PATHOGENESIS OF VIRAL DISEASES

1. PATHOGENESIS OF VIRAL DISEASES General virology (4)

2. Infection and Disease • Disease only results when: • A significant proportion of essential cells, which cannot be replaced by regeneration, are destroyed • The rate of cellular destruction in a vital organ exceeds the rate of regeneration and organ failure occurs • nfection of vascular endothelium is sufficiently severe as to produce circulatory disturbances • The virus causes immunosuppression by destroying lymphoid tissue • By suppressing muco-ciliary activity, viral replication allows bacteria normally non-pathogenic to multiply at the expense of the host

3. Types of Disease • Local infections • Viruses never disseminate via the blood, lymph or neurones to infect other parts of the body • Systemic infections • viruses spread readily through the body, mostly via the lymphatic and blood vascular systems, to produce systemic disease

4. The Course of Infection • The initiation of infection The principal portals of entry are: • Tonsils and pharynx • Respiratory tract • Skin, including the cutaneous capillary network that is important for the initiation of arthropod-borne infections • Intestines • Placenta (in respect of the foetus) • Genital tract

5. The Course of Infection • Incubation period • Viraemic diseases. Dissemination of infection may be occurring in three stages: • Spread of virus to the blood from the portals of entry. • Dispersion of virus to all parts of the body by means of the vascular system (viraemia). • Passage of virus from the blood into the extra-vascular tissues. • Neural spread. E.g. rabies

6. The Course of Infection • The clinical phase • Replication of virus in the target organs results in the destruction of the infected cells and, if the lesions produced are sufficiently severe, leads to the development of clinical signs. • Initially, the abnormalities are usually those associated with fever but these are rapidly reinforced by signs referable to the particular part of the body most severely infected. Eventually either death or recovery ensues.

7. The Course of Infection • Period of infectivity • In some diseases, the infected subject becomes infective for others before the end of the incubation period. In others, infectivity does not develop until clinical signs are present. These differences are related to such factors as the quantity of virus excreted and the proximity of the target organ to the main portal of exit. • Once antibody has appeared in the circulation, virus is eliminated from the tissues, infectivity for others thereby being lost. In some cases, however, virus may persist in certain tissues for months or even years. • Not all carriers excrete virus and even when excretion does occur, insufficient virus may be liberated to infect another individual.

8. Viral Strategies Used to Evade Host Defences • Non-cytocidal infection. • Failure to shut down host cell nucleic acid and protein synthesis. • Cell-to-cell spread. • Membrane fusion • Infection of non-permissive, resting, or undifferentiated cells. • Failure to up-regulate viral gene expression • Little or no viral antigen on cell membrane. • Infection with restricted viral gene expression • Loss of viral antigen by "stripping“ and endocytosis • Destruction of immune effector cells and macrophages

9. Viral Strategies Used to Evade Host Defences • Down-regulation of MHC antigen expression. • Viral proteins inhibit production or maturation of MHC proteins • Evasion of cytokines. • Viral proteins interfere with interferon and other cytokine actions • Evasion of neutralising antibody. • Production of large amounts of soluble viral protein that "soaks up" antibody • Masking of viral epitopes by carbohydrates on glycoproteins • Induction of non-neutralising antibody. • Production of low-affinity antibody or antibody reacting with irrelevant epitopesman immune decoy

10. Viral Strategies Used to Evade Host Defences • Enhancing antibody • Antibody attached to virus enhances infection of host cells • No antibody produced • Nonimmunogenic agent • Induction of immunologic tolerance • Induction of clonal anergy or specific suppressor T cells • Sequestration in immunologically privileged tissues • Viral replication in sites inaccessible to afferent or efferent limbs of immune response • Integration of the viral genome into the host cell genome • Recombination-like process • Genetic/antigenic drift • Mutations leading to antigenic variants