cells

18. The innate response is amplified by cooperation in the immune system Activated macrophages make TNF-alpha TNF-alpha Macrophage NK IFN-g Activated natural killer cells or T cells make Interferon-gamma

19. Proinflammatory cytokines have systemic effects Proinflammatory cytokines act on hypothalamus Fever-most viruses cause fever or Increased body temperature. Colony stimulating factors act on bone marrow to increase WBC output Acute phase proteins are made by the liver 100-1000-fold upregulation Figure 14.3 Virology

20. Proinflammatory cytokines induce liver to produce acute phase reactants-effector proteins made in response to infection. Often bind directly to virus.

21. Acute phase reactants act as opsonins facilitating phagocytosis Mannan-binding lectin (MBL) binds to mannose on viral glycoproteins and acts as an opsonin. MBL can also activate complement via the lectin pathway. Figure 2.39 Janeway

22. Terminal galactose a(1,3)-galactose (also called aGal) is on many viruses that are made in animal hosts. Primates do not have this enzyme. This sugar is on many bacteria, so we make antibodies to it. Cell, Vol. 86, 185–188, 1996 Main line of complement defense against animal viruses is due to aGal

23. Aberrant innate immune response to 1918 influenza caused severe lung damage Seasonal flu 1918 flu 1918Flu.pdf Nature. 2007 Jan 18;445(7125):319-23 1918 Flu caused massive lesions with infiltration of leukocytes

24. Different responses to influenza virus strains 1918 flu Seasonal flu 1918 Pandemic strain caused too much inflammation, which caused pathology 1918Flu.pdf