Emerging mosquito-borne flaviviruses

Abstract

Flaviviruses comprise a genus of enveloped, positive-sense, single-stranded RNA viruses typically transmitted between susceptible and permissive hosts by arthropod vectors. Established flavivirus threats include dengue viruses (DENV), yellow fever virus (YFV), Zika virus (ZIKV), and West Nile virus (WNV), which continue to cause over 400 million infections annually and are significant global health and economic burdens. Additionally, numerous closely related but largely understudied viruses circulate in animals and can conceivably emerge in human populations. Previous flaviviruses that were recognized to have this potential include ZIKV and WNV, which only became extensively studied after causing major outbreaks in humans. More than 50 species exist within the flavivirus genus, which can be further classified as mosquito-borne, tick-borne, insect-specific, or with no known vector. Historically, many of these flaviviruses originated in Africa and have mainly affected tropical and subtropical regions due to the ecological niche of mosquitoes. However, climate change, as well as vector and host migration, has contributed to geographical expansion, thereby posing a potential risk to global populations. For the purposes of this minireview, we focus on the mosquito-borne subgroup and highlight viruses that cause significant pathology or lethality in at least one animal species and/or have demonstrated an ability to infect humans. We discuss current knowledge of these viruses, existing animal models to study their pathogenesis, and potential future directions. Emerging viruses discussed include Usutu virus (USUV), Wesselsbron virus (WSLV), Spondweni virus (SPOV), Ilheus virus (ILHV), Rocio virus (ROCV), Murray Valley encephalitis virus (MVEV), and Alfuy virus (ALFV).

Keywords: antiviral immunity; emerging viruses; flavivirus; infectious disease; species tropism.

Fig 1

Phylogeny and genome structure of emerging mosquito-borne flaviviruses. (A) Phylogenetic tree of the emerging flaviviruses Wesselsbron virus (WSLV), Spondweni virus (SPOV), Rocio virus (ROCV), Ilheus virus (ILHV), Usutu virus (USUV), Alfuy virus (ALFV), and Murray Valley encephalitis virus (MVEV) with reference to established flavivirus threats including yellow fever virus (YFV), dengue virus serotypes 1–4 (DENV1-4), Zika virus (ZIKV), Saint Louis encephalitis virus (SLEV), West Nile virus (WNV), and Japanese encephalitis virus (JEV). Multiple sequence alignment of full genome sequences was performed using the MAFFT algorithm, and phylogenetic analysis was performed using the randomized accelerated maximum likelihood (RAxML) program with 100 bootstrapping iterations available from DNASTAR Lasergene MegAlign Pro (Madison, WI, United States). Serocomplexes are differentially colored with YFV in orange, DENV in green, SPOV in blue, JEV in purple, and Ntaya in red. The GenBank accession numbers of the viral strains used for the alignment are indicated in parentheses. (B) Flavivirus genome organization. Flavivirus genomes are approximately 11 kb long with 5' and 3' UTRs and a 5′ terminal cap structure. The coding region contains one ORF, which is translated as a single polyprotein. Host and viral proteases cleave the polyprotein into three structural proteins (C, prM, E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The host signal peptidase (black arrow) has cleavage activity in the endoplasmic reticulum lumen, while the viral NS2B-NS3 protease (red arrow) is active in the cytoplasm. In the Golgi apparatus, a furin protease (gray arrow) separates the pr and M proteins. Of note, the protease that cleaves between NS1 and NS2A is currently unknown.

Fig 2

An overview of six emerging mosquito-borne viruses: Ilheus virus (ILHV), Rocio virus (ROCV), Wesselsbron virus (WSLV), Usutu virus (USUV), Spondweni virus (SPOV), and Murray Valley encephalitis virus (MVEV). (A) Global distribution of these emerging flaviviruses based on molecular or serological detection in humans, animals, or mosquitoes. (B) Host range of these emerging flaviviruses. The innermost ring indicates the emerging viral species. Moving outwards, the following rings indicate the serocomplex, amplifying host, existing mouse models for each virus, and the primary mosquito vector(s) responsible for transmission of each virus. While antibodies to these viruses may have been detected in a variety of animal species, only the main amplifying host(s), which manifests clinical symptoms during infection, was depicted. While the amplifying host for SPOV is not officially known, it is assumed that non-human primates (NHPs) constitute this population. NHPs are the amplifying host for ZIKV, the most closely related virus to SPOV, and rhesus macaques have been proven to be permissive after experimental inoculation (40).