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CHAPTER 7 Pathogenesis of Viral Infection Viral pathogenesis is the process by which viruses produce disease in the host. The factors that determine the viral transmission, multiplication and development of disease in the host involve complex and dynamic interactions between the virus and the susceptible host. I. General Features 1. The process by which viruses cause disease in the host is called viral pathogenesis 2. Complex interactions between the virus and susceptible host result in disease 3. Epidemiology deals with distribution of determinants of disease in human population 4. Endemic disease is present at fairly low but constant levels 5. Epidemic infection is greater than usually found in the population 6. Pandemic infections spread worldwide 7. Infectivity is the rate of attack 8. Disease index is the number of persons who develop the disease divided by total number infected. 9. Virulence is the number of fatal or severe cases per total number of cases. 10. Incidence is the number of new cases of a disease within a specified period 11. Prevalence is the rate of cases existing in a population at risk II. Pathogenic Mechanisms A. TRANSMISSION AND ENTRY 1. Viruses can enter the host through break in the skin or via mucosal surfaces of various routes such as respiratory, gastrointestinal and genitourinary tracts 2. Viruses are transmitted via horizontal (common routes) and vertical (mother-tochild) transmission Viruses can also be transmitted to humans by animal or insect bites 3. After entry viruses have incubation periods (the time between exposure to the organism and appearance of the first symptoms) which vary from days to months B. SPREAD IN THE HOST 1. Viral infections cause either localized or systemic disease 2. There are two major routes that viruses use to spread are hematogenous (via the bloodstream) and neural (via nerves) 3. Poliovirus enters via fecal-oral route and multiplies in the small intestine but causes the major disease in the central nervous system 4. Some of the viruses that are spread by the neural route include herpes simplex viruses, poliovirus, rabies virus and certain arboviruses 5. Herpes simplex viruses (HSV) are transmitted in vesicle fluids, saliva and vaginal secretion and then travel via nerves to the CNS (neurons) C. TROPISM 1. Tropism is the capacity of viruses to infect a specific cell type within a tissue or organ 2. Tropism is determined by the specific interaction between viral surface proteins and cellular receptors 3. Some viruses such as HIV use a receptor and coreceptor 4. Different viruses may use the same receptor on the host cells 5. Enveloped viruses enter cells via receptor mediated endocytosis (viropexis) and fusion 6. Naked capsid viruses enter cells via viropexis without membrane-membrane fusion 7. Genetic changes in viral surface proteins alter viral tropism 8. Besides viral surface protein–cellular receptor interactions, viral gene expression also contributes to tropism III. VIRULENCE AND CYTOPATHOGENICITY 1. The ability of a virus to cause degenerative changes in cells or cell death is called cytopathogenicity 2. Virulence is defined as the ability of a virus to cause disease in infected host 3. Virulence can be measured as the degree of pathogenicity between viruses to cause disease 4. Viruses can cause abortive, lytic or latent infections 5. Features of cytopathic effects are morphological changes of the cell organelles followed by cellular lysis 6. Molecular and genetic determinants of viral virulence are located throughout the viral genome 7. Some viruses such as poxviruses and herpesviruses encode virokines and viroreceptors to help cells proliferate and avoid host defenses, respectively IV. PATTERNS OF VIRAL INFECTION AND DISEASE 1. Infections are more common than disease 2. Infection involves multiplication of virus in the host and disease represents clinical manifestations 3. The severity of the disease depends on the role of both viral and host factors in influencing viral infection and disease progression 4. Viral infections could be either lytic, latent or chronic 5. Persistent infection could be either latent or chronic 6. Some persistent viruses can cause oncogenic transformation 7. Most infections have some kind of acute phase followed by either being eliminated from the host or becoming latent or chronic 8. Acute viral infections that are cleared by the immune system are mainly due to RNA viruses such as picornaviruses, orthomyxoviruses and paramyxoviruses 9. Acute infection caused by herpesviruses is followed by a latent infection and periodic reactivation 10. Acute infection caused by hepatitis B (10-20% of cases) and C (~80% of cases) viruses is followed by a chronic infection with little or no damage to target tissue and accumulation of the injury over time 11. HIV acute infection is followed by a persistent infection (viral set point) and over time leads to impairment of the immune system, over production of HIV, opportunistic infection and full-blown AIDS 12. Some unconventional infectious agents cause slow, chronic infection without acute symptoms V. VIRAL TRANSFORMATION 1. Many DNA and some RNA viruses can transform normal cells into tumors 2. Malignant cells fail to respond to signals controlling the growth and location of normal cells 3. Malignant transformation of cells in culture can be accomplished by most DNA viruses and some retroviruses A. Transformation by DNA Human Viruses 1. Some oncogenic viruses cause tumors in their natural hosts 2. In nearly all cases viral transformation is the result of the continual expression of one or more viral genes that are directly responsible for the loss of growth control 3. Transformation by DNA viruses is analogous to lysogenic conversion B. Transformation by Retroviruses 1. Most retroviruses produce virions without causing host cell death 2. A DNA copy of the retroviral genome is integrated, but not at a specific site 3. Retroviruses may carry transforming oncogenes 4. Oncogenes encode a protein that interferes with cell signaling 5. Insertional mutagenesis causes inappropriate expression of a protooncogene adjacent to integrated viral genome 6. Human T-cell leukemia is caused by transactivating factor encoded in integrated HTLV-1 7. Transactivating factor turns on cellular genes, causing cell proliferation C. Transformation by other RNA Viruses 1. Hepatitis C virus (HCV) chronic infection increases the risk of cirrhosis of liver and hepatocellular carcinoma (HCC) 2. One of the HCV nonstructural proteins (NS3) may be involved in transformation. VI. HOST FACTORS 1. Host factors such as immune status, genetic background, age and nutrition play important roles in the outcome of viral infections 2. Elevated levels of chemokines or 32CCR5 allele slow down HIV disease progression 3. Homozygous 32CCR5 allele provides strong protection against HIV infection but increases the risk for symptomatic West Nile virus infection 4. Age of the host also plays an important role in the severity of some viral infections 5. Some viruses cause severe diseases in infants, whereas adults are more vulnerable to others 6. Hormones may influence viral infections such as polio, hepatitis A, B, E and small poxviruses 7. Malnutrition and personal habits (smoking) increase the severity of some viral infections 8. Fever and inflammation can combat viral infections VII. HOST DEFENSES A. Interferons 1. Interferons are chemokines produced by virally infected cells that inhibit virus production in infected and protect other cells 2. Interferons are not virus specific 3. Interferons are produced in response to accumulation of double-stranded viral RNA during viral synthesis 4. Interferon is the first line of defense against viral infection by activating two pathways that degrade mRNA and inhibit protein synthesis 5. Interferons inhibit viral protein synthesis by inducing cellular enzymes that require double-stranded RNA 6. Interferons inhibit protein synthesis but only in infected cells B. Other Host Defenses 1. Natural killer cells destroy virus-infected cells by secreting perforins and granzyme causing apoptosis 2. -Defensins and APOBEC3G reduce HIV infectivity C. Adaptive Immune Responses 1. Immunity could be either active, in that it is elicited by exposure to a pathogen or vaccine, or passive, in which it is transferred by immune serum 2. After viral infection, the first specific immune response is T-cell mediated where CD8 T-cells recognize viral antigen presented by class I MHC and kill virus infected cells by secreting perforins and granzyme and activating FAS proteins causing apoptosis 3. NK cell killing of infected cells is non-specific 4. Antibodies generated against surface antigens are most effective in eliminating virus. 5. Antibody in conjunction with complement can also kill virus-infected cells VI. Immunologic Interactions A. VIRUS INDUCED IMMUNOPATHOLOGY 1. Besides providing protection against viral infections, immune responses may also destroy target cells 2. Antigen-antibody complex, cytotoxic T lymphocytes, complement and cytokines mediate virus-induced immunopathology 3. Proinflammatory cytokines such as INF-, TNF- and some interleukins play important roles in clinical manifestation of virus-induced immunopathology 4. Chronic hepatitis B, measles, and mumps are immune mediated as opposed to direct cytopathic effects of the virus 5. Dengue hemorrhagic fever and shock syndrome is caused by antibodymediated immunopathology 6. Some autoimmune diseases are initiated by viral infections because of molecular mimicry of viral protein with a host protein B. VIRUS-INDUCED IMMUNOSUPPRESSION 1. Viral infections can cause suppression of the immune response 2. Viruses infecting either CD4+ helper T cells or antigen presenting cells cause immunosuppression 3. Viral gene products can also cause immunosuppression by stimulating proinflammatory cytokines 4. Immunosuppression in HIV infected individuals is due to direct and indirect depletion of CD4 T lymphocytes 5. In measles infection, the functions of CD4 and CD8 T lymphocytes are compromised 6. Immunosuppression in congenital rubella is due to reduced cellular immune response during fetal infection