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Lec 7 virology Negative single strand RNA viruses *General and Molecular characteristics 1-Medically important negative-strand RNA viruses 2- They are all enveloped; . 3-Their virions contain an RNA-dependent RNA polymerase (transcriptase) that synthesizes viral mRNAs using the genomic the genomic negative-strand viral negative-strand RNA as a template RNAs are not infectious, 4- Some negative-strand RNA viruses have segmented genomes, whereas others have nonsegmented genomes . 5- Negative ssRNA viruses include many important medically families such as Paramyxoviridiae ( e.g : parainfleunza 1-5 ,mumps, measles ) , Orthmyxoviridae (e.g : influenza H1N1), Rhabdoviridae (e.g Rabies virus ) and Filoviridae ( e.g : Ebola virus ) 6-The v irion contains five proteins, one of which, the G (for “glyco-“) protein, is an envelope protein composed of viral spikes . The rabies virion attaches via its glycoprotein spikes to cell-surface receptors. Note : Although most of these viruses replicate in the cytosol, the replication of influenza virus RNA (an orthomyxovirus occurs in the nucleus ) *Replication of negative- ssRNA virus genome: 1- the first step in the replication of negative-strand RNA viruses is the synthesis of mRNAs by RNA dependent RNA polymerase presence in virus particle whereas with positive-strand RNA viruses, the first step in replication is translation of the incoming genomic RNA. 2- Translation the new mRNA (+RNA) into viral protein including capsid protein . 1 3- New mRNA serve as templete for synthesis (- RNA ) by same enzyme. 4- Assembly into necleocapsid 5- releasing from infected host cell . Figure (1) Replication of negative ssRNA viruses . 2 *Some families of Negative ssRNA viruses 1-Rhabdovirdae : are enveloped, bullet-shaped viruses each contains a helical nucleuocapsid . The viruses in the family Rhabdoviridae known to infect mammals are divided into two genera: Lyssa virus (rabies virus, the rhabdovi us of greatest medical importanceto humans), and Vesiculovirus [vesicular stomatitis virus (VSV), a virus of horses and cattle, Other rha bdovir uses infect invertebrates, plants, or other vertebrates. *Rabies virus *Epidemiology A wide variety of wildlife, such as, squirrels, foxes,and bats, provide reservoirs for the rabies virus. In developing countries, domestic dogs and cats also constitute important reservoirs for rabies. Humans are usually infected by the bite of an animal, but, in some cases, infection is via inhalation (for example, of droppings from infected bats). *Pathogenesis: 1-Following inoculation, the virus may replicate locally but then travels via retrograde transport within peripheral neurons to the b rain, 2- it replicates primarily in the gray matter . 3-From the brain, the rabies virus can travel along autonomic nerves, leading to infection of the lungs, kidney, adrenal medulla, and salivary Glands. 4-The extremely variable incubation period depends on the host’s resistance, amount of virus transferred, and distance of the site of initial infection from the central nervous system (CNS). Inc ubation generally lasts 1 to 8 weeks but may range up to several months. 3 *Clinical illness 1-May begin with an abnormal sensation at the site of the bite. 2-Then progress to a fatal encephalitis, with neuronal degeneration of the brain and spinal cord. 3-Symptoms include hallucinations; seizures; weakness; mental dysf unction. 4-paralysis. coma; and, finally, death. Many, but not all, patients show the classic rabid sign of hydrophobia. Figure (2) : Schematic representation the pathogenesis of rabies infection. *Laboratory identification 1-clinical diagnosis may be difficult. Postmortem, in approximately 80 percent of cases, characteristic eosinophilic cytoplasmic inclusions Negri bodies) may be identified in certain regions of the brain 4 2-These cytoplasmic inclusion bodies are virus production foci and diagnostic of rabies . 3-The diagnosis can be made by identification of viral antigens in biopsies of skin from the back of the neck or from corneal cells or by demonstration of the viral nucleic acid by reverse transcription polymerase chain reaction (RT-PCR) in infected saliva. Figure (3): An oval Negri body in a brain cell from a human rabies case 2-Paramyxoviridae : Paramyxov iruses are spherical, enveloped particles that contain a nonsegmented, negative-strand R N A genome (Paramyxo viridae typically consist of a helical nucleocapsid surrounded by an envelope that contains two types of integral membrane or envelope proteins. The first, the H N protein (H stands for hemagglutinin and N for neuraminidase), is involved in the binding of the virus to a cell. [Note: Measles virus lacks the neuraminidase activity.] The second, the F protein (F stands for f usion) 5 *Mumps virus: Mumps used to be one of the commonly acquired childhood infections. Adults who escape the disease in childhood could also be infected. In the prevaccine period, mumps was the most common cause of viral encephalitis. Complete recovery, however, was almost always achieved. The virus spreads by respiratory droplets. Although about one third of infections are subclinical, the classic clinical presentation and diagnosis center on infection and swelling of the salivary glands, primarily the parotid glands. However, infection is widespread in the body and may involve not only the salivary glands but also the pancreas, CNS, and testes. Orchitis (inflammation of the testis) caused by mumps virus may cause sterility. A live, attenuated vaccine has been available for many year and has resulted in a dramatic drop in the number of cases of mumps. [Note: Individuals who have had the disease develop lifelong immunity 6 3-Orthomyxoviridae : Orthomyxoviruses are spherical, enveloped viruses containing a segmented, negative strand RN A genome. Viruses in this family infect humans, horses, and pigs, as well as nondomestic waterfowl, and are the ca use of influenza. Orthomyxo vir uses are di vided into three types: influenza A, B, and C. Only influenza virus types A and B are of medical importance. Type A influenza viruses differ from type B viruses in that they ha v e an animal reservoir and are divided into subtypes. Influenza vi us C is not a significant human pathogen. Structure Influenza virions are spherical, en veloped, pleomorphic particles Two types of spikes project from the s urface: One is composed of H protein and the second of N protein. [Note: This is in contrast to the paramyxoviruses, in which H and N activities reside in the same spike protein.] Both the H and N influenza proteins are integral membrane proteins. The M (matrix) proteins underlie the viral lipid membrane. The RNA genome, located in a helical nucleocapsid, is composed of eight distinct segments of R N A, each of which encodes one or more viral proteins. Each nucleocapsid segment contains not only the viral R NA but also four proteins ( NP, t h e major nucleocapsid protein, and three P (polymerase) proteins that are present in much smaller amounts than NP and are involved in synthesis and replication of viral R NA). 7 Figure (4): Influenza virus by Electron micro-graph. and Schematic drawing showing envelope proteins called H and N spikes that protrude from the surface. M protein = matrix protein. 8