Viral and host genetic determinants of LA crosse virus neuroinvasive disease

The National Institute of Allergy and Infectious Diseases awarded the University of North Carolina at Chapel Hill $771,510 on July 9, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to profile La Crosse virus genetic diversity in human neuroinvasive disease cases and peridomestic mosquitoes in Western North Carolina.

The research establishes and executes a prospective cohort study collecting serum and cerebrospinal fluid samples from La Crosse virus patients presenting at a hospital in Asheville, North Carolina that typically encounters 10–30 cases annually, alongside collection of mosquitoes from the homes of affected patients. The study site will generate the largest collection of La Crosse virus patient samples to date, enabling strain comparisons between virus populations circulating in peridomestic mosquitoes and human neuroinvasive disease cases at unprecedented resolution. Primary objectives include profiling La Crosse virus genetic diversity across both human cases and mosquitoes at case households and defining virus seroprevalence in the region. La Crosse virus causes the most common pediatric arboviral encephalitis in the United States, with approximately 25 percent of reported cases occurring in North Carolina; three rural counties in Western North Carolina carry the highest national incidence.

Work is performed in Chapel Hill, North Carolina with a period of performance through June 30, 2031. The award is classified as a Project Grant under the federal grant assistance mechanism.

Abstract

LA crosse virus is the most common cause of pediatric arboviral encephalitis in the US. LA crosse virus (LACV) is a mosquito-borne orthobunyavirus that can cause neuroinvasive disease (e.g. encephalitis, seizures, paralysis). Unlike other neuroinvasive arboviruses in the US, which predominantly affect the elderly, LACV neuroinvasive disease occurs almost exclusively in children. The pathogenic mechanisms of LACV and the host immune mechanisms that control age-dependent susceptibility to neuroinvasive disease are not well- understood, in part due to a lack of sufficiently large patient cohorts and concomitant lack of high-quality sequence data from clinical specimens and field samples. We have established a prospective cohort of LACV patients and peridomestic mosquitoes in western north carolina, an epicenter of LACV neuroinvasive disease. Three rural counties in western north carolina have the highest incidence of LACV neuroinvasive disease in the US and ~25% of LACV neuroinvasive disease cases reported to CDC occur in north carolina. Our team has established a prospective cohort study to collect remnant serum and cerebral spinal fluid (CSF) samples from LACV patients presenting at a hospital in asheville, NC that typically sees 10-30 LACV patients per year, as well as to collect mosquitoes near the homes of LACV patients. Our study site in western north carolina will generate the largest collection of LACV patient samples to date and allow comparisons between LACV strains circulating in peridomestic mosquitoes and in human neuroinvasive disease cases at a level not previously possible. Aim 1: profile LACV genetic diversity in human cases and peridomestic mosquitoes at case households in western north carolina and define LACV seroprevalence in the region. We hypothesize that diverse LACV populations are maintained in mosquitoes and that patient sequences will reflect significant genetic bottlenecks. 1A: identify and sequence LACV from peridomestic mosquitoes. 1B: sequence LACV in serum and CSF from LACV neuroinvasive disease patients. 1C: assess the pathogenic phenotypes of LACV isolates from mosquitoes and human patients. 1D: evaluate pediatric clinic and hospital remnant samples to define LACV seroprevalence and determine the rate of subclinical infection. Aim 2: investigate host genetic factors that restrict LACV neuroinvasive disease in mice. We hypothesize that variation in host antiviral response genes contributes to differential disease outcome following LACV infection and that these polymorphic responses act differently in children compared to adults. 2A: evaluate the tissue tropism and immune response in collaborative cross (CC) mice resistant to LACV. 2B: map quantitative trait loci associated with LACV susceptibility in CC mice and investigate the mechanisms by which candidate genes impact LACV pathogenesis. 2C: evaluate the susceptibility of CC071 mice to other orthobunyaviruses. Our proposed studies will reveal viral and host determinants of LACV neuroinvasion and neurovirulence.