Impact of BDGR-49 treatment on VEEV induced neurological sequelae

ABSTRACT Venezuelan equine encephalitis virus (VEEV) can cause significant morbidity including neurocognitive impairment, resulting in a significant impact on population health, healthcare costs, and workforce productivity. VEEV is an important human and veterinary pathogen belonging to one of seven antigenic complexes in the genus Alphavirus, family Togaviridae. Its importance is recognized by multiple government agencies, with VEEV being classified as a category B priority pathogen by NIAID and as a select agent by both the CDC and the USDA. NIAID has also listed VEEV as a prototype pathogen for the Togaviridae family, indicating it should be utilized for medical countermeasure development for other Togaviruses. Neurological cases of VEEV have a mortality rate as high as 35% in children and 10% in adults, with long-term neurological deficits observed in 4-14% of survivors. Sequelae observed include convulsions, seizures, paralysis, confusion, photophobia, intellectual disability, emotional instability, and behavioral changes. There are currently no FDA-approved antiviral therapeutics for the treatment of VEEV. However, there has been significant effort on the development of small molecule compounds targeting encephalitic alphavirus infections, with a few candidates showing efficacy in animal models. Of these, ML-336 and its derivatives (BDGR compounds) have shown great promise in mouse models of encephalitic alphavirus infections. BDGR-49, a new chemotype, has shown prophylactic efficacy against VEEV and EEEV and 100% therapeutic efficacy against VEEV in mouse models. A critical gap in knowledge is whether BDGR-49 can prevent VEEV induced long-term neurological sequelae when administered therapeutically. We hypothesize that BDGR-49 treatment will result in reduced VEEV replication and neuroinflammation allowing prevention of long-term neurological sequelae. To address this hypothesis, we propose the use of a well characterized mouse model of VEEV TC-83 infection which recapitulates neurological sequelae observed in humans infected with VEEV and an antiviral, BDGR-49, which has also been extensively characterized in VEEV-infected mice. Specifically, mice infected with VEEV TC- 83 display deficits in prepulse inhibition (the inability to filter out extraneous sensory stimuli), thalamus damage (glial nodules and calcification), and glial activation in the posterior nuclear complex of the thalamus and the hippocampus dentate gyrus, a central hub for cognitive function. We have preliminary data showing that mice have anxiety and memory deficits, and multiple neuropathological markers including gliosis, perivascular cuffing, and neuroinflammation and cell death, and neuronal loss within the dentate gyrus up to 90 days post-infection. Collectively, these preliminary studies established the utility of this model for studying neuroinflammation and cognitive impacts following VEEV infection. This model will be used to test our hypothesis in two specific aims: Aim 1: Determine the impacts of prophylactic BDGR-49 treatment on VEEV induced neurological sequelae and Aim 2: Determine the impacts of therapeutic BDGR-49 treatment on VEEV induced neurological sequelae.