Viral myocarditis is a heterogeneous disease that is difficult to study and diagnose. Because of the
heterogeneous nature of acute viral myocarditis and the difficulty and low diagnostic sensitivity of
endomyocardial biopsies (considered the gold standard for diagnosis of viral myocarditis), there is limited
knowledge of the molecular pathogenesis of this disease, particularly in infants and neonates where
endomyocardial biopsies are less often performed. The specific cells within the heart that respond to viral
infection, the nature of their responses, and the spatiotemporal distribution of such responses are not well known.
A better understanding of the spatiotemporal response of the heart to viral infection at the cellular and molecular
level will provide much needed insight into the pathological processes that drive the active inflammatory process
that ensues following viral infection of the heart.
The lack of understanding of the molecular pathogenesis of viral myocarditis is in part due to the lack of tools to
investigate viral infection in complex native tissues at single cell-resolution. Here we will use innovative spatially
resolved transcriptomics, single-cell RNA sequencing (scRNA-seq) tools and bioinformatics, in conjunction with
classical virology techniques, and mouse models to study myocarditis in mammalian orthoreovirus (REOV).
We have three aims: In Aim 1, we will study the viral and host factors that define the outcome of REOV infection
of cardiac tissues. In Aim 2, we will determine the role of pyroptosis in REOV-induced myocarditis. In Aim 3, we
will combine our high-resolution single-cell atlas of myocarditis with the principles of liquid biopsies based on
cell-free RNA to develop highly specific blood biomarkers of viral myocarditis, thereby addressing an urgent and
unmet medical need. We anticipate our studies will provide unprecedented insight into the pathobiology of viral
myocarditis. Our experiments will clarify which cell types are infected in complex cardiac tissues and will reveal
how infection success depends on both cell state and cellular environment. We will elucidate the role for
endothelial cells in viral myocarditis and we will explore whether and how immune cell responses switch from
host defense to host injury. We will explore the effects of infected cells on uninfected bystander cells in close
physical proximity, and we will map the cellular interactions that mediate this bystander effect. We will also
explore the spatial and cell type heterogeneity of innate immune responses within infected and uninfected
cardiac tissues.
Successful implementation of these studies will lead to new approaches and molecular tools to study viral
myocarditis and other viral diseases and may identify novel diagnostic approaches and therapeutic targets for
acute viral myocarditis.