Togavirus Infection And Immunity

Ian McConnell, Department of Clinical and Veterinary Medicine, University of Cambridge, Cambridge, UK

Copyright © 1998 Elsevier Ltd. All Rights Reserved.

The Togaviridae family of small positive-strand RNA viruses are responsible for a large number of diseases of domestic animals and humans. Illness varies from mild inapparent infection to acute fevers and in many cases severe fulminating diseases with high morbidity and mortality. Many of the infections reach epidemic proportions, are arthropod borne (usually mosquitoes) and, for some of the viruses, reservoirs of infection exist within wild vertebrates such as birds, rodents and primates, where infection is inconsequential. In other cases the major source of infection is human. The viruses cause their characteristic diseases on transmission to humans and domestic animals which can be tangential to the wildlife cycle. Togaviruses are important zoonoses with humans becoming infected as a consequence of vector transmission from domestic livestock (e.g. pigs, horses). Studies on infection and immunity with these viruses have revealed particular facets of immune responses to viruses in terms of mechanisms of immunity, immunopathology and immunological tolerance.

Togaviridae are small (60-65 nm diameter) positive-stranded RNA viruses with a characteristic ico-sahedral capsid and 'close fitting' envelope (hence the original description as TOGA-viridae). Many of the viruses of the various genera have now been cloned and sequenced (Table 1). Prior to molecular data the flaviviruses were regarded as a genus within the

Table 1 Some properties of Togaviridae Genus Disease

Togaviridae, but they are now considered a separate family.

The Togaviridae are amongst the most simple enveloped viruses and comprise three genera and two members: alphaviruses (e.g. Sindbis virus, Semliki Forest virus, eastern equine encephalitis,1; rubivirus (e.g. rubella); pestiviruses (e.g. hog cholera or swine fever virus, bovine viral diarrhea virus - BVDV - and border disease virus of sheep - BD). Also included in the Togaviridae are equine arteritis virus (arterivirus) and lactate dehydrogenase (LDH) virus of mice. The latter is nonpathogenic but represents a good model for studying factors involved in control of viremia in vivo as it grows to extremely high titers in infected mice (109 infectious particles ml ' of serum) which can persist for the lifetime of the animal without causing significant disease. Not all viral infections with these viruses are transmitted by vectors. Rubella and pestiviruses are directly transmitted between individuals by droplet infection and transplacental transmission.

The small nonsegmented RNA genome (10-11 kb 4X 106 mol.wt) functions as mRNA and encodes three to four nonstructural (NS) proteins, a core protein closely associated with the nucleocapsid and one or two envelope proteins designated HI and E2. The Togaviridae 49S RNA genome has a 7-methylguano-sine cap and is polyadenylated at the 3' end with the order of the genes being nonstructural at the 5' end

Main host(s) Vector Virus

Mosquito Eastern equine encephalitis Western equine encephalitis Venezuelan equine encephalitis — Sindbis-'

Semliki Forest Mosquito O'Nyong-nyong

Chikungunya Mosquito Ross River None Rubella

None Bovine viral diarrhea

None Hog cholera

None Border disease

Not known Equine arteritis

Togaviridae

Alphavirus (26) Fever, encephalitis

Horse/human

Rubivirus (1) Pestivirus (3)

Arterivirus (1)

Myositis, encephalitis

Fever, arthritis, rash

Epidemic polyarthritis Fever, rash, arthritis, congenital infection Viral diarrhea mucosal disease Swine fever

Congenital disease of skin and nervous system Arteritis, abortion

Mouse/human

Human

Human

Human

Cattle

Pigs

Sheep

Horse

(four genes) and structural at the 3' end (four genes). The nonstructural proteins are translated directly from the full length RNA but the structural proteins are derived from a subgenomic 26S mRNA which is identical in sequence to one-third of genomic RNA at the 3' end. The Flaviviridae genome comprises a single uninterrupted reading frame which is not poly-adenylated at the 3' end. Molecular cloning of one of the pestiviruses (BVDV) has revealed that the bovine pestivirus is closer to the Flaviviridae family than the Togaviridae. A strong case has been made for the reclassification of pestiviruses as members of the Flaviviridae family.

Rubella in humans, and BVDV and BD in ruminants can be inapparent infections in young individuals but severe problems arise if infections occur during pregnancy. Infection of the fetus results either in abortion or congenital malformations, or birth of animals which are immunologically tolerant to the infecting virus. Rubella in adults can induce an acute arthritis and skin lesions, and in 0.06% of cases a viral-induced encephalopathy can be a serious complication.

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