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FE A. BARTOLOME, MD, FPASMAPDepartment of Microbiology &
ParasitologyOur Lady of Fatima University
Reovirus, Rhabdovirus andReovirus, Rhabdovirus andGastrointestinal VirusesGastrointestinal Viruses
Reoviridae
respiratory and enteric viruses not associated with any known disease process Respiratory, Enteric, Orphan
Members:
1. Orthoreovirus – mild URT illness, GIT illness, biliary atresia
2. Orbivirus/Coltivirus – febrile illness associated with headache and myalgia (zoonosis)
3. Rotavirus – GIT illness, respiratory tract illness (?)
Non-enveloped; double-layered protein capsids with dsRNA genomes (“double:double”)
Stable over wide pH & temperature changes & in airborne aerosols
ReoviridaeReoviridae
STRUCTURE:
Icosahedral with double stranded segmented genome
Reovirus – 10 segments
Rotavirus – 11 segments
(+) re-assortment of gene segments create hybrid viruses
ReoviridaeREPLICATION:
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
Reoviridae
REPLICATION:
Occurs in the cytoplasm
dsRNA remains in the core
Virus leaves the cell during cell lysis
Mammalian reovirus
Ubiquitous present in sewage & river water
3 serotypes (1, 2 & 3) based on neutralization and hemagglutination-inhibition tests
Most people infected during childhood (+) antibodies in 75% of adults
Reoviridae: Orthoreovirus
PATHOGENESIS & IMMUNITY
No significant disease in humans
After ingestion & proteolytic production of ISVP, binds to M cells in small intestines transfer virus to lymphoid tissue of Peyer’s patches replicate (+) viremia
(+) humoral & cellular immune response to outer capsid protein
Reoviridae: Orthoreovirus
CLINICAL SYNDROMES:
1. Usually asymptomatic
2. Common cold-like mild upper respiratory tract illness
3. Gastrointestinal disease
4. Biliary atresia
LABORATORY DIAGNOSIS:
1. Assay of viral antigen or RNA in clinical material
2. Virus isolation
3. Serologic assays
Reoviridae: Orthoreovirus
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.
Rota “wheel”
One of the most common agents of infantile diarrhea worldwide
Ubiquitous worldwide
95% of children infected by 3 – 5 years old
Stable at: room temperature, treatment with detergents, pH 3.5 – 10, repeated freezing & thawing; survives on fomites
Divided into:
1. Serotypes – based primarily on VP7 outer capsid protein
2. Groups – based on antigenicity of VP6 & electrophoretic mobility of genomic segments A to G group A causes human disease
Reoviridae: Rotavirus
PATHOGENESIS:
• MOT: fecal-oral, possibly respiratory route
• 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
Reoviridae: Rotavirus
NSP4 protein promotes:1. calcium influx into enterocytes2. release of neuronal activators3. neuronal alteration in water absorption
Shortening and blunting of microvilli; mononuclear cell infiltration into lamina propia
1010 viral particles/gm of stool released during disease maximal shedding 2 – 5 days after start of diarrhea
(+) outbreaks in pre-schools and daycare centers
Reoviridae: Rotavirus
CLINICAL SYNDROMES:
• I.P. = 48 hrs
• self-limited
• vomiting, diarrhea, fever, dehydration
• (-) fecal leukocytes and blood
• may be fatal in infants from developing countries & who are malnourished and dehydrated before the infection
Reoviridae: Rotavirus
LABORATORY DIAGNOSIS:
1. direct detection of viral antigens in stool – method of choice
2. enzyme immunoassay
3. latex agglutination
4. serology – four fold increase in antibody titer
Reoviridae: Rotavirus
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.
Reoviridae: Coltivirus & Orbivirus
features different from other Reoviridae:
1. Orbivirus – outer capsid without discernible capsomeric structure; inner capsid icosahedral
2. Causes viremia – long lasting
3. Infects erythrocyte precursors without damaging them remains within the cells protected from immune response (+) viremia
Reoviridae: Coltivirus & Orbivirus
Coltivirus:
causes Colorado Tick Fever vector: Dermacentor andersoni (wood tick) one of the most common tick-borne diseases in the U.S. symptoms of acute disease resemble dengue infect vascular endothelial & vascular smooth muscle cells & pericytes weak capillary structure (+) hemorrhage hypotension shock neuronal infection – meningitis & encephalitis (+) leukopenia involving both neutrophils and lymphocytes HALLMARK
Reoviridae: Coltivirus & Orbivirus
LABORATORY:
Immunofluorescence – most rapid and best technique detection of viral antigen on surface of red blood cells on blood smear
Antibody titer – specific IgM (+) 45 days after onset of illness presumptive evidence of acute or very recent infection
Other Gastrointestinal Viruses
CALICIVIRUSES
5 groups:1. Norwalk 4. Marine virus2. Sapporo viruses 5. Rabbit hemorrhagic dse virus3. Hepatitis E
approx. same size as Picornaviruses naked, positive sense ssRNA viruses viruses distinguishable by capsid morphology compromise function of intestinal brush border
prevent re-absorption of water and nutrients cause outbreaks of gastroenteritis
Other Gastrointestinal Viruses
I.P. = 24 – 48 hrs MOT: 1. fecal-oral – water, shellfish, food service
2. possible airborne
Immunity short-lived & not protective
Symptoms similar to Rotavirus infection- Norwalk & related viruses diarrhea, n & v, esp. in children; fever in 1/3 of patients
Resolve within 12 – 60 hrs
Other Gastrointestinal Viruses
ASTROVIRUSES seen in stools from infants & young children with
diarrhea
may be shed in extraordinarily large amounts in feces
associated with diarrhea in young children in daycare centers
symptoms similar to Norwalk but without vomiting
minimally pathogenic
Other Gastrointestinal Viruses
ADENOVIRUS Replicates in intestinal cells
Adenovirus group F serotypes 40 & 41 infantile gastroenteritis detected by electron microscopy or antigen-based assays
Usually sub-clinical
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.
Rhabdovirus
“rhabdo” rod
bullet-shaped; enveloped; icosahedral nucleocapsid
negative ssRNA prototype for replication of negative stranded enveloped viruses
Rhabdovirus
• encode 5 proteins:1. G – synthesized by membrane-bound
ribosomes; attach to host cell & internalized by endocytosis; generates neutralizing antibodies; prototype for studying eukaryotic glycoprotein processing
2. N – major structural protein; protects the RNA from ribonuclease digestion
3. L and NS – constitute the RNA-dependent RNA pol
4. M – matrix protein; lies between envelope & nucleocapsid
Rhabdovirus
RABIES VIRUS
most significant pathogen
reservoir: wild and domestic animals
source of virus:1. Major – saliva in bite of rabid animal2. Minor – aerosols in bat caves containing
rabid bats
found worldwide; no seasonal incidence
Rhabdovirus
PATHOGENESIS & IMMUNITY
• MOT: 1. bite of rabid animal 2. inhalation of aerosolized virus 3. transplanted infected tissue (e.g. cornea) 4. inoculation through intact mucosal membrane
• rabies infection of animal cause secretion of the virus in the animal’s saliva & promotes aggressive behavior “mad dog” promote transmission
• not very cytolytic remains cell associated
RhabdovirusMOT
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
Wks to mosWks to mos
Afferent neuronsAfferent neurons
CNS (hippocampus, brainstem, ganglionic cells of pontine nuclei,
Purkinje cells of cerebellum)
Incubation phaseIncubation phase
Travel by retrograde axoplasmic transport to DRG & to SC
Prodrome phaseProdrome phase
Neurologic phaseNeurologic phase
Rhabdovirus
• length of incubation period determined by:1. concentration of virus in inoculum2. proximity of wound to brain3. severity of the wound4. host’s age5. host’s immune status
• rarely causes inflammatory lesions• CMI with little or no role in protection• antibody can block spread of virus to CNS if
administered or generated during the incubation period
• long incubation period allows active immunization as post-exposure treatment
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
Rhabdovirus
LABORATORY DIAGNOSIS:
• done to confirm the diagnosis
1. detection of viral antigen in CNS or skin via immunofluorescence most widely used
2. virus isolation – cell culture 3. serology – antibody titers in serum and CSF 4. detection of Negri bodies – intracytoplasmic
inclusions containing aggregates of viral nucleocapsids in affected neurons HALLMARK
Rhabdovirus
PRE-EXPOSURE VACCINATION:• HDCV IM or intradermally x 3 doses 2 years
protection
POST-EXPOSURE PROPHYLAXIS:1. local treatment of wound – wash immediately with soap
& water2. WHO Expert Committee on Rabies – instillation of anti-
rabies around the wound3. active + passive immunization
• HDCV IM on day of exposure then on days 3, 7, 14 & 28 + 1 dose human rabies immune globulin (HRIG)