Introduction

Objective

The goal of this study is to predict differences in the behavior of proteins based on the differences in their structures. Specifically, we aim to determine whether structural differences between two polymorphic siblings could predict the increased susceptibility towards cleavage of one over another. If successful, this type of analysis could be very helpful in analyzing the effects of polymorphs.

CVB3 Viral Mechanism

Coxsackievirus B3 (CVB3) is a human enterovirus that has been linked to serious inflammatory conditions. When entering a host cell, as part of its infection pathway, CVB3 encodes a nonfunctional polyprotein along with two viral proteases, 2Apro and 3Cpro. These proteases autolytically cleave CVB3 and create individual functional proteins. Therefore, the activity of these proteases is vital to the infectivity of the virus.

When infected with CVB3, a host cell begins an immune response which includes the activation of Interferon Regulatory Factor 3 (IRF3). This factor is responsible for sending antiviral signals to the cell’s nucleus, which are then transmitted to neighboring cells as they begin to elicit a larger immune response. Therefore, IRF3 activation is essential in ensuring an adequate host immune response.

Potential Cleavage of IRF3-R96Q

A naturally occurring polymorphic mutant of IRF3, R96Q, results in a glutamine-serine site. This may create a candidate cleavage site for CVB3’s 3Cpro, which has already been shown to preferentially cleave other elements in the host cell at similar sequences, such as at glutamine-alanine, glutamine-glycine, or glutamine-serine. If cleavage does occur, these results would imply that those with the IRF3-R96Q mutant may have a weaker or nonexistent immunological response when exposed to CVB3.

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