Infection and Immunity

1. Infection and Immunity

3. What does a pathogen have to do? • Infect (infest) a host • Reproduce (replicate) itself • Ensure that its progeny are transmitted to another host

4. Mechanisms of Transmission • Aerosols - inhalation of droplets, e.g. Rhinoviruses, the 'Common Cold Virus' or Adenoviruses. • Faecal-Oral - e.g. Astroviruses, Caliciviruses; these viruses cause acute gastroenteritis. • Vector-borne - e.g. in Arthropods such as mosquitos, ticks, fleas: Arboviruses. • Close personal contact - especially exchange of bodily fluids: Sex; Blood, e.g. Herpesviruses

5. Entry into the Host • Skin- dead cells, therefore cannot support virus replication. Most viruses which infect via the skin require a breach in the physical integrity of this effective barrier, e.g. cuts or abrasions. Many viruses employ vectors, e.g. ticks, mosquitos or vampire bats to breach the barrier. • Respiratory tract - In contrast to skin, the respiratory tract and all other mucosal surfaces possess sophisticated immune defence mechanisms, as well as non-specific inhibitory mechanisms (cilliated epithelium, mucus secretion, lower temperature) which viruses must overcome.

6. Entry into the Host • Gastrointestinal tract - a hostile environment; gastric acid, bile salts, etc • Genitourinary tract - relatively less hostile than the above, but less frequently exposed to extraneous viruses (?) • Conjunctiva - an exposed site and relatively unprotected

7. Sites of virus entry

8. Transmission patterns • Horizontal Transmission: Direct person-to-person spread. • Vertical Transmission: Relies on PERSISTENCE of the agent to transfer infection from parents to offspring. Several forms of vertical transmission can be distinguished: • 1.Neonatal infection at birth, e.g. gonorrhorea, AIDS. • 2.Infection in utero e.g. syphilis, CMV, Rubella (CRS), AIDS. • 3. Germ line infection - via ovum or sperm.

9. Primary Replication • Having gained entry to a potential host, the virus must initiate an infection by entering a susceptible cell. This frequently determines whether the infection will remain localized at the site of entry or spread to become a systemic infection

10. Localized Infections • Viruses Primary Replication • Rhinoviruses U.R.T. • Rotaviruses Intestinal epithelium • Papillomaviruses Epidermis

11. Systemic Infections Virus Primary ReplicationSecondary Replication Enteroviruses Intestinal epithelium Lymphoid tissues, C.N.S. Herpesviruses Oropharynx or Lymphoid cells, G.U.tract C.N.S.

12. Spread Throughout the Host • Apart from direct cell-cell contact, there are 2 main mechanisms for spread throughout the host: • via the bloodstream • via the nervous system

13. via the bloodstream • Virus may get into the bloodstream by direct inoculation - e.g. Arthropod vectors, blood transfusion or I.V. drug abuse. The virus may travel free in the plasma (Togaviruses, Enteroviruses), or in association with red cells (Orbiviruses), platelets (HSV), lymphocytes (EBV, CMV) or monocytes (Lentiviruses). Primary viraemia usually proceeds and is necessary for spread to the blood stream, followed by more generalized, higher titre secondary viraemia as the virus reaches other target tissues or replicates directly in blood cells

14. via the nervous system • spread to nervous system is preceded by primary viraemia. In some cases, spread occurs directly by contact with neurons at the primary site of infection, in other cases via the bloodstream. Once in peripheral nerves, the virus can spread to the CNS by axonal transport along neurons (classic - HSV). Viruses can cross synaptic junctions since these frequently contain virus receptors, allowing the virus to jump from one cell to another

15. Cell/Tissue Tropism • Tropism - the ability of a virus to replicate in particular cells or tissues - is controlled partly by the route of infection but largely by the interaction of a virus attachment protein (V.A.P.) with a specific receptor molecule on the surface of a cell, and has considerable effect on pathogenesis. Many V.A.P.'s and virus receptors are now known.

16. Secondary Replication • Occurs in systemic infections when a virus reaches other tissues in which it is capable of replication, e.g. Poliovirus (gut epithelium - neurons in brain & spinal cord) or Lentiviruses (macrophages - CNS + many other tissues). If a virus can be prevented from reaching tissues where secondary replication can occur, generally no disease results.

17. Localized Infections: Virus: Primary Replication: Rhinoviruses U.R.T. Rotaviruses Intestinal epithelium Papillomaviruses Epidermis Systemic Infections: Virus: Primary Replication: Secondary Replication: Enteroviruses Intestinal epithelium Lymphoid tissues, C.N.S. Herpesviruses Oropharynx or G.U.tract Lymphoid cells, C.N.S. :

18. Incubation periods of viral infections

19. Types of Infection • Inapparent infection( Subclinical infection) . • Apparent infection: • Acute infection • Persistent Infection Chronic infections Latent Infection Slow virus infections

20. Chronic Infection • Virus can be continuously detected ; mild or no clinical symptoms may be evident.

21. Latent infection The Virus persists in an occult, or cryptic, from most of the time. There will be intermittent flare-ups of clinical disease , Infectious virus can be recovered during flare-ups . Latent virus infections typically persist for the entire life of the host

22. Slow virus infection • A prolonged incubation period, lasting months or years, daring which virus continues to multiply. Clinical symptoms are usually not evident during the long incubation period .

23. Overall fate of the cell • The cell dies in cytocidal infectionsthis may be acute (when infection is brief and self-limiting) or chronic (drawn out, only a few cells infected while the rest proliferate)-Cytocidal effect • The cell lives in persistent infectionsthis may be productive or nonproductive (refers to whether or not virions are produced) or it may alternate between the two by way of latency and reactivation-Steady state infection

24. Special cases • Transformation-Integrated infection (Viruses and Tumor) • Apoptosis

26. Types of Viral infections at the cellular level Type Virus production Fate of cell Abortive - No effect Cytolytic + Death Persistent Productive + Senescence Latent - No effect Transforming DNA viruses - Immortalization RNA viruses + Immortalization

27. Mechanisms of viral cytopathogenesis

28. 3. Viral Immunopathology

29. Viral Immunopathogenesis • Influenza-like symptoms( IFN, lymphokins): • DTH and inflammation(Tcell, PMNs): • Immune-complex disease(AB, complement): • Hemorrhagic disease( T cell,AB, Complement): • Postinfection cytolysis( T cells): enveloped viruses • Immunosuppression: HIV; CMV; measlesvirus and influenza

30. Persistence Long term persistence of virus results from two main mechanisms: • a) Regulation of lytic potential • b) Evasion of immune surveillance

31. Persistence vs. Clearance

32. Antiviral Immunity

33. Overview of the Immune System

34. Components of the Immune System complement, interferon, TNF etc. macrophages, neutrophils NK cell antibodies T cells; other effectors cells

35. Innate or Nonspecific Immunity

36. Innate or Nonspecific Immunity • Anatomic andPhysiologic Barriers: Intact skin / Mucus membrane Temperature /Acidity of gastric juices Protein factors • Phagocytic Barriers : 3 major types of phagocytic cells • Inflammatory Barriers and fever • Mucociliary clearance

37. IFN • Interferons are proteins produced by cells infected with viruses, or exposed to certain other agents, which protect other cells against virus infection or decrease drastically the virus yield from such cells. Interferon itself is not directly the anti-viral agent, but it is the inducer of one or many anti-viral mechanisms • Anti-tumor and regulation of immunity

38. Interferon inducing agents • (1) Viruses. • (2) dsRNA is a potent inducer, both viral intermediates, and synthetic polyI-C.   • (4) Certain Bacterial infections, and the production of endotoxin.   • (5) Metabolic activators/inhibitors. Mitogens for gamma induction, also a variety of tumor promoters induce IFNs. , in particular PTA-phorbol tetradecanoate acetate, butyrate, dexamethasone

39. Properties of human interferons

40. Activities of interferon

41. Mechanism of action • Release from an initial infected cell occurs • IFN binds to a specific cell surface receptor on an other cell • IFN induces the “antiviral state” : synthesis of protein kinase, 2’5’ oligoadenylate synthetase, and ribonuclease L • Viral infection of the cell activates these enzymes • Inhibition of viral and cellular protein synthesis occurs

45. Diseases currently treated withIFN-alpha and IFN-beta • hepatitis C • hepatitis B • papilloma warts and early trials with cervical carcinoma • Kaposi sarcoma of AIDS, • colon tumors • kidney tumors ( usually in combination with other drugs). • Basal cell carcinoma • Breast cancer combined with tamoxifan.

46. Nature killer/ NK cell NK cells are Activated by IFN-alpha/beta NK cells are Activated by IFN-alpha and IL-2 and Activate macrophage NK cells target and kill virus infected cells

47. NK cell

48. Macrophages • Macrophages filter ciral particles from blood • Macrophages inactivate opsonized virus particles • Macrophages present viral antigen to CD4 T cells

49. Complement • Enhancing neutralization of Antibody • Enhancing phagocytosis of virus particles • Lysis

50. Specific immunity Active/passive