INTRODUCTION Viruses are not considered true

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INTRODUCTION Viruses are not considered true living organisms because they are metabolically inert outside living cell and lack the metabolic properties that enable the simpler forms of life to live and replicate autonomously. Definition: The viruses are the acellular microorganisms which are submicroscopic in size, obligate intracellular parasites, which reproduce only in living susceptible cells, they contain only one type of nucleic acid (either DNA or RNA) and are produced from the nucleic acid only. They have no mitochondria, ribosomes or other organelles and do not posses energy producing enzyme system. They are completely dependent upon their cellular host for their protein synthesis, energy production and so on. Viruses are metabolically inert and are not sensitive to antibiotics. Some viruses may persists indefinitelyby the integration of their DNA with their host cells. They do not divide by binary fission and converted into a noninfective formas a necessary step of their multiplication. The viruses differ from bacteria in that they are: a. Much smaller, b. Lack the enzymes necessary for synthesis of protein and nucleic acid, c. Do not have cellular organisation or ribosome’s, d. Possess either DNA or RNA, e. Are resistant to antibiotics. CLASSIFICATION AND NOMENCLATURE OF VIRUS The viruses were formerly classified on the basis of tropism or affinity of the virus to different systems or organs of the body. Taxonomic classification of viruses is based on the following features: 1. Nucleic acid characteristics, including: type of nucleic acid (DNA/RNA), molecular weight, polarity (positive or negative sense nucleic acid), number of nucleic acid strands and segments, and enzymes. 2. Homology of nucleic acids. 3. Morphology shape and size. 4. Envelope – presence and absence. 5. Nucleocapsid symmetry. According to the tropism 1. Dermotropic viruses: Affinity for epithelial / dermal cells. e.g. Pox virus 2. Neurotropic virus: Affinity for nervous tissue. e.g. Rabies virus 3. Organotropic virus: Affinity for specific organs e.g. ICH 4. Panotropic virus: Affinity for more than one type of tissue. e.g. Distemper, Rinderpest virus 5. Tumor virus: Capability of producing the tumor e.g. Avian leukosis virus

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Classification of viruses into families based on chemical & physical properties Nucleic Acid Core

DNA

Capsid Symmetry Icosahedral

Virion: Enveloped or Naked Naked

. Complex . Icosahedral

Enveloped Complex coats . Naked

. Unknown or complex

Enveloped Enveloped

Helical

Enveloped

RNA

Physical Type of Nucleic Acid

Viral Family

ss ds circular ds ds ds ds circular ss ss ds segmented ss ss ss segmented ss diploid

Parvoviridae Papovaviridae Adenoviridae Herpesviridae Poxviridae Hepadnaviridae Picornaviridae Caliciviridae Reoviridae Togaviridae Flaviviridae Arenaviridae Retrobiridae

ss segmented ss ss segmented ss ss ss

Bunyaviridae Coronaviridae Orthomyzoviridae Paramyxoviridae Rhabdoviridae Flioviridae

Each viral family can be discussed based on the diseases caused by members of that family. Family Parvoviridae (parvoviruses) These are the smallest of the DNA-containing viruses. The linear DNA is single stranded and contains three to four genes. The virion is a naked icosahedron with 32 capsomers. The word parvo is taken from the Latin word parvus meaning small. The members of this family causing human infections are:

Parvoviridae B19 virus - causes fifth disease (erythema infectiosum), bone marrow aplasia and polyarthralgia. Target tissue is the erythroid cell Adeno-associated virus - cryptic in mucosal epithelial cells

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Family Papovaviridae (papovaviruses) The family name is taken from the disease caused by members of the group i.e., Papilloma, Polyoma and Vacuolating viruses. These are small DNA-containing viruses. The DNA is double-stranded and circular and contains five to eight genes. The virion is naked icosahedron with 72 capsomers. Members of this family include:

Papilloma virus - causes papillomas (warts) by infecting and causing hyperplasia of squamous epithelial cells.BK virus - causes a nephritis and/or urethritis. JC virus - etiological agent of progressive multifocal leukoencephalopathy. Family Adenoviridae (adenoviruses) The original virus in this group was isolated from adenoid tissue, thus the name adenovirus. The 89 members of this group all have double-stranded DNA which contains about 30 genes. The virion is a naked icosahedron. All members of this group have a common family antigen in the hexon capsomer and a second group-specific antigen in the penton capsomere. Species are determined by individual type-specific antigens found in the hexon capsomer. From the vertex at each of the 12 penton capsomers extends a long fiber with a knob at its end. This fiber contains a hemagglutinin that is antigenically distinct for each serotype.

Family Herpesviridae (herpesviruses) The family name is taken from the Greek verb, herpein, meaning "to creep." The name refers to the fact that the members of this family often cause latent recurring infections which progress slowly. These are medium-sized, enveloped, viruses containing double-stranded DNA. Genetically, this is the second most complex family of viruses; there are about 160

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genes in each species. The virion is an icosahedron with 162 capsomeres. There are eight human serotypes:  Human herpesvirus 1 (herpes simplex virus type 1)  Human herpesvirus 2 (herpes simplex virus type 2)  Human herpesvirus 3 (varicella-zoster virus)  Human herpesvirus 4 (Epstein-Barr virus)  Human herpesvirus 5 (cytomegalovirus)  Human herpesvirus 6 (human b-lymphotrophic virus)  Human herpesvirus 8 - causes Kaposi's sarcoma in AIDS patients  Human herpesvirus 7 - causes a cryptic infection of the T-helper cell Cercopithecine herpesvirus 1 (B virus, herpesvirus simiae) - causes a fatal encephalitis Family Poxviridae (poxviruses) The family name is taken from the major disease symptom caused by these organisms, the pox. The pox is an elevated lesion of the skin. The members of this family are the largest of all the viruses and are considered to be an evolutionary intermediate between the viruses and the bacteria. The viral particles (sometimes called elementary bodies) are somewhat rounded, brick-shaped, or ovoid, and have a complex structure consisting of an internal central mass, the nucleoid, surrounded by two membrane layers. The entire replication cycle occurs in the cytoplasm. The viruses causing human disease include:

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Variola virus Monkeypox virus Vaccinia Cowpox Orf virus Pseudocowpox virus

Family Hepadnaviridae The family name comes from the major disease caused by members of this group (hepatitis) and the type of nucleic acid found in the virion (DNA). These are enveloped viruses with a complex capsid symmetry. The nucleic acid is circular and partially double-stranded and encodes four genes. Hepatitis B virus (Dane particle) - causes human hepatitis, type B (serum hepatitis or long incubation hepatitis) and hepatocellular carcinoma

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Family Picornaviridae The family name comes from the word, pico, meaning small and RNA denoting the type of nucleic acid found in these viruses. These are naked viruses containing sufficient single stranded RNA to code for six to nine genes. They are the smallest of the RNA viruses. The naked virus has icosahedral symmetry with 32 capsomers. The members of this family causing human disease are: Poliovirus (3 serotypes) - the agent of polio, an infection of the anterior horn cells of the spinal cord Family Caliciviridae The family name comes from the Latin word, caliculus, meaning "cup-shaped." In electronmicrographs these viruses have the appearance of a small cup in the shape of the Star of David, i.e., a six-pointed star. These are naked icosahedral viruses containing linear singlestranded RNA coding for four to six genes. These viruses are morphologically similar to the Picornaviridae but about 25% larger. There are five antigenic types. The members of this family causing human disease are: Norwalk agent - the cause of epidemic viral gastroenteritis, also called summer diarrhea Hepatitis E virus - the agent of endemic hepatitis, a disease with a high mortality rate among pregnant patients

Family Reoviridae (reoviruses) The name is derived from the phrase "respiratory enteric orphan viruses." The more than 150 members of this group have segmented (10-12 segments) double-stranded RNA which contains 20-30 genes. The virions are naked double icosahedrons with 32 large capsomeres in the outer capsid. The viruses in this family causing human disease are:

Colorado tick fever virus - causes encephalitis Rotavirus - agent of acute infantile diarrhea, also known as winter diarrhea

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Family Togaviridae The name is derived from the Latin word, toga, meaning "coat," which refers to the fact that the icosahedral virion has an envelope. It is thought that the capsid contains 32 capsomeres. The nucleic acid is single-stranded RNA. Members of this family are:  Rubella virus - the agent of rubella (German measles)  Eastern equine encephalitis virus - causes encephalitis  Western equine encephalitis virus - causes encephalitis  Venezuelan equine encephalitis virus - causes encephalitis  Sindbis virus - causes fever, rash, arthritis  Semliki forest virus - causes encephalitis  Chikungunya virus - causes myositis and arthritis  O'nyong-nyong virus - causes fever, rash and arthralgia  Ross river virus - causes fever, rash, arthralgia Family Flaviviridae

The name is taken from the Latin word flavus, meaning "yellow." This refers to the fact that this is the family of the yellow fever virus. These are enveloped viruses containing singlestranded RNA. Their morphology is not well defined. The members of this family causing human disease are:

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Yellow fever virus - causes yellow fever, a hepatitis Dengue virus - causes dengue, a generalized viral infection Hepatitis G virus - causes acute hepatitis via blood transfusions

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Family Arenaviridae The name is derived from the Latin word, arenaceous, meaning "sandy." This refers to the electronmicrographs of the virus which show they have a granular or sandy surface. The granular appearance may be due to the presence of ribosomes in the virus. They contain single-stranded segmented RNA. Their complex morphology is hidden with an envelope. These viruses commonly produce chronic carrier states in their host. The members of this family causing human disease are:

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Lymphocytic choriomeningitis virus - agent of lymphocytic choriomeningitis Junin virus - agent of Argentinean hemorrhagic fever Bolivian hemorrhagic fever virus - agent of Bolivian hemorrhagic fever Lassa fever virus - agent of Lassa hemorrhagic fever

Family Coronaviridae The name refers to a characteristic halo or corona which surrounds each virion. The enveloped virion with a complex morphology contains single-stranded RNA. A member of this family causing human disease is the Coronavirus - causes the common cold Family Retroviridae The name is derived from the fact that these viruses contain a reverse (retro) transcriptase, i.e., RNA-dependent DNA polymerase. This family contains all of the RNA-containing tumor viruses. Superficially they resemble the orthomyxovirus but they have a more complicated internal structure. The segmented RNA contains 20-30 genes.

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Human infections caused by members of this family include: Human T-cell lymphotrophic virus - causes adult leukemia Human immunodeficiency virus - causes acquired immunodeficiency syndrome (AIDS)

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Family Bunyaviridae This group is named after Bunyamwera, Uganda where the type species virus was isolated. These are enveloped helical viruses containing segmented single-stranded RNA which is of sufficient size to allow for 20-50 genes. All members of this group are spread by arthropods.

Members of this family causing human disease are:  California encephalitis virus - causes encephalitis  Hantaan virus - causes Korean hemorrhagic fever, respiratory/renal disease (Muerto Canyon fever or hantavirus pulmonary syndrome)  Sandfly fever virus - causes a syndrome of fever, myalgia, retroorbital pain and conjunctivitis  Rift valley fever virus - causes a hemorrhagic fever  Crimean-Congo hemorrhagic fever virus - causes a hemorrhagic fever Family Orthomyxoviridae The members of this family are all influenza viruses which reproduce in mucous membranes. Myxo is a Greek word meaning mucous. The viruses contain a segmented single-stranded RNA genome and exhibit helical symmetry. They have a layer of surface projections, called spikes, as part of their outer wall, as well. These are major antigenic determinants. The genome consists of eight pieces of RNA. They are exceptions to the rule that RNA viruses replicate in the cytoplasm as they replicate in the nucleus. The target tissue is the upper and lower respiratory tract. Members of this family causing human are: Influenza viruses, types A, B, C - cause influenza Family Paramyxoviridae The members of this family are morphologically similar to the Orthomyxoviridae but are larger. They exhibit helical symmetry and have an envelope, segmented single-stranded RNA and 15-25 genes.

Members of this family causing human disease are:

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Mumps virus - causes an infection of the parotid gland Measles virus (rubeola virus) - causes: Measles - an infection of mucosa and skin epidermal cells Subacute sclerosing panencephalitis

Family Rhabdoviridae The family name is derived from the Greek word, rhabdos, meaning mad which refers to the disposition of animals infected with the rabies virus. This is a bullet-shaped virus with an envelope and single-stranded RNA.

Members of this family causing disease are:  Vesicular stomatitis virus - causes vesicular stomatitis, an infection of the oral mucosa  Rabies virus - causes rabies, an encephalitis

Family Filoviridae The family name is derived from the filamentous form of the virus. These are enveloped helical nucleocapsids which have a uniform diameter of 80 nm but a variable length up to 14,000 nm. They are pleomorphic with branched, circular and U-shaped forms common. They contain linear single-stranded RNA. Members of this family include:

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Marburg virus - causes acute hemorrhagic fever Ebola virus - causes acute hemorrhagic fever

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Two other groups which are not taxonomic groups but rather ecologic groups. These are: Arboviruses The name indicates that these are arthropod-borne viruses, i.e., they are transmitted by a member of the Arthropoda (insects, mites, ticks, lice). The arboviruses include the Togaviridae (except for the rubella virus), the Bunyaviridae, some of the Rhabdoviridae, some of the Arenaviridae and some of the Reoviridae. Oncoviruses Those viruses that are oncogenic or cancer-causing belong in this group. This includes all of the Retroviridae as well as some of the Papovaviridae, Adenoviridae, Parvoviridae, and Herpesviridae. Thus oncoviruses are both RNA- and DNA-containing types. Unclassified viruses 

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Hepatitis C viruses - A group of viruses which resemble picornaviruses in morphology and are antigenically distinct from hepatitis A and hepatitis B virus. They have single stranded linear RNA and an envelope. They cause acute hepatitis. Hepatitis D virus (Delta agent) - A defective virus which requires coinfection with the hepatitis B virus (a helper virus) in order to replicate. It has circular, single-stranded RNA and an envelope. In reality this is a viroid. However, it has historically been classified as a virus. Astrovirus - A naked five to six-pointed star-shaped virus with single-stranded RNA. It causes acute gastroenteritis.

International Committee on Taxonomy of Viruses as of April, 1998. The order of presentation is set by (1) nucleic acid type and strandedness (RNA or DNA, single or double stranded); (2) genome characteristics (e.g. segmentation, genome sense- positive, negative or ambisense); and (3) replication and transcription strategy. Determination of Nucleic acid type of viruses 

Treatment with DNAase or RNAase: Treatment of the virus suspension / preparation with RNAase or DNAase The virus inactivation following exposure to one of the enzyme & not after treatment with other indicates possessing of the nucleic acid type homologus to the acting enzyme.

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Treatment with halogen derivatives of deoxyuridine: Treatment of the virus infected cell cultures with halogen derivatives of deoxyuridine which specifically inhibit viral RNA synthesis & hence multiplication of DNA viruses. Labelling of virus with radioactive nucleic acid precursor such as thymidine C14 & uridine C14: These precursors are added to duplication virus infected cell culture. Radioactivity with virus treated with label thymidine indicates virus is DNA. Radioactivity after treatment with label uridine indicates virus contains RNA. Staining of virus infected cells with flurochrome acridine orange: Viral DNA generally fluoresces yellow-green on microscopic examination with ultraviolet light & RNA generally fluoresces flame red. Treatment of viral preparation with uranile acetate & examination with electron microscope: The electron dense uranile compound selectively stains the DNA coat of DNA viruses. For viruses produce intracellular inclusion, staining of the fixed cells with methyl green pyronin: with this staining the inclusion stain green if the viral DNA is present & red if viral RNA is present.

REPLICATION OF VIRUS The replication cycle of the virus can be divided into a series of define stages which are: i. Attachment ii. Penetration iii. Uncoating (eclipse) iv. Viral synthesis v. Assembly of virus vi. Release of virus Attachment It occurs as a result of the contact between the virus and the host cell in the suspension through random process. Tailed phage or “T” series attach to E. coli by means of tail fibres. Orthomyxo & paramyxo viruses bind via the hemagglutinin, an envelope glycoprotein to glycolipid cellular receptors. Most entero viruses of human, swine & chicken are highly host specific because only the homologus cells carry receptors to which viruses can bind. The infectivity of some viruses is limited to a single species e.g. feline panleukopenia virus because receptors only occur on feline cells while other viruses e.g. rabies are able to infect the nerve cells of all mammals because their receptors are common to neural cells of all mammals. Sometimes only certain strains of a virus have a tropism for a particular cell type e.g. neurotropic strains of NDV has tropism for neural cells. Penetration Electron microscope & other data show that virions can enter cells by at least 3 different mechanism endocytosis, fusion and translocation. Endocytosis: The majority of mammalian cells are continuously engaged in receptor mediated endocytosis, a specific process for the uptake of essential macromolecules. Following attachment to the receptors, virions move down into coated pits. Thes pits coated

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with clathrin, fold inward to produce coated vesicle that enter the cytoplasm & fuse with a lysosome to form a phagolysosome. In enveloped viruses, the envelope of endocytosed virions fuses with the lysosomal membrane, releasing the viral nucleic acid into the cytoplasm. Pox virus have a highly specialized mechanism for penetration & uncoating. They enter cells by engulfment in phagocytic vacoules & are breakdown into cytoplasm. The degradation of this core requires the synthesis of a special “uncoating protein”. Fusion with plasma membrane: The first involves fusion of the viral envelope with the outer cell membrane, thereby liberating the naked nucleocapsid in the cytoplasm. Paramyxo viruses and herpes viruses enters cells by this mechanism. Translocation: It generally occurs in naked icosahedral viruses. These viruses may be able to pass directly across the cell membrane without becoming engulfed in phagocytic vacoules. In case of phage penetration it is actively performed by the virus particle which results in the transfer of genetic materials into the host cell. Penetration of thick rigid cell wall is achieved by lysozyme, which seems to be a component of phage tail. Once enzymic digestion of the cell wall in the vicinity of the tail plate has occurred, the tail sheath contracts and the tail core is injected through cell wall. The injected materials consist of wholly the DNA which no more than 3 % of the total protein. Maximum penetration rate occurring at 370C but no penetration occurs at 00C. Eclipse: The eclipse phase of virus replication covers the entire period from the moment when the virus particle penetrates into the cell to moment of reappearance of progeny viruses. This phase is also called as “vegetative phase” or “dark period” of replication cycle. Viral Synthesis Synthesis of nucleic acid Synthesis of NA- different viral strategies : Baltimore originally used the different mRNA strategies as a basis for grouping viruses as follows:Group 1: Double stranded DNA (ds DNA): 1A; herpes, adeno, papova 1B; pox, asfar Group 2: Single stranded DNA (ss DNA): parvo, circo Group 3: ds RNA: reoviridae Group 4: ss RNA with positive sense (+ ss RNA): picorna, calici, toga, flavi and corona Group 5: -ss RNA: orthomyxo, bunya, arena Group 6: ss RNA with reverse transcriptase: retro viruses Group IA. (Herpes, adeno, papova).The ds DNA uses host cell polymerase DNA-dependent RNA polymerase (cellular transcriptase) to transcribe mRNA. (mRNA is translated into early proteins necessary for viral NA synthesis). Group IB. (pox and irido viruses).Theses larger viruses contain their own DNA-dependent RNA polymerase (viral transcriptase)which enables mRNA to be transcribed in the cytoplasm from viral DNA. Group 2: ss DNA: parvo, circo. The ssDNA is converted to dsDNA using host cell enzymes present during normal synthesis. The dsDNA then produces mRNA.

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Group 3: ds RNA: - reoviridae. The RNA is segmented and viral RNA polymerase carried within the virion transcribes each segment to a separate mRNA. Group 4: ss RNA with positive sense: Some viral RNA can function as mRNA to produce genome-sized polyprotein. Group 5: -ss RNA the viral RNA cannot function as message so the virus contains a structural RNA polymerase which transcribes its negative RNA into mRNA (virion associated RNA dependent RNA polymerase). Group 6: ss RNA with reverse transcriptase. Retroviruses are unique amongst + ss RNA viruses because they convert to ds DNA utilizing the reverse transcriptase (RT) enzyme (an RNA dependent DNA polymerase, virion associated). Synthesis of Protein Viral proteins are translated from viral mRNAs at the ribosomes in the cytoplasm. Each length of viral mRNA either codes for one protein or for several proteins. Viral proteins mature between synthesis at the ribosomes and assembly into the virus particle. Maturation involves 3 processes1. Glycosylation: which is the addition of oligosaccharides onto proteins, affects their charge, theri mobility through the endoplasmic reticulum and their antigenicity. 2. Disulphide bridging: which may be within the molecule or inter the molecule affects the folding size and conformation and obviously the antigenicity of the molecule. 3. Cleavage of terminal peptides: enables immature and non-infectious envelope spike proteins Assembly of Virus Assembly of nucelocapsid takes place separately in the cell. A. Nucleocapsid: Nucleocapsid assembly occurs at the site where nucleic acid is formed e.g. the nucleus for most DNA virus or the cytoplasm for most NRA virus. The aggregations of nucleocapsids may be visible as inclusion bodies. With unenveloped viruses the nucleocapsid become packed into a crystalline array of new virus particles. B. Enveloped virus: All mammalian viruses with helical nucleocapsid as well as some cubical viruses acquire an envelope by budding through cell membranes. Different viruses bud from different sites in the plasma membrane (Ortho & paramyxo, rhabdo, arena, toga & retro viruses). Some bud from intra cytoplasmic smooth ER (flavi virus, bunya & corona viruses) or from the nuclear membrane (herpes virus). Budding may be regarded as a non physiological form of exocytosis. The process begins with insertion of the complete viral glycoprotein into the appropriate cellular membrane. During this process the viruses gain the phospholipid, glycolipid or cholesterol. Release of the Virus: There are basically two mechanisms for the release of mature virions from the infected cell.  Most non-envelope viruses that accumulate within the cytoplasm or nucleus, release occurs only when the cell lyses. These may occur shortly after the completion of viral replication causing immediate release of the progeny of viruses. These happen

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particularly in case of picorna viruses. On the other hand, Parvo viruses accumulate within the cell nucleus & are not released until the cell slowly degenerates & dies. Most enveloped viruses are released by budding, a process which an occur over a prolong period without much damage to the cell, hence may such viruses (e.g. arena & retro virus) are non cytopathogenic & are associated with persistent infections. However some enveloped viruses that are released by budding are cytolytic, e.g. the  herpes virus. Orthopox viruses maybe released as enveloped forms by budding from plasma membrane or as non enveloped forms, by cell lysis; both form are infectious. The release of 1 st virion into the fluid material technically marks the end of replication cycle

INFECTION AND SPREAD OF VIRUS Host-Virus Relationship at Multi-Cellular Level / At the Level of Intact Animal The routes of viral invasion of the body may be listed as:1) Mucous membrane of respiratory, alimentary and genital tracts. 2) Skin and conjunctiva 3) Direct tissue implantation by bite of inoculation 4) Transplacental infection of the fetus. 1. Mucous membrane of respiratory, alimentary and genital tracts: Following the establishment of the infection in the respiratory tract, the subsequent events and the nature of disease produced will vary according to the invasiveness for the virus. Those that lack this invasiveness will produce local infections in R.T. such as respiratory disease produced by myxo virus, adeno-viruses; there are some viruses, which invade by the respiratory tract by causing generalized disease by virtue of their invasive characters such as rinderpest, distemper, rabbit pox, ectromelia (mouse pox). Mouth and nasopharynx are the common grounds to the respiratory and alimentary tract infections. Viruses of animals that initiate infection by entry through the respiratory tract Family / Genus Herpesviridae / several genera Adenoviridae / Mastadeno virus and Aviadeno virus Paramyxoviridae / several genera Orthomyxoviridae / Influenza virus A Corona viridae / Corona virus Picornaviridae / Rhinovirus and Aphthovirus

Virus Herpes viruses of many animals Adenoviruses of many animals Parainfluenza and respiratory syncytial viruses Influenza viruses of swine and horses Infectious bronchitis virus of chicken Rhinoviruses of many animals, FMDV

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Viruses of animals that initiate infection by entry through the intestinal tract Family / Genus Virus Parvoviridae / Parvo virus Feline panleukopenia virus Reoviridae / Rota virus Rota viruses of many animals Coronaviridae/ Corona virus Enteric corona viruses of animals Rinderpest, African-swine fever, FMD and vesicular exanthema are among the generalized viral infection which may initiated by ingestion. Helminths may serve as intermediate host in the transmission of some viral e.g. swine influenza by swine lung worm, Hog cholera by swine lung worm, lymphocytic chorio meningits by trichinella spiralis. The uro-genital tract may be the site of primary lesion in Herpes infection, contagious pustular vulv-vaginitis in cattle, lymphogranuloma in human. Infection in this case is by venereal transmission. 2. Skin and conjunctiva: Feet, mouth, muzzle and other hairless sites are particularly exposed to minor degrees of trauma. Local infections at these sites are exemplified by the ulcerative stomatitis due to Bvirus in monkeys, herpes simplex infection in man / papular stomatitis in cattle and cowpox. The conjunctiva behaves in many respects as an extension of the upper respiratory tract. It is certainly involved in early stages or numbers of upper respiratory tract infections as in the case of common cold and measles. Viruses that initiate by entry through the skin, oral mucosa, genital tract, eye Route Minor abrasions (skin or mucosa)

Family / Genus Papova viridae / Papilloma virus Herpesviridae / several genera Poxviridae / several genera Picornaviridae / enterovirus Rhabdoviridae / Vesiculovirus

Arhtropod bite

Pox viridae / several genera Retroviridae / Lentivirus Rhabdoviridae / Vesiculovirus

Arthropod bite

Asfarviridae / asfivirus Reoviridae/ Orbivirus

Bite of vertebrate

Contaminated needles

Rhabdoviridae / Vesiculovirus Retroviridae / Lentivirus Rhabdoviridae / Lyssa virus Papovaviridae / papilloma

Virus Papilloma viruses of many animals Herpes virus of many animals Cowpox, swine pox, orf Swine vesicular disease Vesicular stomatitis Fowl pox, swine pox, myxoma Equine infectious anemia Vesicular stomatitis African swine fever virus Bluetongue, African horse sickness Vesicular stomatitis virus Feline immuno deficiency virus Rabies virus Papilloma viruses of many animals

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Genital tract

Herpesviridae / several genera Papovaviridae / Papilloma virus Arteriviridae / Arterivirus

Conjunctival tract

Herpes viruses of many animals Bovine papilloma viruses Equine arteritis virus IBR, Equine herpes virus 1 Canine adenoviruses 1 and 2

Herpes viridae / several genera Adenoviridae / Mastadenovirus 3. Direct tissue implantation The virus enters into the body by direct implantation either from injury or from the bites of an arthropod vector. The classical example of a) The infection of Rabies virus through the skin by the bite of rabid animal or reservoir hosts. b) Arbo virus infections and c) Serum hepatitis acquired as a result of direct incidental inoculation of B-virus along with human serum for medicinal purpose. Man is an accidental host in both rabies and B-virus infection as is the bovine host in pseudorabies of cattle. Pseudorabies virus is a normal pathogen to swine where mild respiratory disease produced and is thought to infect cattle through traumatic injury. Myxomatosis is transmitted by the mosquitoes (such as Anopheles) and rabbit flea. Replication of virus within the body of the vector occurs in ARBO viruses, as in the case of yellow fever, dengue and in some case some host may serve as a reservoir of infection as it in the case of Rabies when jackal and vampire bats serve as reservoir of Rabies virus. 4. Transplacental transmission / Transovarian Enzootic abortion in sheep, lymphocytic chorio meningitis infection of the fetus may occur either transplacentally or via the ovum. HIV virus, rubella virus, avian encephalomyelitis and leukosis in chicken. Spread of Virus through the Body This is the sequence of events, which takes place during the interval between the first lodgment of virus in the body and fully manifested clinical disease. This occurs mainly through the reticuloendothelial systems (R.E.) and the circulatory systems. Role of R.E. system: Virus released from the primary multiplication site into the tissue spaces will rapidly reach the local lymph node where further multiplication may occur. From the lymph node the virus is carried to the larger lymphatic vessels and thoracic duct to the blood stream. The lymphatic drainage is followed by the entry of virus into the circulatory system and generalized throughout the body. Role of circulatory system: The primary viremia will normally occur before the onset of clinical disease and is the point at which the virus invasion may be checked by the administration of immune serum. This primary viremia is followed by the secondary viremia and coincides with the clinical disease. The secondary viremia occurs only; if the individual can survive the damage done in the parenchymatous of the virus occurs in the parenchymatous organs from where virus enters into the blood.

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The spread of infection in the CNS The mechanism of infection CNS presents a number of problems which in many respects are more complex than those arising with other organ. Infection may occur from the blood stream, along the olfactory nerves from the nasal cavity, or by spread along the nerve trunks from other parts of the body and some viruses are capable of producing infection by any of these routes. e.g. Louping ill, equine encephalo myelitis, canine distemper, Newcastle disease, Teschen disease. Neural involvement in all the disease is preceded by a well marked viremia. Herpes, rabies & Borna viruses travel to the CNS in axon cytoplasm. Release of the virus from the body Great majorities of the viruses are shed from the internal surface of the body and reach the exterior either through the respiratory or alimentary tract. Some viruses reach exterior through the genito urinary tract and few are shed directly from the external surface of the body such as skin and conjunctiva. Mechanism of the disease production The development of clinical illness in virus infected host may be due to a number of factors. These include the tissue damage produced by the virus and the accompanying inflammatory response, hypersensitivity reaction to viral antigens and secondary bacterial invasion. It is therefore that the disease itself is a blend of two distinct effects of the infecting virus. IMMUNE RESPONSES TO VIRUSES At first 3 phenomena contribute to recovery from acute viral infection: a) Destruction of infected cells by macrophages. b) Protection of interferons. c) Neutralization of the infectivity of virions by antibody.  Destruction of infected cells by macrophages: Shortly after infection some virus particles are phagocytised by macrophages. Then the engulfed virions are destroyed by the macrophages except certain viruses that are capable of growing in macrophages. Destruction of virus infected cells results from any of four different processes: a. Destruction by cytotoxic T cells(Tc). b. By antibody complement mediated cytotoxicity. c. By antibody dependent cell mediated cytotoxicity. d. By Natural Killer (NK) cells.  Destruction by cytotoxic T cells (Tc) : Cytotoxic T lymphocytes carry the CD8 surface marker and posses T cell receptors that recognize viral peptides presented on the surface of virus infected target cells in association with the MHC class-1 molecule. (CD8 is a protein complex first identified on human T helper lymphocytes and subsequently found on other cells.MHC class-1 are glycoproteins that can be expressed on the plasma membrane of most type of cells). Activation and subsequent cytolysis of target cells by T cells require direct Tc target cell contact. Granules within the cytoplasm of the T cell polarize towards the target cell plasma membrane and their contents

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are released. A monomeric protein called perforin is secreted and insert themselves into the target cell plasma membrane, creating a pore that brings about the lysis of the cell. 

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

By antibody complement mediated cytotoxicity: When viral antigens bind with an antibody complement forms a complex by attaching with them and then the complex is lysed by the phagocytic cells. By antibody dependent cell mediated cytotoxicity: This process is mediated by leucocytes that carry Fc receptors, macrophages, polymorphonuclear leucocytes and other kinds of killer cells. Destruction of NK cells: NK cells are activated by interferon or directly by viral glycoproteins. They demonstrate no immunologic specificity , but preferentially lyse virus infected cells. In addition, in presence of antibody, macrophages can phagocytose and digest virus infected cells.

 Production of interferon: Interferons are virus induced cell coded small glycoproteins containing nearly all amino acids.Interferons do not act directly on the virus particles, they act on the cells, the virus inhibitory effect may be exerted not by interferon itself, but by a cellular protein induced by the interferon at the level of different stages of virus replication cycle and thereby inhibiting virus multiplication.  Neutralization of infectivity of virions by antiboby: While a specific of any class can bind to any accessible epitope on a surface protein of a virion, only those antibody that bind with reasonably high affinity to particular epitopes on a particular protein of the outer capsid or envelope of the virion are capable of neutralizing viral infectivity.Viral antibody complex may be destroyed by lysosomal enzyme.Incase of picornavirus, the neutralizing antibody appears to distort the capsid, which renders the virion vulnerable to enzymatic attack. Host Effectors Function Table In Virus Infection Early nonspecific responses

Fever Phagocytosis Inflammation NK cell activity Interferon

Immune responses mediated by cells

Cytotoxic T lymphocytes Activated macrophages Lymphokines ADCC Antibody Antibody + complement

Humoral immune responses

Virus replication Virus Virus replication Virus-infected cell Virus replication, immunomodulation Virus infected cell Virus, virus-infected cell Virus-infected cells, immunomodulation Virus-infected cell Virus, Virus-infected cell Virus, virus-infected cell

Fig: The host defenses against viral infections and it indicates the targets for each of these defenses.

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MECHANISMS OF VIRUS INDUCED TISSUE DAMAGE 1. Inhibition of host cell nucleic acid synthesis: Pox viruses produce DNAase that degrades cellular DNA. 2. Inhibition of host cell RNA transcription: It is an indirect consequence of viral effects on host cell protein synthesis, which decreases the availability of transcription factors required for RNA polymerase activity.eg. pox virus, paramyxovirus, picorna viruses etc.Viruses encode specific transcription factors for the purpose of regulating the expression of their own genes.These factors modulate the expression of cellular genes.eg. Herpes virus. 3. Inhibition processing of host cell mRNAs: Many viruses (eg vesicular stomatities virus, influenza virus, herpes virus) interfere with the spilicing of cellular primary mRNA transcripts that are neededto form mature mRNAs. 4. Inhibition of host cell protein synthesis: In addition to the processes mentioned earlier, there are other processes which inhibit the host cell protein synthesis. a) Production of viral enzymes that degrade cellular mRNAs. b) The production of factors that bind to ribosomes, and inhibit cellular mRNA transcription. c) The alteration of the intracellular ionic environment favouring the translation of viral mRNAs over cellular mRNAs. 5. Cytopathic effects of toxic viral proteins: Most cell damage has been recognized as supervening ofviral replication events on cellular events.eg.the adenovirus penton and fiber proteins seems to have direct toxic effect upon the cells.

REFERENCES Samad, M.A., 2008. Animal Husbandary and Veterinary Science, Vol. 1 and 2. 1 st edition, Bikash Mudran, 56/5, Fakirerpool Bazar, Motijheel, Dhaka, pp. 391-400. Chakraborty.P.,2009. A Textbook of Micribiology, Reprint, New Central Book Agency, New Dilhi (India), pp. 479-498. Bleshe RB (ed) 1991 Text Book of Human Virology. St Louis : Mosby. Murray R, Baron Ej, Pfaller MA, Tenover FC, Yolken RH (eds) 1999 Manual of Clinical Microbiology, 7th edn. Washington, D.C. : American Society for Microbiology. Ali, M. Z., Rahman, M. M and Sultana, S. 2015. Seroprevalence of Mycoplasma gallisepticum antibody by ELISA and serum plate agglutination test of laying chicken. Veterinary World, 8(1): 9-15.