Enterovirus D68 (EV-D68) is an emerging enterovirus that causes severe respiratory and neurologic disease in children. The virus was first isolated in California in 1962, and although it remained relatively hidden for the next several decades, in 2014, it caused a large nationwide outbreak in the United States, resulting in thousands of children being hospitalized and admitted to the intensive care unit due to acute cough, difficult breathing, and wheezing. An unexpected outcome of infection was acute flaccid paralysis that led to several deaths and disabilities. The virus has since caused two more outbreaks in the US: One in 2016 and another in 2018. 

How EV-D68 establishes infection in human tissues and impairs normal cell biology is unknown. Recently, virally encoded proteases have emerged as one of the major determinants of enteroviral pathogenesis, yet the substrate repertoire of these proteases in infected cells remains unexplored. My lab aims to identify proteins and pathways targeted by proteases from diverse viruses and characterize the role of these targets in viral disease. To this end, I have optimized a modern proteomics approach that allows unbiased identification of host proteins cleaved following infection. I then use a suite of molecular biology approaches to systematically analyze the role of these proteins in virus infection.

For this proposed project, I will map the proteolytic landscape of EV-D68 in respiratory and neuronal cells, which are the primary targets of virus infection. I will then use stem cell-derived models of virus infection to assess the role of the identified cleavages in virus replication. This effort is expected to provide unparalleled insights into EV-D68 pathobiology and open up avenues for novel intervention strategies. The aims of this study are stated below:

1.      Global analysis of the site-specific protein cleavage following EV-D68 infection

2.         Systematic characterization of EV-D68 proteolytic targets