Published on March 9, 2014
Virus-Host Interactions: Viral Infections Virus-host interactions may be considered at different levels; the cell, the individual and the community At the cellular level, viral infection may cause a broad spectrum of effects a) Cytocidal effect b) Cellular proliferation c) Steady state infection
Cellular injury may be due to a number of causes 1) Early or nonstructural viral proteins often cause a shut-down of host protein and DNA synthesis 2) Large amounts of viral macromolecules that accumulate in the infected cell may distort the cellular architecture and exert a toxic effect 3) The permeability of plasma membranes may be altered 4) Many viruses produce alterations in the cytoplasmic membrane of infected cells 5) Certain viruses cause damage to the chromosomes of host cells (eg: measles, mumps, adenovirus, varicella, cytomegaloviruses)
Inclusion bodies Virus-specific intracellular globular masses which are produced during replication of virus in host cells They can be demonstrated in virus infected cells under light -microscope after fixation and staining They may be present in the cytoplasm (rabies virus), nucleus (herpes virus) or both (measles virus) Intracytoplasmic inclusions are found in cells infected with rabies virus (Negri bodies), vaccinia (Guarnieri bodies), molluscum contagiosum (molluscum bodies) and fowl pox (Bollinger bodies) Intranuclear inclusions were classified into two types by Cowdry (1934) Cowdry type A includes inclusion bodies of variable size and granular appearance (eg: herpes virus, yellow fever virus) and type B inclusions are more circumscribed and multiple (eg: adenovirus, poliovirus)
Demonstration of inclusion bodies helps in the diagnosis of some viral infections (Negribodies: presumptive diagnosis of rabies) Cytoplasmic inclusion body caused by rabies virus in brain tissue
Pathogenesis of viral infections Depending on the clinical outcome, viral infections can be classified as 1. Inapparent (subclinical) 2. Apparent (clinical or overt) a) acute b) subacute c) chronic Latent infections Herpes simplex and varicella-zoster viruses remain latent in nerve root ganglia, to be reactivated periodically HBV and HIV infections Slow viral diseases
Viruses enter the body through the following routes 1. Respiratory tract 2. Alimentary tract 3. Skin 4. Genital tract 5. Conjunctiva 6. Congenital
Routes of transmission of viral infections Route of transmission Viruses Respiratory tract Influenza, Parainfluenza, RSV, Measles, Mumps, Rubella, Rhinovirus, Adenovirus Coronavirus,Varicella-zoster, CMV, EBV Alimentary tract Poliovirus, Adenovirus, Hepatitis A, E viruses, Rotavirus, Norwalk virus Skin Herpes simplex, Papilloma viruses Molluscum contagiosum, Rabies virus Arboviruses, HBV, HCV, HIV, HTLV Genital tract Herpes simplex viruses, HBV, HCV HIV, Papillomaviruses Conjunctiva Some adenoviruses, Few enteroviruses
Congenital infection Many viruses are transmitted vertically from parent to progeny Congenital infection may occur at any stage from the development of the ovum up to birth In acute systemic infections, congenital infection usually leads to fetal death and abortion Rubella and cytomegalovirus produce maldevelopment or severe neonatal disease HIV, HSV, many tumor viruses cause congenital infection
Spread of virus in the body
Schematic illustration of the pathogenesis of poliomyelitis
Incubation period It is the time taken for the virus to spread from the site of entry to the target organs for the production of lesions Its duration is therefore influenced by the relation between the site of entry, multiplication and lesion The incubation period in HBV may be 2-6 months and in slow viral infections, many years Papillomas and molluscum contagiosum have long incubation periods, probably because the viruses multiply slowly
1. Non-Specific responses 2. Immunological responses Humoral immunity Cell-mediated immunity (CMI) a) b) 13
Non-specific responses 1. Age Most of the viral infections tend to be more serious at extremes of life Rotaviruses cause severe disease only in infants
2. Hormones Corticosteroids administration enhances most viral infections The particularly severe course of many viral infections in pregnancy may be related to the hormonal changes 3. Malnutrition Malnutrition interferes with the humoral and cell-mediated immune responses, therefore it can exacerbate viral infections (eg: measles – higher incidence of complications and a higher case fatality rate in malnourished children) 4. Body temperature Fever may act as a natural defence mechanism against viral infections as most viruses are inhibited by temperatures above 390C
5. Phagocytosis Macrophages phagocytose viruses and are important in clearing viruses from blood stream Polymorphonuclear leucocytes do not play any significant role 6. Interferons Interferons are a family of glycoproteins produced by cells on induction by viral or nonviral inducers Interferon by itself has no direct action on viruses but acts on other cells of the same species, rendering them refractory to viral infection On exposure to interferon, cells produce a protein (translation inhibiting protein, TIP) which selectively inhibits translation of viral mRNA
Types of interferons They are classified into three types 1. IFN-α It is induced by virus infection and produced by leucocytes It has antiviral activity 2. IFN-β It is also induced by virus infection but produced by fibroblasts and epithelial cells It also has antiviral activity
3. IFN-γ Produced by T-lymphocytes and NK cells, on stimulation by antigens or mitogens It is a lymphokine with immunoregulatory functions It enhances MHC antigens and activates cytotoxic T-lymphocytes, macrophages and NK cells Modulates antibody formation and supresses DTH Mechanism of action IFN-α and IFN-β induce the production of three enzymes namely protein kinase, an oligonucletide synthetase and an RNaseL. This leads to inhibition of viral protein synthesis but does not affect host protein synthesis
Immunological responses 1. Antibody-mediated immunity IgG, IgM, IgA antibodies are produced in response to virus infection IgG and IgM play a major role in blood and tissue spaces while IgA is more important in mucosal surfaces IgA is important in resistance to infection of the respiratory, intestinal and urogenital tracts
Antibodies may act in the following ways Neutralisation of virus which prevents attachment, penetration or subsequent events Antibody may attach to viral antigens on the surface of infected cells, rendering these cells prone to lysis by complement or destruction by phagocytes or killer lymphocytes Immune opsonisation of virus for phagocytosis and destruction of virus by macrophages
Cell-mediated immunity (CMI) CMI prevents infection of target organs and promotes recovery from disease by destroying virus and virus-infected cells. The different mechanisms involved for virus destruction are as follows 1. Cytolysis by cytotoxic T-cells and Natural-killer (NK) cells 2. Antibody-dependent cell-mediated cytotoxicity (ADCC) 3. Antibody-complement-mediated cytotoxicity
Laboratory diagnosis of viral infections Following are indications for laboratory diagnosis of viral infections 1. For proper management of certain diseases 2. Diagnosis of diseases caused by viruses for which antiviral chemotherapy is available (herpes viruses) 3. Screening of blood donors for HIV and HBV 4. Early detection of epidemics like influenza, poliomyelitis, encephalitis etc to initiate appropriate control measures In the laboratory, the following methods are commonly employed 1. Direct demonstration of virus and its components 2. Isolation of virus 3. Detection of the specific antibodies
1. Direct demonstration of virus and its components a) Electron Microscopy b) Immunoelectron microscopy c) Fluorescent Microscopy d) Light Microscopy e) Viral antigens can be detected by ELISA, RIA, latex agglutination f) Nucleic acid probes g) PCR
Detection of viruses in specimens by electron microscopy Specimen Viruses Faeces Rotavirus, hepatitis A virus, adenovirus, Norwalk virus, astrovirus Vesicular fluid Herpes simplex, Varicellazoster CSF Enterovirus, Varicella-zoster Urine Cytomegalovirus (CMV)
2. Isolation of virus This is the commonest method used in the diagnosis of virus infections The specimen should be collected properly and transported with least delay to the laboratory Most viruses are heat labile, therefore, refrigeration is essential during transport The methods used for isolation depend on the virus sought Since, many viruses (eg: adenoviruses, enteroviruses) are frequently found in normal individuals, therefore the results of isolation should always be correlated with clinical data
3. Detection of specific antibodies The demonstration of a rise in titre of antiviral antibodies strongly suggest the active infection (Ist sample – early in the course of the disease and the convalescent sample – 10-14 days later) Examination of a single sample of serum is meaningful when IgM specific antibodies are detected The serological techniques employed would depend on the virus, but those in general use are neutralisation, ELISA, haemagglutination inhibition, complement fixation test, immunofluorescence and latex agglutination tests
Serological diagnosis of viral infections
Microplate ELISA for HIV antibody: coloured wells indicate reactivity
HIV-1 Western Blot Lane1: Positive Control Lane 2: Negative Control Sample A: Negative Sample B: Indeterminate Sample C: Positive
Immunoprophylaxis 1. Active immunisation 2. Passive immunisation Active immunisation Viral vaccines a) Live viral vaccines b) Killed viral vaccines
Live viral vaccines They are prepared from Attenuated strain (eg: yellow fever vaccines) Temperature sensitive (ts) mutants (eg: influenza) Live recombinant viruses (eg: influenza) Advantages 1. A single dose of live vaccine is usually sufficient 2. They may be administered by the route of natural infection so that local immunity is induced
3. They induce a wide spectrum of immunoglobulins against the whole range of viral antigens 4. They also induce cell mediated immunity 5. They can in general be prepared more economically, and administered more convenientlly for mass immunisation Disadvantages 1. There is a risk, however remote, of reversion of virulence 2. The vaccine may be contaminated with potentially dangerous viruses (eg: oncogenic viruses) 3. Live viral vaccines are heat-labile and they have to be kept under strict refrigeration
4. Interference by preexisting viruses 5. The virus may spread from the vaccinees to contact 6. Some live viral vaccines may cause local but remote complications Killed viral vaccines Killed vaccines are prepared by inactivating viruses with heat, phenol, beta-propiolactone and formaldehyde Advantages 1. Safety and stability 2. They can be given in combination as polyvalent vaccines 3. There is no danger of spread of virus from the vaccinee
Disadvantages 1. Multiple injections are needed 2. These vaccines have to be given by injection, therefore, local immunity (IgA immunoglobulins) immunity fails to develop 3. Cell mediated immunity is not induced Passive immunisation Passive immunisation with human gammaglobulin, convalescent serum or specific immune globulin gives temporary protection against many viral diseases (eg: measles, mumps and infectious hepatitis) Indicated only when nonimmune individuals who are at special risk are exposed to infection Combined active and passive immunisation is an established method for the prevention of rabies
Commonly used viral vaccines Type of vaccine Mode of preparation Live viral vaccines Measles Attenuated virus grown in cell culture Mumps Attenuated virus grown in chick embryo fibroblast culture Rubella Attenuated virus grown in cell culture Poliomyelitis (Sabin) Avirulent strain grown in monkey kidney cell culture Inflenza a)Live (attenuated) b) Live (mutant) c) Live (recombinant) a)Virus attenuated by serial passage in eggs b)Use of ts mutant which are avirulent c)Recombinants with surface antigens of new strains and growth characters of established strains Yellow fever (17D) Attenuated virus grown in chick embryo Killed viral vaccines Hepatitis B HBs Ag from human carrier sera Rabies Influenza (subunit) Virus disintegrated with sodium deoxycholate Poliomyelitis (Salk) Virulent strain grown in monkey kidney cell culture
Chemoprophylaxis and chemotherapy of viral diseases Mode of action Antiviral agents Inhibits viral DNA polymerase a) b) c) Inhibits reverse transcriptase a) b) c) Inhibits proteases a) b) c) d) Acyclovir Ganciclovir Ribavirin Active against a) b) c) Herpes simplex, VZV Cytomegalovirus RSV, Lassa virus Zidovudine Dideoxycytidine Dideoxyinosine HIV Indinavir Nelfinavir Ritonavir Saquinavir HIV Blocks penetration of virus into cells Amantadine Influenza virus Inhibits protein synthesis Interferons Many viruses Table: Antiviral agents and their modes of action
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