Infection and prevalence of a new segmented flavivirus in the United States

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Summary/abstract Segmented RNA viruses that share phylogenetic relatedness with the prototypic Flaviviruses in their helicase (NS3) and polymerase (NS5) proteins were recently identified from ticks, mosquitoes, and vertebrates, including humans suffering with febrile illness. The first Flavi-like segmented viruses (FLSV) were isolated from ticks and animals in the Jingmen province of China and were thus named Jingmen Tick Virus. Subsequently, highly diverse FLSV variants were found in Africa, Europe and South America. However, no evidence of FLSV infection has been reported in North America, including the United States. Moreover, several recent studies that used metagenomics-based identification of the virome in ticks failed to identify FLSV infection. We were characterizing the virome of free-ranging mice of the genus Peromyscus, the most common wild mouse species of the North America, when we identified a highly diverse FLSV in several deer mice from woodlands in Pennsylvania (FLSV- PN). We acquired partial sequences of all five segments of the FLSV-PN genome and developed serological assays using Luciferase immunoprecipitation systems. Our serological data suggest that FLSV-PN or its related variants have a wide host range and infect several economically important farm and domestic animals. Most importantly, we found strong evidence of FLSV-PN infection in humans with a history of tick-bites and Lyme disease. The long-term goal of our exploratory/developmental proposal is to define the pathogenesis and health relevance of FLSV-PN infection. Development of molecular reagents for this new virus will allow us to test our hypotheses that several genetically diverse FLSV variants are circulating in the United States, and these viruses are predominantly transmitted by ticks to humans and animals. Specific aim-1 is to acquire the complete genomes of several diverse FLSV variants. Our preliminary data suggest that FLSV-PN genome is comprised of five RNA segments that are polyadenylated at the 3’ end. Complete genome sequencing of FLSV-PN is necessary for the development of sensitive and specific diagnostic assays to study infection prevalence and disease associations. Specific aim-2 is to determine the infection prevalence of FLSV in humans, domesticated animals and ticks. These studies will be aided by samples and data available from clinical research studies of Lyme disease at NIAID, NIH (letter of support attached). The proposed aims represent crucial steps toward detailed molecular and biological characterization of FLSV-PN, including the development of a reverse genetics system, replicon systems, cell culture and animal models. Although the health relevance of FLSV infections is currently not known, the proposed studies will inform this knowledge as well as develop the reagents for preventing the spread of this new virus and associated diseases, if necessary.