Flavivirus Persistence in Wildlife Populations

Abstract

A substantial number of humans are at risk for infection by vector-borne flaviviruses, resulting in considerable morbidity and mortality worldwide. These viruses also infect wildlife at a considerable rate, persistently cycling between ticks/mosquitoes and small mammals and reptiles and non-human primates and humans. Substantially increasing evidence of viral persistence in wildlife continues to be reported. In addition to in humans, viral persistence has been shown to establish in mammalian, reptile, arachnid, and mosquito systems, as well as insect cell lines. Although a considerable amount of research has centered on the potential roles of defective virus particles, autophagy and/or apoptosis-induced evasion of the immune response, and the precise mechanism of these features in flavivirus persistence have yet to be elucidated. In this review, we present findings that aid in understanding how vector-borne flavivirus persistence is established in wildlife. Research studies to be discussed include determining the critical roles universal flavivirus non-structural proteins played in flaviviral persistence, the advancement of animal models of viral persistence, and studying host factors that allow vector-borne flavivirus replication without destructive effects on infected cells. These findings underscore the viral-host relationships in wildlife animals and could be used to elucidate the underlying mechanisms responsible for the establishment of viral persistence in these animals.

Keywords: arbovirus; autophagy; flaviviruses; infection; interferon; mosquito; tick; viral persistence; wildlife.

Figure 1

Schematic Representation of the Tick-borne Flavivirus Wildlife Transmission Cycle. Black arrows show the transmission cycle of tick-borne flaviviruses from Ixodid and Argasis ticks to predominate and intermediate hosts, as discussed in this review.

Figure 2

Schematic Representation of the Mosquito-Borne Flavivirus Transmission Cycle Involving Wildlife Hosts. Black arrows show the transmission cycle of mosquito-borne flaviviruses from mosquitoes (e.g., Culex sp.) to predominate and intermediate hosts, as discussed in this review. Unlike tick-borne infections, the transmission cycle for mosquito-borne viruses can differ greatly. For example, the transmission cycle for the West Nile virus (as shown above) differs from that of the dengue virus (DENV). DENV tends to circulate in two relatively distinct transmission cycles vectored by Aedes sp. mosquitoes. DENV infection of humans results in a sufficiently high viremia to support the infection of feeding mosquitoes. DENV may also replicate in a sylvatic cycle, which is more relevant to this review.

Figure 3

Schematic Diagram of the Vector-borne Flavivirus Genome. A representation of the approximately 11 kb flavivirus genome (in blue), capped and polyadenylated, and subsequent translation protein products (in red) are shown to illustrate the important flavivirus replication functions. These features and functions are consistent between tick-borne and mosquito-borne flaviviruses. Functions of the flavivirus genes as they pertain to the establishment of viral persistence in host cells are described in the text. UTR = untranslated region, AAAAA(n) = polyadenylation.