Alphaviruses (Togaviridae) and Flaviviruses



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Alphaviruses (Togaviridae) and Flaviviruses (Flaviviridae)

Alan L. Schmaljohn

David McClain

General Concepts

Alphaviruses

Clinical Manifestations

Disease occurs in either of two general forms, depending upon the virus: one is typified by fever, malaise, headache, and/or symptoms of encephalitis (e.g., eastern, western, or Venezuelan equine encephalitis viruses) and the other by fever, rash, and arthralgia (e.g., chikungunya, Ross River, Mayaro, and Sindbis viruses).



Structure

The enveloped virions are spherical, 60 to 70 nm in diameter with a positive-sense, monopartite, single-stranded RNA genome, ca. 11.7 kilobases long. The lipid-containing envelope has two (rarely three) surface glycoproteins that mediate attachment, fusion, and penetration. The icosohedral nucleocapsid contains capsid protein and RNA. Virions mature by budding through the plasma membrane.



Classification and Antigenic Types

Alphavirus is one of two genera in the family Togaviridae; Rubivirus (rubella virus), the other togavirus genus, is discussed in Chapter 55. The 27 alphaviruses are classified on the basis of antigenic properties. All alphaviruses share antigenic sites on the capsid and at least one envelope glycoprotein, but viruses can be differentiated by several serological tests, particularly neutralization assays.

Multiplication

Genomic RNA is capped and polyadenylated and serves as mRNA for nonstructural proteins (e.g., RNA-dependent RNA polymerase) which are encoded in the 5' two-thirds of the genome. Complementary (antisense) RNA, made from genomic RNA, serves as a template for progeny genomic RNA. A subgenomic mRNA representing the 3' one-third of the genome encodes the structural proteins.





Pathogenesis

Infection is transmitted via infected mosquitoes. In the vertebrate host, transient viremia and dissemination occur as virus is released from cells that later lyse. Infection with seroconversion in the absence of clinical disease is common, but disease can be incapacitating and, in cases of encephalitis, occasionally fatal. Virus is eliminated by the immune system but arthritis or central nervous system impairment may persist for weeks.



Host Defenses

Initial resistance is conferred by nonspecific defenses such as interferon. Antibodies are important in recovery and resistance, and T-cell responses are also involved. Lasting protection is generally restricted to the same alphavirus and is associated with, but not solely attributable to, the presence of neutralizing antibodies.



Epidemiology

Viruses are maintained in nature by mosquito-vertebrate-mosquito cycles. Restricted interactions between viruses, vector species, and vertebrate hosts tend to confine the geographic spread of alphaviruses. Occasionally, a virus may escape its usual ecological niche and cause widespread epizootics (Venezuelan equine encephalitis virus) or urban epidemics (chikungunya virus). Human infections are seasonal and are acquired in endemic areas.



Diagnosis

Diagnosis is suggested by clinical evidence and by known risk of exposure to virus. Confirmation is typically by virus isolation and identification, or by a specific rise in IgG antibody, or the presence of IgM antibody.



Control

Disease surveillance and virus activity in natural hosts are used to determine whether control measures will be undertaken to reduce populations of vector mosquitoes or to vaccinate hosts, especially horses. Human vaccines, where available, are used only in individuals at particularly high risk of exposure, such as laboratory workers.



Flaviviruses

Clinical Manifestations

Major syndromes and examples of causative flaviviruses include: encephalitis (St.Louis encephalitis, Japanese encephalitis, Powassan, and tick-borne encephalitis viruses), febrile illness with rash (dengue virus), hemorrhagic fever (Kyasanur Forest disease virus and sometimes dengue virus), and hemorrhagic fever with hepatitis (yellow fever virus).



Structure

Virions are spherical and 40-50 nm in diameter with a positive-sense, nonsegmented, single-stranded RNA genome of ca. 10.9 kilobases. The lipid-containing envelope has one surface glycoprotein that mediates attachment, fusion, and penetration, and an internal matrix protein. The nucleocapsid contains capsid protein and RNA. Virions mature at intracytoplasmic membranes.



Classification and Antigenic Types

Classification within the genus is based upon antigenic properties. Flaviviruses share one or more common antigenic sites, but viruses can be differentiated by several serological tests, particularly neutralization assays.



Multiplication

Genomic RNA is capped (not polyadenylated) and serves as mRNA for all proteins. Structural proteins are encoded at the 5' end of the genome, and nonstructural proteins (e.g., RNA-dependent RNA polymerase) are encoded in the 3' two-thirds. Complementary (antisense) RNA, made from genomic RNA, serves as a template for progeny genomic RNA.





Pathogenesis

Infection is initiated by the bite of an infected mosquito or tick. Virus disseminates during lytic infection of cells, causing viremia. Infection and seroconversion in the absence of apparent disease are common, but case fatality rates can be high. Virus is eliminated (with rare exception) by the immune system. In dengue hemorrhagic shock syndrome, disease is thought to be exacerbated by preexisting immunity to a related flavivirus (i.e., immune enhancement).



Host Defenses

Initial resistance can be conferred by a variety of nonspecific defenses. Antibodies are demonstrably important in recovery and resistance, and T-cell responses are also evident. Lasting protection is generally restricted to the same flavivirus, and is associated with neutralizing antibodies.



Epidemiology

Viruses are maintained in nature by transmission in mosquito-vertebrate-mosquito or tick-vertebrate-tick cycles. With yellow fever and dengue viruses, humans are important intermediate hosts during urban epidemics. Human infections are seasonal and are acquired in endemic areas.



Diagnosis

Diagnosis is suggested by clinical evidence and by known risk of exposure to virus. It is confirmed by virus isolation and identification. Alternatively, a specific rise in antibody titer may confirm diagnosis, but for individuals immune to more than one flavivirus, it may be difficult to serologically discriminate the more recent infection due to some type of cross reactivity.



Control

Surveillance of disease activity and of virus in natural hosts is used to determine whether control measures will be undertaken to reduce populations of vector mosquitoes. A safe and effective live-attenuated vaccine exists for yellow fever, and inactivated-virus vaccines are available for Japanese encephalitis and tick-borne encephalitis.







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