Project description:Since its first appearance in the US in 1999, West Nile virus (WNV) has emerged as the most common cause of epidemic meningoencephalitis in North America. In the 6 years following the 1999 outbreak, the geographic range and burden of the disease in birds, mosquitoes and humans has greatly expanded to include the 48 contiguous US and 7 Canadian provinces, as well as Mexico, the Caribbean islands and Colombia. WNV has shown an increasing propensity for neuroinvasive disease over the past decade, with varied presentations including meningitis, encephalitis and acute flaccid paralysis. Although neuroinvasive disease occurs in less than 1% of infected individuals, it is associated with high mortality. From 1999-2005, more than 8,000 cases of neuroinvasive WNV disease were reported in the US, resulting in over 780 deaths. In this review, we discuss epidemiology, risk factors, clinical features, diagnosis and prognosis of WNV meningoencephalitis, along with potential treatments.
Project description:The outbreak of West Nile virus (WNV) in 1999 in the USA, and its continued spread throughout the Americas, parts of Europe, the Middle East and Africa, underscored the need for WNV antiviral development. Here, we review the current status of WNV drug discovery. A number of approaches have been used to search for inhibitors of WNV, including viral infection-based screening, enzyme-based screening, structure-based virtual screening, structure-based rationale design, and antibody-based therapy. These efforts have yielded inhibitors of viral or cellular factors that are critical for viral replication. For small molecule inhibitors, no promising preclinical candidate has been developed; most of the inhibitors could not even be advanced to the stage of hit-to-lead optimization due to their poor drug-like properties. However, several inhibitors developed for related members of the family Flaviviridae, such as dengue virus and hepatitis C virus, exhibited cross-inhibition of WNV, suggesting the possibility to re-purpose these antivirals for WNV treatment. Most promisingly, therapeutic antibodies have shown excellent efficacy in mouse model; one of such antibodies has been advanced into clinical trial. The knowledge accumulated during the past fifteen years has provided better rationale for the ongoing WNV and other flavivirus antiviral development.
Project description:Background: West Nile virus (WNV) was first sequenced in Brazil in 2019, when it was isolated from a horse in the Espírito Santo state. Despite multiple studies reporting serological evidence suggestive of past circulation since 2004, WNV remains a low priority for surveillance and public health, such that much is still unknown about its genomic diversity, evolution, and transmission in the country. Methods: A combination of diagnostic assays, nanopore sequencing, phylogenetic inference, and epidemiological modeling are here used to provide a holistic overview of what is known about WNV in Brazil. Results: We report new genetic evidence of WNV circulation in southern (Minas Gerais, São Paulo) and northeastern (Piauí) states isolated from equine red blood cells. A novel, climate-informed theoretical perspective of the potential transmission of WNV across the country highlights the state of Piauí as particularly relevant for WNV epidemiology in Brazil, although it does not reject possible circulation in other states. Conclusion: Our output demonstrates the scarceness of existing data, and that although there is sufficient evidence for the circulation and persistence of the virus, much is still unknown on its local evolution, epidemiology, and activity. We advocate for a shift to active surveillance, to ensure adequate preparedness for future epidemics with spill-over potential to humans.
Project description:Here, we characterize the RIX line CC(032x013)F1, which serves as a mouse model of chronic WNV infection. While studies using C57BL/6 mice have shown that WNV RNA can persist in the CNS up to 3 months post infection in a limited fraction of mice (Appler et al., 2010), to date there is a lack of a robust mouse model of chronic West Nile virus infection that can be used to elucidate the immune responses associated with this viral persistence and chronicity of symptoms described in human patients. Here, we characterize this line in comparison with lines showing either no disease symptoms or significant disease, and suggest a mechanism by which WNV infection can become chronic through alterations in immune responses.