togaviruses & bunyaviruses
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ARBOVIRUSES:TOGAVIRUSES & BUNYAVIRUSES
EDWARD-BENGIE L. MAGSOMBOL, MDFPCP, FPCC, DASNC
Associate Professor, Department of MicrobiologyFatima College of Medicine
I. INTRODUCTION New pathogenic viruses emerging due
to human practices 500 known arboviruses, 100
pathogenic to humans and 50 to animals
includes unrelated viruses that are arthropod-borne but now also includes non-arthropod-borne but morphologically similar viruses (Hantaan)
arthropods: mosquitoes, ticks, flies. mites
clinical syndromes: mostly mild, acute, undifferentiated febrile illness
complications: rash, hemorrhage, encephalitis, hepatitis or renal failure
found in almost all parts of the world including the Arctic
Ex. of outbreaks: Rift Valley Fever, Egypt
(1970s) Yellow fever, West Africa (1986-
1991)
II. VIRUS STRUCTURE AND GENETICS
Families: Togaviridae, Flaviviridae, Bunyaviridae Genera: 1. Togaviridae: 4 members but Alphavirus is the only arthropod borne a. Alphavirus : ssRNA (+) stranded
Spherical, 60-70 nm, enveloped 3 structural CHONs: capsid,
glycosylated E2 and E1 WEE, EEE, VEE
b. Rubivirus : Rubella c. Pestivirus and Arterivirus (non-pathogenic
to humans)
2. Flaviviridae: ssRNA, (+) stranded, 40-50 nm,
enveloped 3 structural CHONs: capsid, glycosylated
CHON small, membrane
associated non-
glycosylated CHON Ex. dengue, yellow fever, Jap B
Encephalitis, St. Louis Encephalitis, Russian
Spring Summer Encephalitis, Prowasan
3. Bunyaviridae: Bunyamwera, Phlebovirus,
Nairovirus, Hantavirus
80-100 nm, 3-segment genome of (-) stranded RNA
3 glycosylated CHONs enveloping virions
nucleocapsid (M or middle RNA segment)
(S or small RNA segment)
(L or large RNA segment)
no matrix proteins polymerase, other CHONs
alpha, flavi, and bunya viruses are all sensitive to lipid solvents and heat
important survival mechanism: generating genetic diversity
escape from immune responses, adaptation to new hosts, alter replication patterns
1. genetic drift = deletions, mutations and inversions (alpha, flavi, rhabdo)
2. genetic shift = genome segment reassortment (bunya, orbivirus)
recombination= not known for arboviruses
III. DIAGNOSIS due to prior exposure, absolute Ab titers
may be misleading virus-specific peptides virus-specific IgM titers helpful only in
some cases most accurate method: isolation of virus from
serum culture via: intracerebral
inoculation of suckling
mice continuous cell
lines (mosquito
cells)
TOGAVIRUSES
• Enveloped, positive, single-stranded RNA viruses with icosahedral nucleocapsid
• Genome encodes early (non-structural) and late (structural) proteins
• Replicate in the cytoplasm and bud at the plasma membrane
TOGAVIRUSES
Virus Group Human Pathogens
AlphavirusRubivirusPestivirusArterivirus
ArbovirusesRubella virusNoneNone
TOGAVIRUSES
Alphavirus Vector Host Distribution Disease
Sindbis Aedes & other mosquitoes
Birds Africa, Australia, India
Subclinical
Semliki Forest
Aedes & other mosquitoes
Birds East and West Africa
Subclinical
VEE Aedes, Culex Rodents, horses
North, South & Central America
Mild systemic, severe enceph.
EEE Aedes, Culiseta
Birds North & South America, Caribbean
Mild systemic; enceph.
WEE Culex, Culiseta
Birds North & South America
Mild systemic; enceph.
Chikungunya Aedes Humans, monkeys
Africa, Asia Fever, arthralgia, arthritis
TOGAVIRUSES: Mosquito Vectors
Culex
Aedes triseriatus Culiseta melanura
TOGAVIRUSES: Alphaviruses
• Classified as arboviruses (arthropod-borne viruses). To be an arbovirus, the virus must be able to:1. Infect both vertebrates & invertebrates2. Initiate sufficient viremia in a vertebrate
host for a sufficient time to allow acquisition of the virus by the invertebrate vector
3. Initiate a persistent productive infection of the salivary gland of the invertebrate to provide virus for the infection of other host animals
TOGAVIRUSES: Alphaviruses
• With broad host range including vertebrates and invertebrates
• Diseases spread by animals or with an animal reservoir zoonotic
• Structurally similar to Picornaviruses but larger
TOGAVIRUSES: Alphaviruses
• Capsid proteins of all Alphaviruses are similar in structure and are antigenically cross-reactive
• Individual viruses with different tissue tropisms
• Enters the cell by receptor-mediated endocytosis bind to ribosomes as mRNA
TOGAVIRUSES: Alphaviruses
• Major differences between Alphaviruses and Flaviviruses are in the organization of their genome and their mechanism of protein synthesiso Entire flavivirus genome translated into a
single polyproteino Replicate in the cytoplasm and bud at the
plasma membraneso Flavivirus structural genes are at the 5’ end
of the genome structural proteins synthesized first and with the greatest efficiency
TOGAVIRUSES: Alphaviruses
• MOT: bite of an arthropod
• Humans are usually “dead-end” hosts due to absence of persistent viremia
• Female mosquito acquire the viruses by taking a blood meal from a viremic vertebrate host
• Most common vector is the mosquito. Birds and mammals are the usual reservoirs.
TOGAVIRUSES: Alphaviruses
• Diseases occur during the summer months and rainy seasons
• Urban outbreaks occur when the reservoirs for the virus are humans or urban animals.
• Humans can be reservoirs for dengue, yellow fever, and chikungunya.
TOGAVIRUSES: Alphaviruses
• Viruses are cytolytic
• Viruses establish systemic infection and viremia.
• Viruses are good inducers of interferon, accounting for the flu-like symptoms of infection.
TOGAVIRUSES: Alphaviruses
Initial viremia Systemic symptoms within 3 to 7 days of infection
Replication in cells of monocyte-macrophage
system
Secondary viremia
Brain via endothelial cells lining small vessels of the brain or the choroid plexus
Liver, skin, vasculature (depending on tissue tropism of the virus)
TOGAVIRUSES: Alphaviruses
• Disease characterized as low-grade disease
• Flu-like symptoms correlate with systemic infection during the initial viremia
• EEE, WEE, and VEE progress to encephalitis in humans (fever, headache & dec. consciousness 3-10 days after infection) generally resolve without sequelae but with possibility of paralysis, mental disability, seizures and death
TOGAVIRUSES: Alphaviruses
Chikungunya
• Swahili for “that which bends up”
• Vector: Aedes aegypti
• Crippling arthritis with serious disease due to infection with the virus
TOGAVIRUSES: Alphaviruses
TOGAVIRUSES: Alphaviruses
Disease Mechanisms of Togaviruses & Flaviviruses
DiseaseFlu-like
symptoms
Ence-phalitis Hepatitis
Hemor- rhage Shock
VEE + +
EEE + +
WEE + +
Dengue + + + +
Yellow fever + + + +
St. Louis enceph + +
Japanese enceph + +
West Nile enceph + +
TOGAVIRUSES: Alphaviruses
Laboratory Diagnosis:
1. Culture• can be grown in both vertebrate and
mosquito cell lines but difficult to isolate
2. Cytopathologic studies3. Immunofluorescence4. Reverse transcriptase-PCR5. Serology – hemagglutination inhibition,
ELISA, latex agglutination• Presence of specific IgM or 4-fold rise in
titer between acute and convalescent sera indicate a recent infection
TOGAVIRUSES: Rubella Virus
• Same structural properties and mode of replication as other togaviruses.
• Unlike other togaviruses:1. It is a respiratory virus2. It does not cause readily detectable
cytopathologic effects
• Rubella means “little red”
• Maternal infection correlated with several other severe congenital defects
TOGAVIRUSES: Rubella Virus
• Replication of the virus prevents replication of superinfecting picornaviruses by means of heterologous interference
• Infects upper respiratory tract local LN (+ LAD) viremia infection of other tissues
• Prodromal period lasts approx. 2 weeks
• Viral shedding: prodromal period and for as long as two weeks after onset of rash
TOGAVIRUSES: Rubella Virus
• Antibody generated after the viremia correlates with appearance of rash limit viremic spread
• Immune complexes most likely cause the rash and arthralgia associated with the infection.
• CMI important in resolving the infection
• Natural infection produces lifelong protective immunity
TOGAVIRUSES: Rubella Virus
Congenital Infection
• Occurs if mother does not have antibody virus replicates in the placenta spread to fetal blood supply & throughout the fetus
• Alter normal growth, mitosis, and chromosomal structure of the fetus’s cells
• Nature of the disorder determined by:1. Tissue affected2. Stage of development disrupted
TOGAVIRUSES: Rubella Virus
Congenital Rubella Syndrome
• Most serious outcome of infection
• Fetus at risk until 20th week AOG
• Most common manifestations: cataracts, mental retardation, deafness
TOGAVIRUSES: Rubella Virus
TOGAVIRUSES: Rubella Virus
Rubella Disease (German Measles)
• Normally benign in childreno I.P. = 14 – 21 dayso 3-day maculopapular or macular
rash + swollen glands
• Infection in adults may be more severeo Arthralgia & arthritiso Thrombocytopenia or post-
infectious encephalopathy – rare
TOGAVIRUSES: Rubella Virus
TOGAVIRUSES: Rubella Virus
Laboratory Diagnosis
• Isolation difficult & rarely attempted
• Diagnosis confirmed by the presence of anti-rubella-specific IgM
• 4-fold increase in specific IgG antibody titer between acute and convalescent sera recent infection
BUNYAVIRIDAE
• “Supergroup” of at least 200 enveloped, segmented, negative-strand RNA viruseso Broken down into four genera on the
basis of structural and biochemical features
• Unlike other negative-strand RNA viruses, they do not have a matrix protein
• Replicates in cytoplasm
BUNYAVIRIDAE
Genus Members Insect vector
Pathologic Conditions
Vertebrate Hosts
Bunyavirus Bunyamwera, California enceph virus, La Crosse virus
Mosquito Febrile illness, encephalitis, febrile rash
Rodents, small mammals, primates, marsupials, birds
Phlebovirus Rift Valley fever virus, sandfly fever virus
Fly Sandfly fever, hemorrhagic fever, encephalitis, conjunctivitis, myositis
Sheep, cattle, domestic animals
Nairovirus Crimean-Congo hemorrhagic fever virus
Tick Hemorrhagic fever
Hares, cattle, goats, sea- birds
BUNYAVIRIDAE
Genus Members Insect vector
Pathologic Conditions
Vertebrate Hosts
Uukuvirus Uukuniemi virus
Tick --- Birds
Hantavirus Hantaan virus
Sin Nombre
None
None
Hemorrhagic fever with renal syndrome, ARDS synd.
Hantavirus pulmonary syndrome, shock, pulmonary edema
Rodents
Deer mouse
BUNYAVIRIDAE
• Virus can infect humans and arthropods
• Virus in arthropod can be transmitted to its eggs allow virus to survive during winter
• Effects:1. Neuronal & glial damage + cerebral
edema encephalitis2. Hepatic necrosis (e.g. Rift Valley Fever)3. Leakage of plasma & erythrocytes through
vascular endothelium hemorrhagic fever
BUNYAVIRIDAE
• MOT: vectors mosquitoes, ticks or Phlebotomus flies
• Virus transmitted to rodents, birds and larger animals become reservoirs
• Transmission occurs during summer but unlike other arboviruses, many of the Bunyaviridae can survive a winter in the ova of the mosquito
BUNYAVIRIDAE
• California encephalitis group: Aedes triseriatus & Culiseta
• Hantaviruses without arthropod vector maintained in a rodent species specific for each viruso Humans are infected by close contact with
rodents or through the inhalation of aerosolized rodent urine
BUNYAVIRIDAE
BUNYAVIRIDAE
Clinical Syndromes:
• Incubation period: approx. 48 hours
• Non-specific febrile flu-like illness
• Fever lasts approximately 3 days
BUNYAVIRIDAE
Clinical Syndromes:
1. Encephalitis illnesses (e.g. La Crosse)• Sudden onset after I.P. of ~ 1 week• Fever, headache, lethargy, vomiting• Seizures in 50% of patients
2. Hemorrhagic fevers (e.g. Rift Valley)• Petechial hemorrhages, ecchymoses,
epistaxis, hematemesis, melena, gum bleeding
BUNYAVIRIDAE
Clinical Syndromes:
Hantaan virus• Korean hemorrhagic fever• Headache, petechial rash, shock, and
renal failure• Rodent-borne
Sin Nombre virus• Hantavirus pulmonary syndrome• Influenza-like symptoms followed by
acute respiratory failure• Endemic in deer mice (Peromyscus)
BUNYAVIRIDAE
Laboratory Diagnosis:
• Serologic tests to confirm diagnosis
• ELISA – detect antigen to clinical specimen from patients with intense viremia
• RT-PCR – Sin Nombre virus
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