Postdoctoral Scientist
Department of Medicine
Cedars-Sinai Medical Center

Project title: Coxsackievirus B subverts host mitophagy to promote viral dissemination and myocarditis

Roberta A Gottlieb, MD – Cedars-Sinai Medical Center
Moshe Arditi, MD - Cedars-Sinai Medical Center

Multidisciplinary expertise:  
Virology, cardiovascular biology, mitochondrial biology, stem cell biology

Project description:
Coxsackievirus B (CVB) is a common pathogen that can cause a wide-array of inflammatory diseases including meningitis, pancreatitis, and myocarditis.  We see that CVB which is a naked virus can escape the cell in membrane-bound vesicles which we hypothesize are derived from autophagosomes.  Additionally, when we infect HL-1 cardiomyocytes, mitochondrial networks fragment, which is an early step in the autophagic degradation of mitochondria (mitophagy).  Normally, the E3 ubiquitin ligase parkin would subsequently ubiquitinate these fragmented mitochondria to target them for destruction; however, we find that following mitochondrial fission, instead of getting degraded mitochondrial fragments and virus are ejected from the cell in membrane-bound vesicles.  We found that treating cells with DRP1-inhibitor Mdivi-1 prior to infection results in reduced intracellular and extracellular virus, suggesting that blocking the early steps in mitophagy suppresses viral dissemination.  We will test the efficacy of Mdivi-1 in suppressing CVB-mediated myocarditis in mice.