Tuesday, September 26, 2023
9/26/2023
PROJECT SUMMARY This proposal is a comparative study on the development of viremia during encephalitic alphavirus infection and the innate immune mechanisms that mediate clearance of circulating virus in the time before the specific antibody response. Eastern- (EEEV) and Venezuelan- (VEEV) equine encephalitis viruses are mosquito- transmitted zoonoses of high public health concern due to their ability to spill-over into human and equine populations, causing neurologic disease and mortality for which no specific treatments are available. Endemic to the Americas, their natural reservoirs are avian (EEEV) and rodent populations (VEEV). Natural transmission of these and other arboviruses is dependent on the development of a viremia of sufficient amplitude and duration within vertebrate hosts. And while arboviruses are capable of replicating (and causing disease) within several vertebrate species, not all hosts support transmission back to the arthropod vector. Yet, the molecular mechanisms that dictate arboviral viremia in amplifying and “dead-end” hosts are poorly defined. My preliminary findings have identified interesting contrasts from previous studies in Dr. Morrison's laboratory on the vascular clearance of arthritogenic alphaviruses. In particular, I found that intravenous-inoculated EEEV particles are cleared from murine circulation, while VEEV-IAB particles escape vascular clearance. My preliminary data on EEEV clearance from circulation supports a central role for phagocytic cells in the control of alphavirus viremia, however, in contrast to arthritogenic alphaviruses, EEEV vascular clearance occurs with slower kinetics and is independent of class A scavenger receptors (SR). I hypothesize EEEV vascular clearance is mediated by a non-class A SR expressed on liver KC which recognizes a surface-exposed basic patch in the viral E2 glycoprotein, and VEEV-IAB escape from clearance is similarly determined by the absence of a surface-exposed basic residue in E2. Moreover, I hypothesize vascular clearance phenotypes of EEEV and VEEV are host-species dependent and correlate with the distinct vertebrate hosts that support the maintenance of these independent viral populations in nature. My proposed studies will: (i) define the host and viral molecular mechanisms by which EEEV is cleared by a non-class A SR, (ii) assess the fate of EEEV particles following vascular clearance, (iii) identify biochemical properties of VEEV virions that determine murine vascular clearance, and (iv) elucidate mechanisms that define viremia in amplifying versus “dead-end” hosts. The knowledge gained from these studies may help identify risk factors for severe disease and aid the development of new treatments or vaccines against EEEV and VEEV.
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