General classification and structure
The family name originates from the Latin word flavus (yellow) after its type species, the yellow fever virus. Among the representatives pathogenic to humans, two main genera are distinguished:
- Genus Flavivirus. Includes classical arboviruses that circulate in nature via arthropod vectors (yellow fever, dengue, tick-borne, and Japanese encephalitis viruses).
- Genus Hepacivirus. Unites the causative agents of parenteral viral hepatitis (hepatitis C and G viruses). It is important to remember that hepaciviruses are not arboviruses.
In terms of morphology, flavivirus virions are spherical and small (40–60 nm). They are enveloped viruses:
- Genome is represented by a linear single-stranded +RNA.
- Capsid has an icosahedral symmetry type and consists of protein C.
- Supercapsid (outer lipoprotein envelope) surrounds the capsid. Its structure contains two key elements: the structural protein M and the surface glycoprotein E.
Antigenic properties and reproduction
The main antigen is glycoprotein E. It carries species-specific and genus-specific determinants and also possesses hemagglutinating properties, which manifest only in a narrow pH range. Additionally, infected cells produce a soluble antigen that is active in the complement fixation test (CFT) and induces the synthesis of virus-neutralizing antibodies.
The penetration of the virion into the host cell occurs via receptor-mediated endocytosis: the virus binds to surface phospholipids and glycolipids, and uncoating occurs upon fusion of the supercapsid with the wall of the endocytic vacuole.
In the infected cell, genomic RNA with a sedimentation coefficient of 45 S is synthesized. A distinctive feature of flaviviruses is that their replication complex is closely associated with the nuclear membrane (whereas in alphaviruses it localizes on the ER membranes). Virions mature by budding through the membranes of the endoplasmic reticulum, after which they form characteristic crystal-like clusters in the vacuole cavities.
Epidemiological features
Flavivirus infections are widespread in nature and are typical natural focal diseases. The main reservoir and vector of infection are blood-sucking arthropods. Viruses are able to persist in insect and tick populations through two mechanisms:
- Transstadial transmission (the pathogen persists during the transition from larva to nymph and adult).
- Transovarial transmission (from an infected female through eggs to her offspring).
Diseases are conventionally divided into mosquito-borne and tick-borne. Mosquito-borne infections (dengue fever, yellow fever, Japanese encephalitis) occur predominantly in southern and tropical latitudes. Tick-borne ones (tick-borne encephalitis, Omsk hemorrhagic fever) are ubiquitous.
Vertebrate animals (rodents, birds, primates, bats) act as maintenance hosts: they carry the infection asymptomatically, but with high viremia, infecting new vectors. Humans in this chain are most often a "dead-end" host, except for urban epidemics of dengue and yellow fever, where humans can serve as a reservoir.
Cultivation and diagnostic methods
Three main biological models are used to isolate viruses: cell cultures (SPEV, BHK-21), bioassays in mice, and chicken embryos. In warm-blooded cell cultures, viruses cause a mild cytopathic effect (CPE), while in arthropod cells they replicate without any CPE at all. Intracerebral inoculation of mice leads to paralysis.
Microbiological diagnostics includes:
- Serological method: study of paired sera. Recent infection is indicated by the appearance of immunoglobulin M (IgM) or a 4-fold or greater rise in antibody titer (in HI, CFT, ELISA). The most accurate reaction to differentiate closely related viruses is the neutralization test (NT).
- Virological method: isolation of the pathogen from blood, CSF (especially in encephalitis), autopsy material, or vectors from the environment.
- Molecular genetic methods: detection of viral RNA using PCR.
Therapy involves antiviral drugs (ribavirin, reaferon) and immunoglobulins. Specific prophylaxis is carried out using killed (formalin-inactivated) vaccines, with the exception of the live yellow fever vaccine. The virions themselves are unstable in the external environment and are rapidly destroyed by formalin and lipid solvents (ether) due to the presence of a lipid envelope.
Briefly: answers to topical questions
Which viruses pathogenic to humans belong to the genus Flavivirus?
The genus Flavivirus includes human-pathogenic arboviruses causing mosquito-borne and tick-borne infections. The main representatives include:
- Yellow Fever Virus (Yellow Fever Virus) — causes yellow fever.
- Dengue virus — causative agent of classical and hemorrhagic dengue fever.
- Tick-borne encephalitis virus — causes tick-borne encephalitis.
- Japanese encephalitis virus — causative agent of Japanese encephalitis.
- West Nile virus — causes West Nile fever.
- Omsk hemorrhagic fever virus — causative agent of Omsk hemorrhagic fever.
- Kyasanur Forest disease virus — causes Kyasanur Forest disease.
Which flavivirus infections belong to the tick-borne group?
The tick-borne flavivirus infections group includes diseases transmitted through tick bites that are ubiquitous. This group includes the following infections:
- Tick-borne encephalitis — a natural focal vector-borne viral infection affecting the central nervous system.
- Omsk hemorrhagic fever (OHF) — proceeds with hemorrhagic syndrome and liver damage.
- Kyasanur Forest disease (Kyasanur Forest disease) — also accompanied by hemorrhagic syndrome and liver damage.
What is the phenomenon of antibody-dependent enhancement (ADE) of infection in dengue fever?
The phenomenon of antibody-dependent enhancement of infection in dengue fever consists of a worsening of the disease course upon reinfection with a different virus serotype. The mechanism of development includes the following stages:
- Formation of virus-antibody immune complexes following primary asymptomatic sensitization.
- Activation of the complement system.
- Penetration of the virus into mononuclear phagocytes and its enhanced replication within them.
- Release of biologically active substances and anaphylatoxins by infected cells.
As a result of this process, hemorrhagic syndrome and shock develop.
Which specific vaccines are used for the specific prophylaxis of flavivirus infections?
Killed vaccines are used for the specific prophylaxis of flavivirus infections; the exception is the live yellow fever vaccine.
- Tick-borne encephalitis vaccines — killed cell-culture vaccines. Tick-borne encephalitis vaccines are also indicated as effective for cross-protection in Omsk hemorrhagic fever.
- Yellow fever vaccine — live vaccine, strain 17D. Robust immunity is formed from the 10th day after administration; duration of protection is at least 10 years.
It is easy to distinguish the replication site of flaviviruses from alphaviruses: Flaviviruses are drawn to the "center" of the cell (nuclear membrane), while Alphaviruses remain at the "periphery" (endoplasmic reticulum membranes).
Class and exam questions
Which serological reaction is considered the most specific for the identification of flaviviruses?
Neutralization test (NT). Unlike the complement fixation test (CFT) and hemagglutination inhibition test (HI), which can yield cross-reactions within the group, the neutralization test allows for the precise differentiation of even closely related arbovirus species.
How are flaviviruses maintained in nature without human involvement?
The main reservoir is arthropods, which transmit the virus to offspring transovarially (through eggs) and preserve it during molting transstadially. Maintenance hosts (rodents, birds) carry asymptomatic viremia, infecting new ticks and mosquitoes.
What else to study on this topic
- Features of the antigenic structure and functions of the surface glycoprotein E
- Pathogenesis and clinical manifestations of tick-borne encephalitis in humans
- Mechanisms of development of hemorrhagic syndrome in Omsk hemorrhagic fever and dengue
- Specifics of using live and inactivated vaccines against flavivirus infections
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