Viral Pathogenesis PDF

Viral Pathogenesis Asmaa Omar Professor of Clinical Pathology- Faculty of Medicine- Assiut University  ANTIVIRAL CHEMOTHERAPY The greatest success in antiviral chemotherapy has been achieved by using: The stages of attachment of virus to host cell Stage of uncoa...

Viral Pathogenesis Asmaa Omar Professor of Clinical Pathology- Faculty of Medicine- Assiut University  ANTIVIRAL CHEMOTHERAPY The greatest success in antiviral chemotherapy has been achieved by using: The stages of attachment of virus to host cell Stage of uncoating of the viral genome Reverse transcription of certain viral genomes Regulation of viral transcription Replication of viral nucleic acid inhibitors of nucleic acid synthesis. Translation of viral proteins Assembly Maturation Release of progeny virus  Viral genetics The study of viral genetics falls into two general areas: (1)mutations and their effect on replication and pathogenesis (2)the interaction of two genetically distinct viruses that infect the same cell. (3)In addition, viruses serve as vectors in gene therapy and in recombinant vaccines. two areas that hold great promise for the treatment of genetic diseases and the prevention of infectious diseases.  MUTATIONS Mutations in viral DNA and RNA occur by the same processes of base substitution, deletion, and frameshift the most important practical use of mutations is: 1- in the production of vaccines containing live, attenuated virus. These attenuated mutants have lost their pathogenicity but have retained their antigenicity; therefore, they induce immunity without causing disease. 2- Antigenic variants such as those that occur frequently with influenza viruses, which have an altered surface protein and are therefore no longer inhibited by a person’s preexisting antibody. The variant can thus cause disease, whereas the original strain cannot. 3- Human immunodeficiency virus and hepatitis C virus also produce many antigenic variants, that causes drug-resistant mutants. which are insensitive to an antiviral drug because the target of the drug, usually a viral enzyme, has been modified.  INTERACTIONS BETWEEN VIRUSES (1) Recombination is the exchange of genes between two chromosomes→ Reassortment is the term used when viruses with segmented genomes, such as influenza virus, exchange segments. Reassortment of influenza virus →major antigenic changes in the virus that are the basis for recurrent influenza epidemics. (2) Complementation can occur when either one or both of the two viruses that infect the cell have a mutation → a nonfunctional protein. The nonmutated virus “complements” the mutated one by making a functional protein that serves for both viruses. Such as complementation is hepatitis B virus (helper) providing its surface antigen to hepatitis delta virus (defective). Types of viral Vaccines  Live attenuated whole virus vaccines  Killed or Inactivated whole virus vaccines  Subunit vaccines;- purified or recombinant viral antigen  Recombinant virus vaccines  DNA vaccines 7 LIVE ATTENUATED whole VACCINES -Virus alive and fully immunogenic but no virulence - Example 17D strain of yellow fever Polio viruses Measles Killed or Inactivated whole virus vaccines - Simply inactivated by heat or chemicals, the outer virion coat should be left intact but the replicative function should be destroyed, must contain much more antigen than live vaccines. 8 Live vs Killed vaccines Feature Live Dead  Dose low high  no. of doses single multiple  need for adjuvant no yes  Duration of immunity many years less  antibody response IgG IgA, IgG  CMI good poor  Reversion to virulence possible not possible 9  Viral pathogenesis Three potential outcomes from a viral infection of a cell:  Abortive infection (failed infection)  Lytic infection (cell death) → a cytopathic effect that can be detected in the laboratory.  Persistent infection (infection without cell death) Persistent infection include: Chronic(Non-Lytic or productive) infection Latent( no virus synthesis )infections Recurrent infections 10  Effects of viral infection on host cell On entry into the body:  The virus may replicate and remain at the primary site  May disseminate to other tissues via the blood stream or the mononuclear phagocyte and lymphatic system  Or may disseminate through neurons. The blood stream and the lymphatic system are the predominant means of viral transfer in the body.  The transport of virus in the blood is termed viremia. The virus may be either free in the plasma or may be cell – associated in lymphocytes or macrophages. Replication of a virus in macrophages, the endothelial lining of blood vessels, or the liver can cause the infection to be amplified and initiate the development of secondary viremia. In many cases, a secondary viremia precedes delivery of the virus to the target tissue (e.g. liver, brain, skin) 12 Determinants of viral disease A. Nature of the disease and target tissue  Portal of entry of virus  Access of virus to target tissue  Tissue tropism of viruses  Permission of cells for viral replication  Viral pathogen (strain) B. Severity of disease and Cytopatic ability of virus Immune status : Competence of the immune system & poor immunity to the virus Virus inoculum size General health of the person :Nutrition & other disease influencing immune status Genetic make up of the person & age  Cytopathogenesis A. Cell death → a cytopathic effect due to cell lysis and that can be detected in the laboratory. B. Inclusion body formation The replication of virus in the cytoplasm or nucleus of infected cells → the accumulation of viral as well as cellular products ( may be nucleic acids, proteins, and so on ), can be stained and are referred to as inclusion bodies. Example Negribodies- rabies virus. Owl’s eye-Cytomegalovirus C. Cell fusion (syncytia formation) Enveloped viruses release specific proteins that become incorporated in to cytoplasmic membrane of the infected cell. These proteins act as magnets on the infected cell and attract uninfected cells to their surface. This results in infection of the originally un infected cell. Repetition of this process results in the aggregation of several infected cells. These aggregated cells eventually fuse, producing a giant multinucleated cell or syncytium  Host defense against Viral infection I- Non-specific Immune defense -Body temperature and fever → Limit replication & destabilized some virus - Interferon : - Interfere replication - Block viral protein synthesis - Inhibit cell growth - Interferon alpha and beta → activate NK cells - Interferon alpha and gamma → activate macrophage - Mononuclear phagocytic system →phagocytized viral & cell debris from virus infected cells →Macrophage-present antigen to T-cells. -NK-cells → kill virus infected cells 17 II-Specific host defense Antibody mediated Neutralize extra cellular virus Block viral attachment proteins opsonizes viruses for phagocytosis promote killing of target cells by the complement &ADDC Antibody resolves viral infections Antibody blocks viremic spread to target tissue 18  Classification of Viruses 1.Type of Nucleic Acid: -DNA (Ss /Ds) or RNA - Strategy of replication 2. By Size & morphology: - Type of symmetry (Icosahedral, Helical, Complex) - Number of capsomers - Presence or absence of envelope 3. By Presence of specific enzymes: - E.g: RNA and DNA polymerase - Neuraminidase - Reverse transcriptase 4. By Host tissue or cell tropism E.g: -Hepatitis viruses, HIV, etc 5. By Mode of Transmission 6. Host range : E.g. Animal, bacteria, plant 7. Type of disease E.g. encephalitis  Transmission of viruses  Route of transmission: depends on the source and the ability of the environment and the body route to the target tissue. Naked viruses can withstand drying, the effect of detergents, and extremes of pH and temperature →transmitted by the respiratory and fecal-oral routes and can often be acquired from contaminated objects. Enveloped viruses are comparatively fragile and require an intact envelope for infectivity →These viruses must remain wet and are spread: A. In respiratory droplets, blood, mucus, saliva, or semen. B. By injection Susceptibility to Transmission: The persistence of a virus in a community depends on the availability of a critical number of susceptible people. Immunization produced by natural means or by vaccination, is the best way of reducing the number of such susceptible people. The age of the person is an important factor in determining susceptibility to viral infection: Infants, children and the elderly are susceptible to different viruses. The competence of a person’s immune response and immune history determine how quickly and efficiently the infection is resolved and can also determine the severity of symptoms.  Epidemiology Terms - Epidemics occur over a larger geographic area and generally result from the introduction of a new strain of virus in to an immunologically naïve population. Pandemics are worldwide epidemics, usually resulting from the introduction of a new virus (example Influenza virus). Control of Transmission by quarantine, good hygiene, elimination of the vector, or immunization of the population.  Medically Important Viruses DNA Viruses Sometimes referred to as the HHAPPPy viruses: Herpes, Hepadna, Adeno, Papilloma, Parvo, Pox Most DNA viruses are double-stranded, show icosahedral symmetry, and replicate in the nucleus. Two DNA viruses break these rules: 1) Parvoviridae: This virus is so simple that it only has a single strand of DNA 2) Poxviridae: This virus is at the opposite end of the spectrum and is extremely complex. Although it does have double- stranded DNA, the DNA is complex in nature, coding for hundreds of proteins. This virus does not have icosahedral symmetry. The DNA is surrounded by complex structural proteins looking much like a box ( POX IN A BOX). This virus replicates in the cytoplasm Three of the DNA viruses have envelopes: Herpes, Hepadna, Pox Three are naked: PAP → Papilloma, Adeno, Parvo