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  1. 1. Reovirus, Rhabdovirus and Gastrointestinal Viruses FE A. BARTOLOME, MD, FPASMAP Department of Microbiology & Parasitology Our Lady of Fatima University
  2. 3. Reoviridae <ul><li>respiratory and enteric viruses not associated with any known disease process  R espiratory, E nteric, O rphan </li></ul><ul><li>Members: </li></ul><ul><ul><li>Orthoreovirus – mild URT illness, GIT illness, biliary atresia </li></ul></ul><ul><ul><li>Orbivirus/Coltivirus – febrile illness associated with headache and myalgia (zoonosis) </li></ul></ul><ul><ul><li>Rotavirus – GIT illness, respiratory tract illness (?) </li></ul></ul><ul><li>Non-enveloped; double-layered protein capsids with dsRNA genomes (“double:double”) </li></ul><ul><li>Stable over wide pH & temperature changes & in airborne aerosols </li></ul>
  3. 4. Reoviridae <ul><li>STRUCTURE : </li></ul><ul><li>Icosahedral with double stranded segmented genome </li></ul><ul><ul><li>Reovirus – 10 segments </li></ul></ul><ul><ul><li>Rotavirus – 11 segments </li></ul></ul><ul><li>(+) re-assortment of gene segments  create hybrid viruses </li></ul>
  4. 5. Reoviridae REPLICATION : Ingestion Proteolytic cleavage of outer capsid in GIT Formation of intermediate/infectious viral particle (ISVP) ISVP release core into cytoplasm Enzymes in core initiate mRNA production using + strand as template
  5. 6. Reoviridae <ul><li>REPLICATION : </li></ul><ul><ul><li>Occurs in the cytoplasm </li></ul></ul><ul><ul><li>dsRNA remains in the core </li></ul></ul><ul><ul><li>Virus leaves the cell during cell lysis </li></ul></ul>
  6. 7. <ul><li>Mammalian reovirus </li></ul><ul><li>Ubiquitous  present in sewage & river water </li></ul><ul><li>3 serotypes (1, 2 & 3)  based on neutralization and hemagglutination-inhibition tests </li></ul><ul><li>Most people infected during childhood  (+) antibodies in 75% of adults </li></ul>Reoviridae: Orthoreovirus
  7. 8. PATHOGENESIS & IMMUNITY <ul><li>No significant disease in humans </li></ul><ul><li>After ingestion & proteolytic production of ISVP, binds to M cells in small intestines  transfer virus to lymphoid tissue of Peyer’s patches  replicate  (+) viremia </li></ul><ul><li>(+) humoral & cellular immune response to outer capsid protein </li></ul>Reoviridae: Orthoreovirus
  8. 9. Reoviridae: Orthoreovirus CLINICAL SYNDROMES: <ul><li>Usually asymptomatic </li></ul><ul><li>Common cold-like mild upper respiratory tract illness </li></ul><ul><li>Gastrointestinal disease </li></ul><ul><li>Biliary atresia </li></ul>LABORATORY DIAGNOSIS: <ul><li>Assay of viral antigen or RNA in clinical material </li></ul><ul><li>Virus isolation </li></ul><ul><li>Serologic assays </li></ul>
  9. 10. A 6-month-old boy was seen in the emergency room after two days of persistent watery diarrhea and vomiting accompanied by a low-grade fever and mild cough. The infant appeared dehydrated and required hospitalization.
  10. 11. <ul><li>Rota  “wheel” </li></ul><ul><li>One of the most common agents of infantile diarrhea worldwide </li></ul><ul><li>Ubiquitous worldwide </li></ul><ul><li>95% of children infected by 3 – 5 years old </li></ul><ul><li>Stable at: room temperature, treatment with detergents, pH 3.5 – 10, repeated freezing & thawing; survives on fomites </li></ul><ul><li>Divided into: </li></ul><ul><ul><li>Serotypes – based primarily on VP7 outer capsid protein </li></ul></ul><ul><ul><li>Groups – based on antigenicity of VP6 & electrophoretic mobility of genomic segments  A to G  group A causes human disease </li></ul></ul>Reoviridae: Rotavirus
  11. 13. <ul><li>PATHOGENESIS: </li></ul><ul><li>MOT: fecal-oral, possibly respiratory route </li></ul><ul><li>Adsorption to columnar epithelial cells covering villi of SI  release of NSP4 protein  (+) cytolytic & toxin-like activity  loss of electrolytes & prevention of water re-absorption  watery diarrhea  severe dehydration </li></ul>Reoviridae: Rotavirus
  12. 15. <ul><li>NSP4 protein promotes: </li></ul><ul><ul><li>calcium influx into enterocytes </li></ul></ul><ul><ul><li>release of neuronal activators </li></ul></ul><ul><ul><li>neuronal alteration in water absorption </li></ul></ul><ul><li>Shortening and blunting of microvilli; mononuclear cell infiltration into lamina propia </li></ul><ul><li>10 10 viral particles/gm of stool released during disease  maximal shedding 2 – 5 days after start of diarrhea </li></ul><ul><li>(+) outbreaks in pre-schools and daycare centers </li></ul>Reoviridae: Rotavirus
  13. 16. <ul><li>CLINICAL SYNDROMES: </li></ul><ul><li>I.P. = 48 hrs </li></ul><ul><li>self-limited </li></ul><ul><li>vomiting, diarrhea, fever, dehydration </li></ul><ul><li>(-) fecal leukocytes and blood </li></ul><ul><li>may be fatal in infants from developing countries & who are malnourished and dehydrated before the infection </li></ul>Reoviridae: Rotavirus
  14. 17. <ul><li>LABORATORY DIAGNOSIS: </li></ul><ul><li>direct detection of viral antigens in stool – method of choice </li></ul><ul><li>enzyme immunoassay </li></ul><ul><li>latex agglutination </li></ul><ul><li>serology – four fold increase in antibody titer </li></ul>Reoviridae: Rotavirus
  15. 18. A 24-year old mountaineering student developed fever, chills, and headache 4 days after hiking in the forest. He also complained of photophobia, muscle pain, joint pains and lethargy. P.E. showed redness of conjunctiva, (+) LAD, and palpable liver margins. Maculopapular rashes were noted. Laboratory exam revealed leukopenia with neutropenia and lymphopenia. He remembers being bitten by an insect during the hike.
  16. 19. Reoviridae: Coltivirus & Orbivirus <ul><li>features different from other Reoviridae: </li></ul><ul><ul><li>Orbivirus – outer capsid without discernible capsomeric structure; inner capsid icosahedral </li></ul></ul><ul><ul><li>Causes viremia – long lasting </li></ul></ul><ul><ul><li>Infects erythrocyte precursors without damaging them  remains within the cells  protected from immune response  (+) viremia </li></ul></ul>
  17. 20. Reoviridae: Coltivirus & Orbivirus <ul><li>Coltivirus: </li></ul><ul><li>causes Colorado Tick Fever </li></ul><ul><li>vector: Dermacentor andersoni (wood tick) </li></ul><ul><li>one of the most common tick-borne diseases in the U.S. </li></ul><ul><li>symptoms of acute disease resemble dengue </li></ul><ul><li>infect vascular endothelial & vascular smooth muscle cells & pericytes  weak capillary structure  (+) hemorrhage  hypotension  shock </li></ul><ul><li>neuronal infection – meningitis & encephalitis </li></ul><ul><li>(+) leukopenia involving both neutrophils and lymphocytes  HALLMARK </li></ul>
  18. 23. Reoviridae: Coltivirus & Orbivirus <ul><li>LABORATORY: </li></ul><ul><li>Immunofluorescence – most rapid and best technique  detection of viral antigen on surface of red blood cells on blood smear </li></ul><ul><li>Antibody titer – specific IgM (+) 45 days after onset of illness  presumptive evidence of acute or very recent infection </li></ul>
  19. 24. Other Gastrointestinal Viruses <ul><li>CALICIVIRUSES </li></ul><ul><li>5 groups: </li></ul><ul><li>1. Norwalk 4. Marine virus </li></ul><ul><li>2. Sapporo viruses 5. Rabbit hemorrhagic dse virus </li></ul><ul><li>3. Hepatitis E </li></ul><ul><li>approx. same size as Picornaviruses </li></ul><ul><li>naked, positive sense ssRNA viruses </li></ul><ul><li>viruses distinguishable by capsid morphology </li></ul><ul><li>compromise function of intestinal brush border  prevent re-absorption of water and nutrients </li></ul><ul><li>cause outbreaks of gastroenteritis </li></ul>
  20. 26. Other Gastrointestinal Viruses <ul><li>I.P. = 24 – 48 hrs </li></ul><ul><li>MOT: 1. fecal-oral – water, shellfish, food service </li></ul><ul><li> 2. possible airborne </li></ul><ul><li>Immunity short-lived & not protective </li></ul><ul><li>Symptoms similar to Rotavirus infection </li></ul><ul><li>- Norwalk & related viruses  diarrhea, n & v, esp. in children; fever in 1/3 of patients </li></ul><ul><li>Resolve within 12 – 60 hrs </li></ul>
  21. 27. Other Gastrointestinal Viruses <ul><li>ASTROVIRUSES </li></ul><ul><li>seen in stools from infants & young children with diarrhea </li></ul><ul><li>may be shed in extraordinarily large amounts in feces </li></ul><ul><li>associated with diarrhea in young children in daycare centers </li></ul><ul><li>symptoms similar to Norwalk but without vomiting </li></ul><ul><li>minimally pathogenic </li></ul>
  22. 29. Other Gastrointestinal Viruses <ul><li>ADENOVIRUS </li></ul><ul><li>Replicates in intestinal cells </li></ul><ul><li>Adenovirus group F serotypes 40 & 41  infantile gastroenteritis  detected by electron microscopy or antigen-based assays </li></ul><ul><li>Usually sub-clinical </li></ul>
  23. 30. An 11-year old boy was brought to the hospital after falling. His bruises were treated and he was released afterwards. The following day, he refused to drink water with his medicine, and he became more anxious. That night, he began to act up and hallucinate. He was also salivating and had difficulty breathing. Two days later, he had high grade fever and experienced two episodes of cardiac arrest. His condition continued to deteriorate, and he died 11 days later. When the parents were questioned, it was learned that the boy had been bitten on the finger by a dog 6 months earlier.
  24. 32. Rhabdovirus <ul><li>“ rhabdo”  rod </li></ul><ul><li>bullet-shaped; enveloped; icosahedral nucleocapsid </li></ul><ul><li>negative ssRNA  prototype for replication of negative stranded enveloped viruses </li></ul>
  25. 34. Rhabdovirus <ul><li>encode 5 proteins: </li></ul><ul><ul><li>G – synthesized by membrane-bound ribosomes; attach to host cell & internalized by endocytosis; generates neutralizing antibodies; prototype for studying eukaryotic glycoprotein processing </li></ul></ul><ul><ul><li>N – major structural protein; protects the RNA from ribonuclease digestion </li></ul></ul><ul><ul><li>L and NS – constitute the RNA-dependent RNA pol </li></ul></ul><ul><ul><li>M – matrix protein; lies between envelope & nucleocapsid </li></ul></ul>
  26. 35. Rhabdovirus <ul><li>RABIES VIRUS </li></ul><ul><li>most significant pathogen </li></ul><ul><li>reservoir: wild and domestic animals </li></ul><ul><li>source of virus: </li></ul><ul><ul><li>Major – saliva in bite of rabid animal </li></ul></ul><ul><ul><li>Minor – aerosols in bat caves containing rabid bats </li></ul></ul><ul><li>found worldwide; no seasonal incidence </li></ul>
  27. 36. Rhabdovirus <ul><li>PATHOGENESIS & IMMUNITY </li></ul><ul><li>MOT: </li></ul><ul><li>1. bite of rabid animal </li></ul><ul><li> 2. inhalation of aerosolized virus </li></ul><ul><li> 3. transplanted infected tissue (e.g. cornea) </li></ul><ul><li> 4. inoculation through intact mucosal membrane </li></ul><ul><li>rabies infection of animal  cause secretion of the virus in the animal’s saliva & promotes aggressive behavior  “mad dog”  promote transmission </li></ul><ul><li>not very cytolytic  remains cell associated </li></ul>
  28. 37. Rhabdovirus Wks to mos Afferent neurons Incubation phase Prodrome phase Neurologic phase MOT Bind to nicotinic Ach or ganglioside receptors of neurons Muscle at site of inoculation Replicate at site of bite Skin of head & neck, salivary glands, retina, cornea, nasal mucosa, adrenal medulla, renal parenchyma, pancreatic acinar cells CNS (hippocampus, brainstem, ganglionic cells of pontine nuclei, Purkinje cells of cerebellum) Travel by retrograde axoplasmic transport to DRG & to SC
  29. 38. Rhabdovirus <ul><li>length of incubation period determined by: </li></ul><ul><ul><li>concentration of virus in inoculum </li></ul></ul><ul><ul><li>proximity of wound to brain </li></ul></ul><ul><ul><li>severity of the wound </li></ul></ul><ul><ul><li>host’s age </li></ul></ul><ul><ul><li>host’s immune status </li></ul></ul><ul><li>rarely causes inflammatory lesions </li></ul><ul><li>CMI with little or no role in protection </li></ul><ul><li>antibody can block spread of virus to CNS if administered or generated during the incubation period </li></ul><ul><li>long incubation period allows active immunization as post-exposure treatment </li></ul>
  30. 39. Rhabdovirus PROGRESSION OF RABIES DISEASE Disease Phase Symptoms Time (days) Viral Status Immunologic status Incubation Asymptomatic 60 – 365 after bite Low titer, virus in muscle Prodrome Fever, n & v, anorexia, headache, lethargy, pain at bite site 2 – 10 Low titer, virus in CNS and brain Neurologic Hydrophobia, pharyngeal spasms, hyperactivity, anxiety, depression CNS: loss of coordination, paralysis, confusion 2 – 7 High titer, virus in brain and other sites Detectable antibody in serum & CNS Coma Coma: cardiac arrest, hypotension, hypoventilation, secondary infections 0 – 14 High titer, virus in brain and other sites Death
  31. 42. Rhabdovirus <ul><li>LABORATORY DIAGNOSIS: </li></ul><ul><li>done to confirm the diagnosis </li></ul><ul><li>1. detection of viral antigen in CNS or skin via immunofluorescence  most widely used </li></ul><ul><li>2. virus isolation – cell culture </li></ul><ul><li>3. serology – antibody titers in serum and CSF </li></ul><ul><li>4. detection of Negri bodies – intracytoplasmic inclusions containing aggregates of viral nucleocapsids in affected neurons  HALLMARK </li></ul>
  32. 44. Rhabdovirus <ul><li>PRE-EXPOSURE VACCINATION: </li></ul><ul><ul><li>HDCV IM or intradermally x 3 doses  2 years protection </li></ul></ul><ul><li>POST-EXPOSURE PROPHYLAXIS: </li></ul><ul><li>local treatment of wound – wash immediately with soap & water </li></ul><ul><li>WHO Expert Committee on Rabies – instillation of anti-rabies around the wound </li></ul><ul><li>active + passive immunization </li></ul><ul><ul><li>HDCV IM on day of exposure then on days 3, 7, 14 & 28 + 1 dose human rabies immune globulin (HRIG) </li></ul></ul>