Funding
The Klein Lab is a recipient of a Canada Excellence Research Chair (CERC) in Neurovirology and Neuroimmunology in the amount of 8 million dollars. Additionally, the Klein Lab is a recipient of a National Institute of Allergy and Infectious Diseases (NIAID) Multi-PI Grant.
Canada Excellence Research Chair: CERC-2022-00107
The goal of this research is to define neuroimmune mechanisms, therapeutic targets and neuroimaging biomarkers of virus-induced memory disorders. The Klein lab uses in vivo models of neutropic viral infections pioneered to demonstrate how virus-driven innate immune responses within the hippocampal circuitry induce cognitive deficits. This project will also use in vitro and in vivo models to define the dynamic interface between peripheral viral infections their effects on blood-brain barrier (BBB) function. Genetic and pharmacologic approaches, optimized next-generation sequencing technologies, interactome profiling OMICs, in conjunction with functional connectivity mapping, and positron emission technology magnetic resonance imaging (PET-MRI), allow us to define cellular/molecular interfaces between innate immune signaling, virus infection, BBB biology, and cognitive recovery, and use neuroimaging biomarkers to diagnose and monitor these effects.
NIAID Multi-PI Grant: R01 AI160188
The long-term objective of this multi-PI project is to determine how host-pathogen interactions impact entry, infection, and spread of encephalitic alphaviruses in the central nervous system (CNS). We hypothesize that type I interferon responses differentially impact the entry and infection of EEEV and VEEV at the NVU via virus-specific induction of replication-restricting innate immune responses. To test these hypotheses we will: Define alphavirus and host specific mechanism in vitro that regulate viral entry and infection at the NVU; and Define the in vivo functional role of type I IFN in protection from alphavirus neuroinvasion at the NVU.
RELEVANCE
In 2019, EEEV exhibited an unprecedented outbreak in the United States resulting in 38 confirmed cases and 15 deaths, as opposed to a recent average of 5-8 cases and 1-3 deaths. The outbreak occurred throughout the EEEV-endemic areas of the US (northern tier of eastern states, New England, southeastern seaboard and gulf coast) and Canada (southern Quebec and Ontario) suggesting a multination-wide increase in virus activity (www.cdc.gov/easternequineencephalitis). Considering the virulence of EEEV, this raises significant concerns regarding the future incidence of EEEV disease, which may be impacted by climate change, mosquito vector and reservoir abundance, and human activity. In contrast with EEEV, Venezuelan equine encephalitis virus (VEEV), a related member of Alphaviruses, causes a much less severe disease in humans and 0.5-1% mortality in symptomatic cases. VEEV is endemic along the gulf coast of the US and also Latin and South America. Reflecting the human virulence of EEEV and potential biowarfare/bioterrorism uses of both viruses, they have been placed on the National Select Agent Registry and the viruses are considered Category B Priority Pathogens by the National Institutes of Healt
