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Medical biology, microbiology, virology, immunology department RNA-VIRUSES: PICORNAVIRUSES ORTHOMYXOVIRUSES PARAMYXOVIRUSES DNA-VIRUSES: HERPESVIRUSES. ADENOVIRUSES By as. Pyatkovskyy Genera of Picornaviruses Enterovirus Polio, types 1-3 Coxsackie A , 1-24 types Diseases of the human (and other) alimentary tract (e.g. polio virus) Coxsackie B, types 1-6 Echo, types 1-34 Other enteroviruses, types 68-71 Rhinovirus, types 1-115 Cardiovirus Aphthovirus Hepatovirus Others Disease of the nasopharyngeal region (e.g. common cold virus) Murine encephalomyocarditis, Theiler's murine encephalomyelitis virus Foot and mouth disease in cloven footed animals Human hepatitis virus A Drosophila C virus, equine rhinoviruses, cricket paralysis virus Pathogenesis of enterovirus infection Replication in oropharynx Rhino,echo, coxsackie,polio Primary viremia Secondary viremia Target Tissue Skin Muscle Brain Meninges Liver Echo Echo Polio Echo Echo Coxsackie Coxsackie Coxsackie Polio Coxsackie A A, B Coxsackie Clinical Picornavirus Syndromes Virus Polioviruses (types 1-3) Diseases (Virus Type) Undifferentiated febrile illnesses (types 1- 3) Aseptic memingitis (types 1-3) Paralisis and encephalitic diseases (types 1-3) Coxsackievirus group A (A1-A, A-24)* Acute hemorrhagic conjunctivitis (type 24) Herpangina (types 2-6, 8, 10, 22) Exanthem (types 4, 5, 6, 9, 16) Hand-foot-mouth disease (types 5, 10, 16) Aseptic memingitis (types 1, 2, 4-7, 9, 10, 14, 16, 22) Paralysis and encephalitic diseases (occasional types 4, 7, 9, 10) Hepatitis (types 4, 9) Virus Diseases (Virus Type) Upper and lower respiratory illnesses Coxsackievirus 9, 10, 16, 21, 24) group A (A1-A, A- (types Lymphonodular pharyngitis (10) 24)* Infantile diarrhea (types 18, 20, 21, 22, 24 variant) Undifferentiated febrile illnesses (types 1- 6) Pleurodinia (types 1-5) Pericarditis, myocarditis (types 1-5) Aseptic meningitis types (1-6) Paralysis and encephalitic diseases (occasional types 1-5) Severe systemic infection in infants, meningoencephalitis and myocarditis (types 1-5) Upper and lower respiratory illnesses (types 4, 5) Exanthem, hepatitis, diarrhea (types 5) Virus Echoviruses (1-7, 9, 11, 29-33)* Diseases (Virus Type) Aseptic meningitis (many seroypes ) Paralysis and encephalitic diseases (occasional types 1, 2, 4, 6, 7, 9, 11, 14-16, 18, 22, 30) Exanthem (types 1-9, 11, 14, 16, 18, 19, 25, 30, 32) Hand-foot-mouth disease (19) Pericarditis, myocarditis (types 1, 6, 9, 19, 22) Upper and lower respiratory illnesses (types 4, 9, 11, 20, 22, 25) Neanatal diarrhea (types 11, 14, 18, 20, 32) Epidemic mialgia (types 1, 6, 9) Hepatitis (types 4, 9) Virus New enteroviruses Diseases (Virus Type) Pneumonia and bronchiolitis (types 68, 69) Acute hemorrhagic conjunctivitis (type 70) Rhinoviruses (1-115) Hepatovirus (Hepatitis A) Aseptic meningitis, meningoencephalitis Hand-foot-mouth disease (71) Hepatitis (type 72) Upper and lower respiratory illnesses (types 1-115) Gastroenteritis and hepatitis A * Reclassification of coxsackievirus A23 as echovirus 9, echovirus 8 as 1, echovirus 10 as reovirus, echovirus 28 as rhinovirus type 1A, and echovirus 34 as coxsackievirus A24. Properties of enteroviruses Property Enteroviruses Size (nm) 22-30 Capsid form Icosahedral Polypeptide VP1, VP2, VP3, VP4 ‘+’, single RNA type stain Stable Acid Optimal temperature for growth(oC) 37 RNA Properties of enteroviruses This genome RNA serves as an mRNA and initiates the synthesis of virus macromolecules. The poliomyelitis virus has neither an outer membrane nor lipids and is therefore not sensitive to the effect of ether and sodium desoxycholate. POLIOMYELITIS Picornavirus 3 types: Poliovirus 1,2,3 30 nm in size Cultivation. SPE. The poliomyelitis virus is cultivated on kidney cells of green African monkeys and on diploid human cells devoid of latent SV40 viruses. The cytopathic effect is attended by destruction and the formation of granules in the infected cells. Pathogenesis Source of infection: Apparent and subclinical patients Incubation: is usually 7-14 days, but it may range from 3 to 35 days. Transmission Fecal – oral route: poor hygiene, dirty diapers (especially in day-care settings) Ingestion via contaminated food and water Contact with infected hands Inhalation of infectious aerosols Pathogenesis 1. The mouth is the portal of entry of the virus. 2. The virus first multiplies in the tonsils, the lymph nodes of the neck, Peyer's patches, and the small intestine. 3. Viremia 4. The central nervous system may then be invaded by way of the circulating blood. Poliovirus can spread along axons of peripheral nerves to the central nervous system , and there it continues to progress along the fibers of the lower motor neurons to increasingly involve the spinal cord or the brain. The anterior horn cells of the spinal cord are most prominently involved. Clinical Findings. When an individual susceptible to infection is exposed to the virus, one of the following responses may occur: inapparent infection without symptoms (asymptomatic illness), the minor illness – 90% infected people aseptic meningitis – 1%-2% of patients with poliovirus infections, paralytic poliomyelitis, the major illness 0.1% to 2% of persons with poliovirus Only about 1% recognized clinically. of infections are Abortive Poliomyelitis. This is the commonest form of the disease. The patient has only the minor illness, characterized by fever, malaise, drowsiness, headache, nausea, vomiting, constipation, and sore throat in various combinations. The patient recovers in a few days. The diagnosis of abortive poliomyelitis can be made only when the virus is isolated or antibody development is measured. Nonparalytic Poliomyelitis (Aseptic Meningitis). In addition to the above symptoms and signs, the patient with the nonparalytic form presents stiffness and pain in the back and neck. The disease lasts 2-10 days, and recovery is rapid and complete. In a small percentage of cases, the disease advances to paralysis. Paralytic Poliomyelitis. The major illness usually follows the minor illness described above, but it may occur without the antecedent first phase. The predominating complaint is flaccid paralysis resulting from lower motor neuron damage. The maximal recovery usually occurs within 6 months, with residual paralysis lasting much longer. Child with polio sequelae Lab Diagnosis Definitive diagnosis is made by osolation of the virus from stool, CFS, oropharyngeal secretions Cell culture involves fibroblastic MRC-5 cells CPE is usually evident within 36 hours Serotyping is based on neutralization of CPE by standardized antisera using intersecting pool followed by specific sera. ELISA IFA neutralizing Test CFT Prevention Both oral polio vaccine (OPV live, attenuated, Sabin, 1957) and inactivated poliovirus vaccine (IPV, Salk, 1954) are avilable IPV is used for adult immunization and Immunocopromised patients COXSACKIEVIRUSES The coxsackieviruses comprise a large subgroup of the enteroviruses. They produce a variety of illnesses in human beings, including aseptic meningitis, herpangina, pleurodynia, hand, foot, and mouth disease, myo- and pericarditis, common colds, and possibly diabetes. Coxsackieviruses have been divided into 2 groups, A and B, having different pathogenic potentials for mice. Group A viruses produce widespread myositis in the skeletal muscles of newborn mice, resulting in flaccid paralysis without other observable lesions. Group B viruses may produce spasticity effect in sucking mice, focal myositis, encephalitis, and, most typically, necrotizing steatitis involving mainly fetal fat lobules. Some B strains also produce pancreatitis, myocarditis, endocarditis, and hepatitis in both suckling and adult mice. Normal adult mice tolerate infections with group B coxsackieviruses. Herpangina: There is an abrupt onset of fever, sore throat, anorexia, dysphagia, vomiting, or abdominal pain. The pharynx is usually hyperaemic, and characteristic discrete vesicles occur on the anterior pillars of the fauces, the palate, uvula, tonsils, or tongue. The illness is self-limited and most frequent in small children. Exanthems – Rubelliform rashes Hand, Foot, and Mouth Disease: The syndrome is characterized by oral and pharyngeal ulcerations and a vesicular rash of the palms and soles that may spread to the arms and legs. Vesicles heal without crusting, which clinically differentiates them from the vesicles of herpes- and poxviruses. The rare deaths are caused by pneumonia. Hand-foot-and-mouth disease Hand-foot-and-mouth disease: mostly coxackie A fever, malaise, sore throat, vesicles on bucсal mucosa, tongue, hands, feet, buttocks highly infectious resolution – 1w ECHOVIRUSES (enteric cytopathogenic human orphan viruses) Not produce diseases in sucking mice, rabbits, or monkeys. Monkey kidney and human embryonated kidney cell culture Aseptic meningitis, febrile illnesses with or without rash, common colds, and acute hemorrhagic conjunctivitis are among the diseases caused by echoviruses. Boston exanthem disease. Rashes are commonest in young children. RHINOVIRUSES Rhinoviruses are isolated commonly from the nose and throat but very rarely from feces. These viruses cause upper respiratory tract infections, including the "common cold." Orthomyxovirus Family The name myxovirus was originally applied to influenza viruses. It meant virus with an affinity for mucins. A model of the influenza virion Types: A, B, C Influenza A: In Birds 16 H variants 9 N variants In Humans 3 H variants (H1, H2, and H3) 2 N variants (N1 and N2) Subtypes: H1N1, H2N2,H2N3 Influenza Viruses: Antigenic Shift Avian Reservoir Human virus Avian virus Other mammals? Swine New Reassorted virus Influenza Viruses: Antigenic Drift Gradual accumulation of mutations that allow the hemagglutinin to escape neutralizing antibodies (Point mutation in HA gene) Epidemic strains thought to have changes in three or more antigenic sites Pathogenesis and Pathology The virus enters the respiratory tract in airborne droplets. Viremia is rare. Virus is present in the nasopharynx from 1-2 days before to 1-2 days after onset of symptoms. Inflammation of the upper respiratory tract causes necrosis of the ciliated and goblet cells of the tracheal and bronchial mucosa but does not affect the basal layer of epithelium. Interstitial pneumonia may occur with necrosis of bronchiolar epithelium and may be fatal. The pneumonia is often associated with secondary bacterial invaders: staphylococci, pneumococci, streptococci, and Haemophilus influenzae. Clinical Findings The incubation period is 1 or 2 days. Chills, malaise, fever, muscular aches, prostration, and respiratory symptoms may occur. The fever persists for about 3 days; complications are not common, but pneumonia, myocarditis, pericarditis, and central nervous system complications occur rarely. The latter include encephalomyelitis, polyneuritis, Guillain-Barre syndrome, and Reye's syndrome (see below). Influenza Vaccines Whole virus vaccine: inactivated virus vaccine grown in embryonated eggs; 7090% effective in healthy persons <65 years of age, 30-70% in persons ≥65 years Split virus vaccine: previously associated with fewer systemic reactions among the elderly and children <12 years Subunit vaccine: composed of H and N Live, attenutated influenza virus vaccines under development Influenza: Chemoprophylaxis Amantadine and rimantadine: effective against type A, but not type B, influenza viruses; block the M2 ion channel 70-90% effective in preventing illness Administered to individuals at high risk of complications who are vaccinated after outbreak of infection, persons with immune defficiency Influenza: Chemotherapy Amantadine (adults and children ≥ 1 year) and rimantadine (adults) Zanamivir and oseltamivir: neuraminidase inhibitors active against both type A and B influenza viruses Reduce duration of illness by ~1 day when administered within 2 days of the onset of illness (uncomplicated influenza) Laboratory Diagnosis Throat washings or garglings are obtained within 3 days after onset and should be tested at once or stored frozen. Penicillin and streptomycin are added to limit bacterial contamination. For rapid detection of influenza virus in clinical specimens, positive smears from nasal swabs may be demonstrated by specific staining with fluorescein-labeled antibody. Paired sera are used to detect rises in HI, CF, or Nt antibodies. Family Paramyxoviridae Genes: Morbillivirus – measles virus, Respirovirus – parainfluenza virus (serotypes 1 and 3) Rubulavirus - mumps virus, parainfluenza virus 2, 4а, 4b), Pneumovirus – RS-virus (serotypes PARAMYXOVIRUSES pleomorphic HN/H/G glycoprotein SPIKES F glycoprotein SPIKES helical nucleocapsid (RNA minus NP protein) lipid bilayer membrane polymerase complex M protein STRUCTURE-PARAMYXOVIRUSES Cell fusion. In the course of infection, paramyxo- viruses cause cell fusion, long recognized as giant cell formation. MUMPS (Epidemic Parotitis) Mumps is an acute contagious disease characterized by a nonsuppurative enlargement of one or both of the parotid glands, although other organs may also be involved. Properties of the Virus: The mumps virus particle has the typical paramyxovirus morphology. Typical also are the biologic properties of hemagglutination, neuraminidase, and hemolysin. Epidemiology The disease reaches its highest incidence in children age 5-15 years, but epidemics occur in army camps. Humans are the only known reservoir of virus. The virus is transmitted by direct contact, airborne droplets, or fomites contaminated with saliva and, perhaps, urine. The period of communicability is from about 4 days before to about a week after the onset of symptoms. Pathogenesis and Pathology The virus travels from the mouth to the parotid gland, where it undergoes primary multiplication. This is followed by a generalized viremia and localization in testes. ovaries, pancreas, thyroid, or brain. The ducts of the parotid glands show desquamation of the epithelium, and polymorphonuclear cells are present in the lumens. There are interstitial edema and lymphocytic infiltration. Orchitis PARAINFLUENZA VIRUS The parainfluenza viruses are paramyxoviruses with morphologic and biologic properties typical of the genus. They grow welt in primary monkey or human epithelial cell culture but poorly or not at all in the embryonated egg. They produce a minimal cytopathic effect in cell culture but are recognized by the hemadsorption method. Laboratory diagnosis may be made by the HI, CF, and Nt tests. PIV STRUCTURE MEASLES (Rubeola) Measles is an acute, highly infectious disease characterized by a maculopapular rash, fever, and respiratory symptoms. Properties of the Virus: Measles virus is a typical paramyxovirus. It lacks neuraminidase activity. Measles virus Pathogenesis and Pathology Infection is contracted by inhalation of droplets expelled in sneezing or coughing. Measles is spread during the catarrhal prodromal period; they are infectious from 1-2 days prior to the onset of symptoms until a few days after the rash has appeared The virus enters the respiratory tract, enters cells, and multiplies there. During the prodrome, the virus is present in the blood, throughout the respiratory tract, and in nasopharyngeal, tracheobronchial, and conjunctival secretions. It persists in the blood and nasopharyngeal secretions for 2 days after the appearance of the rash. Transplacental transmission of the virus can occur. Pathogenesis and Pathology Koplik's spots are vesicles in the mouth formed by focal exudations of serum and endothelial cells, followed by focal necrosis. In the skin the superficial capillaries of the corium are first involved, and it is here that the rash makes its appearance. Generalized lymphoid tissue hyperplasia occurs. Multinucleate giant cells are found in lymph nodes, tonsils, adenoids, spleen, appendix, and skin. In encephalomyelitis, there are petechial hemorrhages, lymphocytic infiltration, and later, patchy demyelination in the brain and spinal cord. Koplik's spots RESPIRATORY SYNCYTIAL (RS) VIRUS This labile paramyxovirus produces a characteristic syncytial effect, the fusion of cells in human cell culture. It is the single most serious cause of bronchiolitis and pneumonitis in infants. Properties of the Virus: RS virus does not hemagglutinate. RSV- Structure immunofluoresent stain RSV- syncytium formation Pathogenesis and Pathology This disease is transmitted by coughing, sneezing, sharing wash cloths towels and other things with someone with RSV. This disease is extremely serious when it comes to children and infants under the age of 3 and elders. This disease can result in death. Symptoms for this disease are: sneezing, runny nose, sore throat, low fever, common cold symptoms just more severe. Treatment: Supportive Fluids, oxygen, respiratory support, bronchodilators Antiviral Agents Ribavirin (Virazole), a synthetic guanosine analogue, given as an aerosol RSV Bronchiolitis- clinical features Prophylaxis Combination live virus (measles-mumps-rubella) vaccines Live attenuated measles virus vaccine effectively prevents measles. Properties of the Viruses: All herpesviruses have a core of double-stranded DNA surrounded by a protein coat that exhibits icosahedral symmetry. The nucleocapsid is surrounded by an envelope. Common and important herpesviruses of humans include herpes simplex virus types 1 and 2, varicella-zoster virus, EpsteinBarr (EB) virus, and cytomegalovirus. HERPES SIMPLEX: Human Herpesvirus 1 (Herpes Labialis) & Human Herpesvirus 2 (Herpes Genitalis). Infection with herpes simplex virus may take several clinical forms. The infection is most often inapparent. The usual clinical manifestation is a vesicular eruption of the skin or mucous membranes. Infection is sometimes seen as severe keratitis, meningoencephalitis, and a disseminated illness of the newborn. Cytopathic effect (infected cells develop intranuclear acidophilic inclusion and then undergo necrosis ) Herpes labialis (cold sores, herpes febrilis). This is the most common recurrent disease produced by type 1. Clusters of localized vesicles occur, usually at the mucocutaneous junction of the lips. The vesicle ruptures, leaving a painful ulcer that heals without scarring. The lesions may recur, repeatedly and at various intervals of time, in the same location. The permanent site of latent herpes simplex virus is the trigeminal ganglion. Herpes labialis Keratoconjunctivitis. The initial infection with herpesvirus may be in the eye, producing severe keratoconjunctivitis. Recurrent lesions of the eye appear as dendritic keratitis or corneal ulcers or as vesicles on the eyelids. With recurrent keratitis, there may be progressive involvement of the corneal stroma, with permanent opacification and blindness. Genital herpes (herpes progenitalis). Genital herpes is characterized by vesiculoulcerative lesions of the penis of the male or the cervix, vulva, vagina, and perineum of the female. The lesions are more severe during primary infection and may be associated with fever, malaise, and inguinal lymphadenopathy. Type 2 virus remains latent in lumbar and sacral ganglia. Neonatal herpes. Herpesvirus type 2 may be transmitted to the newborn during birth by contact with herpetic lesions in the birth canal. The spectrum of illness produced in the newborn appears to vary from subclinical or local to severe generalized disease with a fatal outcome. Severely affected infants who survive may have permanent brain damage. Laboratory Diagnosis The virus may be isolated from herpetic lesions (skin, cornea, or brain). The appearance of typical cytopathic effects in cell culture suggests the presence of herpesvirus in 18-36 hours. Scrapings or swabs from the base of early herpetic lesions contain multinucleated giant cells. Serology: The agent is then identified by neutralization test or immunofluorescence staining with specific antiserum. Antibodies appear in 4-7 days; can be measured by NT, IHT, CFT, RIA and reach a peak in 2-4 weeks. HV, immune fluorescence test VARICELLA-ZOSTER VIRUS (Human Herpesvirus 3) (Chickenpox, Herpes Zoster, Shingles, Zona) Varicella (chickenpox) is a mild, highly infectious disease, chiefly of children, characterized clinically by a vesicular eruption of the skin and mucous membranes. The causative agent is indistinguishable from the virus of zoster. Zoster (shingles) is a sporadic, incapacitating disease of adults (rare in children) that is characterized by an inflammatory reaction of the posterior nerve roots and ganglia, accompanied by crops of vesicles (like those of varicella) over the skin supplied by the affected sensory nerves. VARICELLA-ZOSTER VIRUS (Human Herpesvirus 3) (Chickenpox, Herpes Zoster, Shingles, Zona) Both diseases are caused by the same virus. Varicella is the acute disease that follows primary contact with the virus, whereas zoster is the response of the partially immune host to a reactivation of varicella virus present in latent form in sensory ganglia. Pathogenesis & Pathology. Varicella: The route of infection is probably the mucosa of the upper respiratory tract. The virus probably circulates in the blood and localizes in the skin. Swelling of epithelial cells, ballooning degeneration, and the accumulation of tissue fluids result in vesicle formation. In nuclei of infected cells, particularly in the early stages, eosinophilic inclusion bodies are found. Varicella virus, pathogenesis Varicella Chickenpox Pathogenesis & Pathology. Zoster: In addition to skin lesions — histopathologically identical with those of varicella — there is an inflammatory reaction of the dorsal nerve roots and sensory ganglia. Often only a single ganglion may be involved. As a rule, the distribution of lesions in the skin corresponds closely to the areas of innervation from an individual dorsal root ganglion. There is cellular infiltration, necrosis of nerve cells, and inflammation of the ganglion sheath. Zoster Shingles CYTOMECALOVIRUS (Human Herpesvirus 5) Cytomegalic inclusion disease is a generalized infection of infants caused by intrauterine or early postnatal infection with the cytomegaloviruses. The disease causes severe congenital anomalies. Cytomegalovirus can be found in the cervix of up to 10% of healthy women. Cytomegalic inclusion disease is characterized by large intranuclear inclusions that occur in the salivary glands, lungs, liver, pancreas, kidneys, endocrine glands, and occasionally, the brain. Most fatalities occur in children under 2 years of age. Inapparent infection is common during childhood and adolescence. Severe cytomegalovirus infections are frequently found in adults receiving immunosuppressive therapy. Cytomegalovirus Inclusion Diseases. Electron micrograph of a single animal cell infected with the cytomegalovirus. The intranuclear inclusion body has a typical” owl-eyed” apearence. Pathogenesis. Cytomegalovirus can cause persistent infection in various tissues, including those of the salivary glands, breasts, kidneys, endocervix, seminal vesicles and peripheral blood leukocytes. This persistent infection leads to chronic viral excretion by the involved organ. Transmission of virus is through contact with infected secretions. The average incubation period is four to six weeks. It should also be noted that the kidneys of organ donors can be a source of cytomegalovirus for the recipient, and that peripheral blood leukocytes have been implicated in the transmission of cytomegalovirus via blood transfusion. Clinical Manifestations. Cytomegalovirus infection can result in one of three distinct clinical syndromes. Congenital cytomegalovirus infection: hepatosplenomegaly, retinitis, a petechial/purpuric skin rash, and involvement of the central nervous system (ventriculomegaly, intracranial calcifications, etc). Mononucleosis syndrome (fever, malaise, atypical lymphocytosis, pharyngitis and, rarely, cervical adenopathy or hepatitis) Third clinical entity is cytomegalovirus infection in severely immunocompromised individuals. In these patients, infection can involve the lungs, gastrointestinal tract, liver, retina, and central nervous system EB HERPESVIRUS (Human Herpesvirus 4). EB (Epstein-Barr) virus is the causative agent of infectious mononucleosis and has been associated with Burkitt's lymphoma and nasopharyngeal carcinoma. Epidemiology. Epstein-Barr virus is transmitted by intimate contact. Pathogenesis. Epstein-Barr virus is tropic for Blymphocytes. Infectious mononucleosis Nasopharyngeal carcinoma Burkitt's lymphoma Oncogenic Properties: Herpesviruses have been linked with malignant diseases in humans : herpes simplex virus type 2 with cervical and vulvar carcinoma; EB virus with Burkilt 's lymphoma of African children and with nasopharyngeal carcinoma. acute respiratory disease, pharyngoconjunctival fever, nonstreptococcal exudative pharyngitis, and primary atypical pneumonia Laboratory Diagnosis. The viruses have been recovered from throat swabs, conjunctival swabs, rectal swabs, stools of patients with acute pharyngitis and conjunctivitis, and urine of patients with acute hemorrhagic cystitis. Virus isolations from the eye are obtained mainly from patients with conjunctivitis. The viruses are isolated by inoculation of tissue cultures of human cells in which characteristic cytopathic changes are produced. A new serotype that has not been isolated in cell cultures can be detected by direct examination of fecal extracts by electron microscopy or by enzyme-linked immunosorbent assay. Serology. In most cases, the neutralizing antibody titer of infected persons shows a 4fold or greater rise against the type recovered from the patient in NT. The CF test, using the common antigen, is an easily applied method for detecting infection by any member of the group. A sensitive radioimmunoassay can measure serum antibody to type 5 fiber antigen.