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Picornaviruses Genera of the family Picornaviridae Enterovirus Parechovirus Rhinovirus Hepatovirus Aphtovirus Cardiovirus Structure of virion Ss +RNA. Virion is icosahedral 22-30nm in diameter. Capsid has 60 copies of 4 proteins: VP1, VP2, and VP3 are exposed on the virion surface, VP4 lies buried in close association with the RNA core. Immunogenic sites are located on the external parts of the capsid. Reproduction Cycle of Picornaviruses Unique properties of human Picornaviruses Small nonenveloped viruses. Because they contain no essential lipids, they are ether, acidic pH, and detergents resistant. Rhinoviruses are labile at acidic pH. They replicate in the cytoplasm. Most viruses are cytolytic. Picornaviruses do not have a common group- specific antigen. Each serotype has a type-specific antigen, which is identifiable by neutralization tests GENUS ENTEROVIRUSES The enterovirus genus is so-called because these viruses generally replicate in the intestine. History Poliovirus - first identified by Karl Landsteiner in 1908 by inoculation of specimens into monkeys. The virus was first grown in cell culture in 1949 which became the basis for vaccines. Coxsackieviruses - were identified in 1948 by inoculation into newborn mice from two children with paralytic disease. These agents were named coxsackieviruses after the town in New York State. Echoviruses - were identified in 1951 which produced cytopathic changes in cell culture and was nonpathogenic for newborn mice. More recently, new enterovirus types have been allocated sequential numbers (68 - 71). Pathogenesis of enteroviruses infections Routes of transmission: fecal-oral, via salivary and respiratory droplets, via conjunctival secretions and skin lesion exudates, Portal of entry: nasopharynx and intestinal mucosa. Replication: in the nasopharyngeal and intestinal epithelium and regional lymph nodes. Spread: by the bloodstream in the reticuloendothelial system and to target organs such as the spinal cord, brain meninges, heart, liver and skin. From the CNS the virus travel via neural pathways to skeletal and heart muscles. Pathogenesis of enterovirus infections Pathogenesis of enteroviruses infections Cox = Coxsackie virus A or B, Hep A = hepatitis A virus, Echo = echovirus, Polio = poliovirus Poliovirus 3 serotypes of poliovirus (1, 2, and 3) but not common antigen. Humans are the only susceptible host Transmission electron micrograph of poliovirus Polio endemic countries (where polio is prevalent) EPIDEMIOLOGY Source human with clinical and subclinical infection. Transmission: primarily via the fecal-oral, by ingesting contaminated food or water . Incubation period - 3 to 35 days, on average 7 -14 days. Polio is most infectious between 7 and 10 days before and after the appearance of symptoms, but transmission is possible as long as the virus remains in the saliva (2 weeks) or feces (3-5 months). Pathogenesis of polio viruses infection The alimentary phase: Primary replication in the oropharyngeal and intestinal mucosa. The lymphatic phase: Virus spreads to the tonsils and Peyers patches. The viremic phase: The virus is carried by the bloodstream to various internal organs and regional lymph nodes. The neurologic phase: The virus spreads hematogenously to the spinal cord or brain stem or to both. Damage results in paralysis of the muscles innervated by the affected motor nerves. Paralysis is usually irreversible, and residual paralysis remains for life. Pathogenesis of polio viruses infection Poliovirus can survive and multiply within the blood and lymphatics for 17 weeks Poliomyelitis - infammation of the gray (polios) anterior matter of the spinal cord (myelos) Death of motor neurons Sensory neurons unaffected The location of motor neurons in the anterior horn cells of the spinal column . Diagram of healthy spinal cord section with nerve cells (motor nerve cells) branching to muscles Neuron structure Degeneration of Nerve cells (Neurons) during Acute Polio The nerve cell is invaded by poliovirus One of the nerve cells has been infected by the poliovirus, while its neighbor has not Destruction of the infected nerve cells results a lack of nerve supply to the muscles If this process occurs on a large enough scale, it can result in loss of muscular function, and can cause weakness or paralysis Recovery From Acute Paralytic Polio Immediately following paralytic polio, surviving motor nerve cells in the brain stem and spinal cord extend new branches to re-connect the nerve cell to the muscle. These are called sprouts. The new sprouts are now capable of triggering contraction in the muscles and muscle function can be partially or fully regained Thus, many motor nerve cells end up supplying several times the number of muscle fibers they would normally supply. Recovery is usually complete in 6 to 8 months. A single motor neuron that once controlled 200 muscle cells might control 800 to 1000 cells. Mechanism of Post-Polio Syndrome These new sprouts are not indefinitely stable. After many years these motor neurons begin to break down, causing new muscle weakness. Clinical syndromes associated with polio viruses Inapparent (subclinical) infection. Abortive infections (a minor influenza-like illness). Aseptic meningitis. Encephalitis. Paralytic poliomyelitis: spinal poliomyelitis - complete flaccid paralysis of one or more limbs; bulbar poliomyelitis - paralysis of neck and respiratory muscles; bulbospinal poliomyelitis. Post-polio syndrome: the virus is no longer present. It may occur many years after the infection and involves further loss of function in affected muscles as a result of further neuron loss. Outcomes of poliovirus infection OutcomeProportion of cases Asymptomatic9095% Minor illness48% Aseptic meningitis12% Paralytic poliomyelitis0.10.5% Spinal polio79% of paralytic cases Bulbospinal polio19% of paralytic cases Bulbar polio2% of paralytic cases Symptoms of poliomyelitis Early symptoms: high fever, headache, stiffness in the back and neck, asymmetrical weakness of muscles, sensitivity to touch, difficulty swallowing, muscle pain, paresthesia (pins and needles), constipation, or difficulty urinating. Paralysis generally develops 1 to 10 days after early symptoms begin, progresses for 2 to 3 days, and is usually complete by the time the fever breaks. Egyptian stele from the 18th dynasty showing a victim of polio with a withered leg Children with polio sequelae Muscle paralysis can sometimes result in skeletal deformities, tightening of the joints and movement disability. IMMUNITY Active immunity: Life-long, type-specific Mechanism: Local: IgA are present in the tonsils and gastrointestinal tract, and are able to block virus replication; Humoral: IgG and IgM can prevent the spread of the virus to motor neurons of the CNS. Passive immunity: Maternal antibodies cross the placenta, and protect the infant from polio infection during the first 2-3 months of life. Jonas Edward Salk (1914-1995) was an American medical researcher and virologist, developed the first inactivated polio vaccine in 1952. Albert Sabin (1906-1993), an American medical researcher, developed an oral attenuated live polio vaccine in 1955 and perfected and tested widely in 1961 Prevention Intramuscular Poliovirus Vaccine (IPV) consists of formalin inactivated virus of all 3 serotypes. Produces serum antibodies only: does not induce local immunity and thus will not prevent local infection of the gut. However, it prevent paralytic poliomyelitis since viraemia is essential for the pathogenesis of the disease. No risk of vaccine-related disease. Oral Poliovirus Vaccine (OPV) Consists of live attenuated virus of all 3 serotypes. Produces local immunity through the induction of an IgA response as well as systemic immunity. Lifelong immunity. Rarely causes paralytic poliomyelitis, around 1 in 2 million doses. Serum and secretory antibody response to intramuscular inoculation of IPV and to live attenuated OPV Inactivated polio vaccine Live polio vaccine Schedule of immunization New guidelines suggest administration of the IPV for the first two doses to eliminate the risk of vaccine-related paralytic polio disease followed by two doses of the OPV on a schedule of 2 months of age (inactivated), 4 months (inactivated), 12-18 months (oral), 4-6 years (oral). In children with varies immune deficiencies the live vaccine is not used! Clinical syndromes associated with non-polio Enteroviruses Aseptic meningitis, encephalitis and ascending paralysis. Common cold syndrome. Coxsackie A Herpangina (sore throat, fever, vesicles). Hand-foot-and mouth disease. Coxsackie B Myocarditis, pericarditis. Pleurodynia (Bornholms disease or Devils Grippe). ECHO viruses: exanthematous disease (rash). Enterovirus 70: acute hemorrhagic conjunctivitis. Enterovirus 71: severe CNS disease. Diseases associated with Enteroviruses Syndrome PolioCox A Cox B Echo Asymptomatic infection + Paralytic disease + Meningitis-encephalitis + Respiratory infection + Hand-foot-mouth disease + Herpangina + Pleurodynia + Carditis + Rash disease + Hemorr. conjunctivitis + Aseptic meningitis and encephalitis Both Coxsackie virus A and B can cause aseptic meningitis which is so-called because it is not of bacterial origin. Headache, stiff neck, fever, avoidance of light, and eye pain are characteristic. Drowsiness may be prominent, and other symptoms include sore throat, cough, muscle pain, and rash. Occasionally, not only the meninges, the covering around the brain and spinal cord is infected, but also brain tissue itself, producing encephalitis. The illness resolves after about a week or so, and permanent damage is unusual. Enteroviruses can also produce the Guillian-Barr syndrome, which involves weakness and paralysis of the extremities and even the muscles of respiration. The disease is most prevalent in the summer and fall. Hand-foot-and-mouth disease Herpangina Hemorrhagic conjunctivitis Coxsackie viruses A can cause a fever with painful ulcers on the palate and tongue leading to problems swallowing and vomiting. Symptoms can persist for several weeks. EV70 have been linked as the causative agents of acute hemorrhagic conjunctivitis The echoviruses (enteric, cytopathic, human, and orphan viruses) are grouped together because they produce cytopathogenic effects in cell cultures but generally are not pathogenic for mice, and they differ antigenically from the polioviruses. They were first named “orphan viruses“ because their relationship with disease was obscure. Maculopapular Rash. Echovirus 19 Echoviruses cause diseases: aseptic meningitis, encephalitis, paralysis, febrile rash, minor respiratory illness, diarrhea. Laboratory diagnosis of enteroviruses infection 1. Culture and isolation of viruses from feces, pharyngeal swabs, saliva, nasal aspirates, skin lesions, conjunctiva, cerebrospinal fluid, spinal cord, brain, heart, and blood. Choice of Virus Isolation System Virus Tissue cultureSuckling mice Polioviruses+- Coxsackieviruses group A -+ Coxsackieviruses group B+ Echoviruses+- Identification: NtT, CFT, ELISA, HAIT. CPE of enteroviruses in monkey kidney cells Normal cell culture Coxsackieviruses are differentiated by their pathogenicity for suckling mice and by classification of their antigenicity. Group A viruses produce a diffuse myositis with acute inflammation and necrosis of fibers of voluntary muscles. Group B viruses produce focal degeneration in the brain and spinal cord, spastic paralysis, and necrosis of fat pads between the shoulders. Laboratory diagnosis of enteroviruses infection (2) 2. Serology (four-fold or greater rise in neutralizing antibody titer between paired sera or high IgM titers to a single serotype): NT; CFT; IF; ELISA; HAIT. Enterovirus 71 infection Transmission: fecal-oral, by respiratory droplets, through contact with the fluid in the blisters. The virus can be in the faeces for at least 2 months after symptoms develop. A person is infectious for as long as the virus is present in the faeces. Incubation period: 3-5 days. Infection may be asymptomatic, mild or severe neurological disease. After fever develops it usually takes 1-3 days before meningitis occurs, but paralysis can occur within 10-30 hours after symptoms begin. Treatment usually focuses on the persons symptoms. Prevention: Good hygiene is the single most effective way of preventing the spread of the disease. Hands should be washed thoroughly in soap and water for at least 15 seconds and then dried thoroughly. Entervirus 71 Symptoms: rashes, diarrhea, colds, hand-foot-mouth disease, myocarditis, paralytic poliomyelitis-like disease, bulbar and brain encephalitis, meningitis, rapidly fatal pulmonary edema and hemmorrhage. Hand-foot-mouth disease caused by the Enterovirus 71 It is spread from person to person by direct contact with the nasal discharge, saliva, and fluid from the rash of an infected person. There is no specific treatment for the infection. Symptomatic treatment is given to provide relief from fever,