Flavivirus Infection And Immunity

Thomas J Chambers, Department of Molecular Microbiology and Immunology, St Louis University Health Sciences Center, St Louis, Missouri, USA

The family Flaviviridae includes 69 viruses, the majority of which are transmitted by mosquitoes and ticks. Some are zoonotic agents without known arthropod vectors. More than half of these arboviruses have been associated with human disease. The viruses are distributed worldwide in many distinct ecological patterns, and cause three principal syndromes in humans: febrile illness, encephalitis and hemorrhagic fever. The most important viruses are yellow fever (YF), dengue (DEN), Japanese encephalitis (JE) and tickborne encephalitis (TBE). Flaviviruses are enveloped RNA viruses containing a single linear RNA molecule of approximately 10 000 nucleotides, encoding three structural and at least seven nonstructural proteins (Figure 1). The genome is encapsidated by a core protein and enclosed within a lipid envelope containing the M and E proteins. The E protein is critical for infection and immunity, as it contains cellular receptor-binding determinants, a membrane fusion activity and epitopes for neutralizing antibodies.

Characteristics of flaviviruses

Flaviviruses have been traditionally classified on the basis of antigenic cross-reactivity of the E protein, including both neutralization and hemagglutinating properties. Group-reactive, serocomplex-reactive and type-specific determinants have been described, although these underrepresent the antigenic relation ships of many viruses. Eight different antigenic groups can be defined (Table 1).

YF, the prototype of the flavivirus family, is anti-genically distinct and classified with 16 other viruses which are serologically unrelated to defined groups. YF is a zoonotic disease which causes hemorrhagic fever in subsaharan Africa and tropical regions of South America. Up to a few hundred cases in South America, and several thousand cases in Africa have been reported annually.

JE virus, the prototype of the JE serogroup, is distributed throughout many countries of Asia, and is responsible for 30 000-40 000 cases annually in China, with an associated mortality rate of approximately 30%. It is the most important arthropod-transmitted viral encephalitis worldwide. Other JE serocomplex viruses are also important human pathogens.

The tickborne encephalitis (TBE) virus complex includes 14 viruses, of which eight are known human pathogens. TBE occurs in regions of Europe and the former Soviet Union where the ixodid tick vector is prevalent and is a serious disease with variable mortality depending on the subtype of virus and age of onset in clinical cases. Two viruses within the TBE complex cause hemorrhagic fever.

The dengue (DEN) antigenic complex includes four serotypes associated with dengue fever (DF), and dengue hemorrhagic fever/shock syndrome (DHF/DSS). Together these cause large epidemics


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