Jamestown Canyon virus (JCV), family Bunyaviridae, is a mosquito-borne pathogen endemic in the United States and Canada and considered an emerging threat to public health . JCV is a member of the California serogroup of viruses in the genus Orthobunyavirus and contains three genome segments, small (S), medium (M), and large (L) consisting of a single strand of negative-sense RNA. JCV was first isolated from Culiseta inornata mosquitoes collected near Jamestown Canyon, northwest of Boulder, CO . The serogroup contains members found on five continents that include human pathogens such as La Crosse (LACV) and snowshoe hare viruses in North America; Guaroa virus in North and South America; Inkoo and Tahyna viruses in Europe; and Lumbo virus in Africa.
JCV is distributed over a large geographic range, including much of the United States and Canada. This broad range overlaps with other orthobunyaviruses, such as La Crosse, Trivittatus, and snowshoe hare, and raising the possibility for generation of viruses with reassorted genome segments [1, 3, 4]. The principal vectors for JCV are Aedes and Ochlerotatus species, with virus isolations made from 26 species of mosquitoes and 3 species of tabanid flies[3, 5]. In the US, white-tailed deer are the primary amplifying host, but mule deer, sika deer, moose, caribou, elk and bison can be naturally infected [1, 6–9]. Livestock are also susceptible to infection with virus being isolated from lesions on a horse and antibodies detected in both horses and goats [8, 10]. It has been suggested that white-tailed deer populations living close to human residents have been responsible for the observed rise in JCV seroprevalence in humans . Seroprevalance among white-tailed deer in North Carolina, the Delmarva peninsula, and Indiana ranges from 18- 82% with seropositivity increasing with age [7, 8, 11]. Although JCV does not appear to cause disease in adult deer, it has been shown to be teratogenic, with JCV infection during pregnancy resulting in fawns born paralyzed, dead or aborted . Serum cross neutralization studies have suggested JCV, South River virus, and Jerry Slough virus, all endemic to the United States, are antigenically related [3, 13, 14]. The virus is genetically similar to Inkoo virus circulating in Europe, suggesting much of the northern hemisphere contains JCV or similar variants [15, 16].
In humans, JCV infection causes a mild febrile illness that can lead to infection of the central nervous system (CNS) resulting in meningitis and encephalitis. Unlike LACV, which mainly causes serious disease in children, JCV appears to cause disease predominantly in adults . JCV disease is generally associated with headache, fever, neck stiffness, photophobia, nausea, vomiting, and seizures [18, 19]. Respiratory involvement has been reported for JCV . Although JCV infection has been confirmed by PCR of a brain biopsy, human isolates of JCV have not been reported . Serological studies of residents of Alaska indicate an overall JCV infection rate of 17.6% . By age 15, 17% of the Alaskan population has been exposed to JCV, and after age 15, seroprevalence increases to 24 - 30% with 25% of the population showing serological evidence of infection with multiple orthobunyaviruses . JCV seropositivity rates in the continental United States range from 3.5-12.9% in New York, 2.5-10% in Wisconsin, 3.0-15% in Indiana, and 27.7% in Michigan . The precise incidence of CNS disease attributable to JCV is unknown, although retrospective analysis of serum collected from patients with CNS disease in New York State between 1966 and 1981 indicated that 41 cases resulted from JCV infection . Orthobunyavirus infection of animals, and most likely humans, during pregnancy has the potential for teratogenicity . It is evident that the majority of JCV infections are subclinical or associated with mild symptoms.
Little is understood about the genetic relationship of JCV isolates from different regions of the United States. We sought to generate complete genome sequences including the previously unreported L segment sequence, with encodes the RNA dependent RNA polymerase (RDRP). Here we describe the complete genome sequence of three JCV isolates and their level of neurovirulence and neuroinvasiveness in Swiss Webster mice. We also describe the first reported infection of non-human primates with JCV that resulted in viremia of short duration in the absence of clinical disease. Since one of the long-term goals of our laboratory is the development of a live-attenuated virus vaccine for one or more members of the California serogroup viruses, the characterization of JCV was seen as an important step in this process. The mouse model we developed will be useful for studying the pathogenesis of the infection in the central nervous system, and the mouse and monkey models will be useful for future testing of attenuated vaccine candidates.