Aetiology
VEEV is an arthropod-borne virus belonging to the family Togaviridae and to the genus Alphavirus (formerly Group A arboviruses), and is responsible for causing Venezuelan equine encephalitis. VEEV is a lipid-membrane encapsulated positive-sense single-stranded RNA virus with icosahedral symmetry. Six subtypes of VEEV have been identified (classified I-VI). In subtype I, five antigenic varieties exist (IAB, IC, ID, IE, and IF). Varieties IAB and IC are epizootic and have been responsible for most large outbreaks in humans, while other subtypes and varieties are enzootic.[4] It is thought that epizootic subtypes have descended from enzootic subtypes.
The mosquito is the most common vector for the virus. The virus incubates in the mosquito for one week after it has become infected by feeding on the blood of a viraemic equine or rodent host. Transmission of the virus occurs when the infected mosquito feeds on the blood of an uninfected host (e.g., horse or human). The enzootic subtypes are transmitted between rodents and Culex mosquito species of the subgenus Melanoconion; these subtypes can cause disease in humans but do not generally cause disease in horses. The epizootic subtypes (IAB and IC) are amplified in horses and can be transmitted by various mosquito species; one of the most important species is Aedes (Ochlerotatus) taeniorhynchus.[6] Other mosquito genera capable of transmitting epizootic subtypes of VEEV include Anopheles, Deinocerites, Mansonia, and Psorophora. The Aedes albopictus mosquito (also known as the Asian tiger mosquito), which can spread chikungunya virus, dengue, and Zika virus, is also a viable host vector for VEEV.
As well as the natural transmission of VEEV via the mosquito vector, laboratory-acquired infections have been reported via aerosol inhalation, accidental subcutaneous inoculation (e.g., bite from an infected animal), and contact of the virus with broken skin or mucosal membranes.[1] There is no evidence for human-to-human transmission.[7] Furthermore, infected humans do not generally develop sufficient viraemia to infect mosquitoes and, therefore do not contribute to the transmission cycle.[Figure caption and citation for the preceding image starts]: Transmission electron micrograph showing VEEV virions in a tissue specimenCDC Public Health Image Library (PHIL) [Citation ends].
Pathophysiology
The mosquito is the most common vector for VEEV. VEEV has a single-stranded, positive-sense RNA genome that encodes 4 nonstructural proteins (nsP1-4), and 5 structural proteins (E1, E2, E3, 6K/TF, and CP [capsid protein]) for replication and pathogenesis in its host.[15] E2 is a key glycoprotein that is present in the lipid envelope of the virus and is responsible for binding the virus to host cell receptors.[15] Upon subcutaneous inoculation by an infected mosquito, the virus first binds and replicates in Langerhans cells and cells of mesenchymal origin in the skin. Dendritic cells in the skin also become infected. These infected cells transport the virus to the lymph nodes where it infects other immune cells, as well as the neurological cells of the central nervous system (CNS).[16] The virus enters the host cell via clathrin-mediated endocytosis, and undergoes fusion of the viral envelope, disassembly of the core, and release of genomic RNA. Genomic RNA is used for translation of proteins and transcription of RNA. Viral proteins are transported to the cell surface, where conformational changes in the envelope proteins drive the budding process and release of virions.[17] The virus is able to replicate efficiently in lymphoid tissues, giving rise to high serum viraemia (3.0 x 10^2 to 6.7 x 10^5 PFU/mL), and neuroinvasion.[2][4][18] Neuroinvasion and neurological disease appears to be more prevalent among the epizootic VEEV subtypes (IAB and IC) compared with the enzootic subtypes.[4] It is hypothesised that VEEV utilises the olfactory neuroepithelium as a primary entryway into the CNS, where in addition to centripetal spread of the virus along the neurons, local opening of the blood brain barrier and local invasion into the CNS takes place.[19] The virus also has tropism for mesenchymal cells, such as osteoblasts and fibroblasts.[18]
The incubation period of the virus in human hosts is usually between 1 and 10 days post-exposure. In early infection, type I interferon (IFN) plays a prominent role in the ability of the virus to replicate; the ability to respond to type I IFN is a determinant of disease severity.[20][21] It has also been observed that pathogenic alphaviruses, such as VEEV, use the secondary structural motif within the 5’ untranslated region of their RNA to impede the cellular mechanisms responsible for the antiviral effects of type I IFN.[22] Subsequent adaptive humoral responses include the production of immunoglobulin M, followed by immunoglobulin G. Neutralising and non-neutralising antibodies against epitopes on E1, E2, and E3 glycoproteins have been shown to protect against infection, and promote alphavirus recovery in murine studies.[23][24] Neutralising antibodies mainly target the E2 glycoprotein, which prevents the virus from binding to host cells. Recovery also requires T cells, as demonstrated by fatal encephalitis ensuing despite administration of high-dose neutralising antibodies in alpha beta T-cell receptor knockout (TCR alpha beta -/-) mice.[25]
Classification
Baltimore classification
Group IV: positive-sense single-stranded RNA viruses.
Venezuelan equine encephalitis virus (VEEV) subtypes
There are six subtypes of VEEV, each with a separate genetic lineage. The subtypes can be classified according to whether they are involved in epizootic or enzootic transmission.
Epizootic transmission:
Subtype I (antigenic variants: IAB, IC).
Enzootic transmission:
Subtype I (antigenic variants: ID, IE, IF [Mosso das Pedras virus])
Subtype II (Everglades virus)
Subtype III (antigenic variants IIIA, IIIC, and IIID [Mucambo virus], IIIB [Tonate virus])
Subtype IV (Pixuna virus)
Subtype V (Cabassou virus)
Subtype VI (Rio Negro virus).
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