Human Rhinovirus (HRV) is a human pathogen of significant medical importance, being a major cause of upper respiratory tract infections and causing majority of the virus-induced asthma exacerbations. In this study, we investigated whether HRV could regulate apoptosis, a key antiviral innate immune response. The apoptotic signal is generated either via receptors (extrinsic) or disruption of homeostasis within the cell (intrinsic) and is propagated via caspase cascades that lead to cell death, thereby reducing HRV viral replication which relies on cellular machinery.
We have used HRV16 (a group A HRV that uses ICAM-1 as receptor) infected cells, cells treated with chemical inducers and inhibitors of extrinsic apoptosis, and in vitro protease cleavage assays to show that HRV16 3C protease cleaves a key intermediate in extrinsic apoptosis. RIPK1, an extrinsic apoptosis adaptor protein, was cleaved by caspase 8, as expected, during chemical induction of extrinsic apoptosis. RIPK1 was also cleaved in HRV infection albeit at a different cleavage site. Interestingly, caspase 8 activation, which is associated with extrinsic apoptosis, was required for optimal HRV 3C protease mediated cleavage of RIPK1. This was potentially achieved by increasing the accessibility of the HRV 3C cleavage site within RIPK1.
The caspase 8 mediated RIPK1 cleavage product has a pro-apoptotic function, and further cleavage of this pro-apoptotic cleavage product by HRV 3C may provide a mechanism by which HRV regulates apoptosis.