Viral Pathogenesis Lecture Notes PDF

Pathogenesis of Viral Diseases Viral persistence  Viral Pathogenesis Viral pathogenesis is the process by which a viral infection leads to disease. The majority of viral infections are subclinical. It is not in the interest of the virus to severely harm or kill the host. T...

Pathogenesis of Viral Diseases Viral persistence  Viral Pathogenesis Viral pathogenesis is the process by which a viral infection leads to disease. The majority of viral infections are subclinical. It is not in the interest of the virus to severely harm or kill the host. The consequences of viral infections depend on the interplay between a number of viral and host factors.  Pathogenesis of Viral Diseases Steps in viral pathogenesis 1. Entry and primary replication 2. Viral spread and cell tropism 3. Cell injury and clinical illness 4. Recovery from infection 5. Viral shedding 1- Entry and primary replication: Most viruses enter the host through the mucosa of the respiratory or GIT in which the viruses replicate at these primary sites like influenza (respiratory infection) or rotaviruses (GIT infection); and produce the disease at the portal of entry with no further systemic spread. Other viruses are introduced into the blood stream by needles, blood transfusion (HBV, HIV) or by insect vectors (arboviruses).  Viral Entry Skin - 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. Conjunctiva and other mucous membranes - rather exposed site and relatively unprotected Respiratory tract - In contrast to skin, the respiratory tract and all other mucosal surfaces possess sophisticated immune defense mechanisms, as well as non-specific inhibitory mechanisms (cilliated epithelium, mucus secretion) which viruses must overcome. Gastrointestinal tract - a hostile environment; gastric acid, bile salts, etc. Viruses that spread by the GI tract must be adapted to this hostile environment. Genitourinary tract - relatively less hostile than the above, but less frequently exposed to extraneous viruses (?) 2- Viral spread and cell tropism: A) Many viruses cause only a localized infection as they are unable to spread. B) Viruses that spread further from the infecting site may use virus-encoded proteins to direct their transport within the cell in a way that enhances their spread via blood or along nerves (polio and rabies viruses). C) Other viruses, such as CMV, EBV and HIV, are carried by infected blood cells to distant parts. D) Measles virus, varicella-zoster virus and rubella virus all spread via the respiratory route but cause systemic infections. These viruses have a transient ‘primary viraemia’ just after infection to lodge in the RES (lymph nodes and spleen). The virus replicates there for a period of time (incubation period) without causing disease symptoms. This is followed  Cell Tropism Viral affinity for specific body tissues (tropism) is determined by – Cell receptors for virus. – Cell transcription factors that recognize viral promoters and enhancer sequences. – Ability of the cell to support virus replication. – Physical barriers. – Local temperature, pH, and oxygen tension enzymes and non-specific factors in body secretions. – Digestive enzymes and bile in the gastrointestinal tract that may inactivate some viruses. 3- Cell injury and clinical illness: Destruction of virus-infected cells in the target tissue and the physiologic alterations produced in the host by the tissue injury are partly responsible for the development of disease.  Cellular Pathogenesis Cells can respond to viral infections in 3 ways: (1) No apparent change, (2) Death, and (3) Transformation Direct cell damage and death from viral infection may result from – diversion of the cell's energy – Rupture of infected cell – shutoff of cell macromolecular synthesis – competition of viral mRNA for cellular ribosomes Indirect cell damage can result from – integration of the viral genome – induction of mutations in the host genome – inflammation – host immune response.  Most common damage viruses do? Direct damage to cells due to cell death/apoptosis Disruption of normal cell functions (eg protein synthesis, secretion, membrane trafficking) Immune response to virus infected cells Immune cell release of cytokines Virus hijacking/expressing host genes  Viruses might evoke autoimmunity Evoking an autoimmune response that affects uninfected cells – Mimicry – Exposing protected sites – Infecting immune cells - B cell antibody production against variety of proteins – Hyperexpression of MHC class I  4- Recovery from infection: The host either submits or recovers from the viral infection. Recovery mechanisms involve humeral, cell- mediated immunity, interferon and other cytokines. In acute infection recovery is associated with viral clearance.  Immune Response The immune response to the virus probably has the greatest impact on the outcome of infection. In the most cases, the virus is cleared completely from the body and results in complete recovery. In other infections, the immune response is unable to clear the virus completely and the virus persists. In a number of infections, the immune response plays a major pathological role in the disease. In general, cellular immunity plays the major role in clearing virus infection whereas humoral immunity protects against reinfection.  Immune Pathological Response Enhanced viral injury could be due to one or a mixture of the following mechanisms;- – Exaggerated response by T-cytotoxic cells e.g. HBV – Excessive ADCC or complement mediated cell lysis – Binding of virus-Ab complexes to cell surface Fc receptors, and thus increasing the number of cells infected e.g. Dengue haemorrhagic fever, HIV. – Immune complex deposition in organs such as the skin, brain or kidney e.g. rash of rubella and measles (immune complex diseases).  5- Viral shedding The last stage in the pathogenesis is shedding of the virus into the environment, shedding usually occurs from body surfaces involved in viral entry. It is the time at which the person becomes infectious to the contacts. In some viruses eg rabies human is a dead end and virus shedding does not occur.  Viral persistence 1. Chronic infection: in which the virus can be continuously detected, often at low levels; severe, mild clinical feature may be evident e.g. HBV (unfinished battle). 2. Chronic carrier: The patient who has been infected with certain virus continues to produce significant amount of the virus for a long period. e.g. HBV and HCV (Immune system adapts to the presence of the virus with no symptoms) 3. Latent infections: in which the virus persists in an occult or cryptic form most of the time. There will be intermittent flair-ups. HSV type 1 is latent in the trigeminal ganglia (virus hides and hits). 4. Slow virus infections: Prolonged period between the initial infection and the onset of the disease, which is usually measured in years. Subacute sclerosing panencephalitis (SSPE) which follows several years after measles virus infection, and the second disease is progressive multifocal leukoencephalopathy (PML) caused by JC virus a papovavirus (gradual change in host-microbe reaction) Clinical latency  Viruses are able to persist to cause chronic infection: (1) by escaping the immune system by constantly mutating e.g. HIV; (2) by downregulating the host immune system e.g. CMV, which codes for proteins that reduce the expression of major histocompatibilitycomplex (MHC) class 1 receptors on the cell surface; (3) by integrating in the host genome and replicating with the cells e.g. HIV, hepatitis B virus (HBV). Other slow infections in human are caused by Prions: protein-containing particles with no detectable nucleic acid that is highly resistant to inactivation by heat, formalin, and UV light that inactivate the viruses. They cause CNS diseases like Kuru and Creutzfeldt-Jakob diseases which are called transmissible spongiform encephalopathies. And also mad cow disease.  Infectious Cell death Signs/ Duration of progeny symptoms infection Acute + + + S