PROJECT SUMMARY/ABSTRACT
La Crosse virus (LACV) is one of the most significant arboviral pathogens in North America, annually causing
clinical pediatric encephalitis, which are occasionally fatal. Severe neuroinvasive disease cases of LACV most
often occur in the Appalachian and Midwest regions of the United States (US) in children under the age of 16,
and can result in lifelong neurologic complications, including recurrent seizures, partial paralysis, and cognitive and
neurobehavioral abnormalities. Long-term sequelae represent a substantial health and economic burden in terms
of cost per patient. No licensed countermeasures, such as vaccines or antivirals, are currently available. To
date, only two of the three known LACV lineages, Lineages I and II (principally active within the Appalachian and
Midwest regions of the US), are associated with human disease. Lineage III, which is now identified in the
Northeastern region of the US, has not yet been associated with clinical disease. My research group recently
highlighted the existence of regional variants of LACV in the Northeast (Eastwood et al. 2020) and showed that
Lineage III LACV persists locally in multiple species of Aedes mosquitoes. This virus lineage presents an
undetermined health threat and investigation is warranted to determine whether the lack of Lineage III-derived
cases, to date, is due to under-diagnosis of clinical illness (lack of case recognition), differences in virus virulence,
low prevalence of infection in mosquito vectors (effectively limiting human exposure to biting activity in regions
where the virus circulates), or limited vector competence by these mosquito species. Our long-term goal is to
evaluate the public health significance and risk of emergence of lineage III LACV. We question why human
cases have not occurred in the face of entomological risk, and aim initially to study the mosquito vector
competency of different lineage strains to determine whether the known presence of LACV in the Northeast is a
threat to public health, consistent with the more traditional regions. Having established that Lineage III LACV is
circulating in mosquitoes in the Northeastern US, and that isolates of LACV strains present different in vitro
phenotypic characteristics, such as altered growth rates, plaque morphologies, and murine virulence (Wilson et
al. 2021), this pilot study seeks to address the ability of novel LACV strains to transmit in the vector, with the
central hypothesis that this distinct lineage is maintained vertically in local populations of mosquitoes with
limited horizontal transmission, resulting in the observed reduced incidence of human disease. We will evaluate
both horizontal and vertical transmission of LACV in both a native mosquito species (Aedes triseriatus) and an
invasive species (Aedes albopictus) as candidate LACV III disease vectors. The proposed project is an important
step to understanding whether Lineage III LACV poses a public health risk to a substantially urbanized
geographical region. Subsequent studies will be aimed at understanding mechanisms of lineage differences,
climatic impacts in vector competency for LACV, and surveillance of humans and vertebrate hosts to explore the
incidence, prevalence, and risk of further emergence of LACV in novel regions of the US.
