The molecular mechanisms regulating emerging highly pathogenic human respiratory coronavirus pathogenesis are complex and include dampening of the host innate immune response allowing higher viral titers immediately following entry. Previous studies tracking the expression of interferon stimulated gene (ISG) expression in Middle East respiratory syndrome coronavirus (MERS-CoV) infected continuous human lung epithelial cells demonstrated that specific ISG expression patterns could be detected and these patterns could be used to determine how CoV were modulating the innate immune response. Epigenetic/chromatin remodeling mechanisms were found to be important regulators of host chromatin remodeling that altered host expression ISG patterns. This proposal will build on these foundational studies performed in continuous human lung cell lines and define ways that MERS-CoV regulates innate immunity in primary human lung fibroblasts and microvascular endothelial cells.
By identifying common mechanisms used by MERS-CoV to regulate the innate immune response, we can identify critical nodes and host genes that are essential for efficient virus replication, leading to new targets for broad spectrum therapeutic design, improved public health preparedness and rapid response to new emerging or deliberately designed respiratory virus disease threats of the future.
