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Abstract
Human rhinoviruses (HRV) are a major cause of exacerbations of airways disease. Aspects of cell signalling responses to HRV infection remain unclear, particularly with regard to signalling via PI3K, and the PI3K-dependent pathway, autophagy. We investigated the roles of PI3K and autophagy in the responses of epithelial cells to major and minor group HRV infection. The PI3K inhibitor 3-MA, commonly used to inhibit autophagy, markedly reduced HRV-induced cytokine induction. Further investigation of potential targets of 3-MA and comparison of results using this inhibitor to a panel of general and class I-selective PI3K inhibitors showed that several PI3Ks cooperatively regulate responses to HRV. Targeting by siRNA of the autophagy proteins Beclin-1, Atg7, LC3, alone or in combination, or targeting of the autophagy-specific class III PI3K had at most only modest effects on HRV-induced cell signalling as judged by induction of proinflammatory cytokine production. Our data indicate that PI3K and mTOR are involved in induction of proinflammatory cytokines after HRV infection, and that autophagy has little role in the cytokine response to HRV or control of HRV replication.
Highlights
Rhinoviruses are a leading cause of exacerbations of asthma and chronic obstructive pulmonary disease (COPD) [1]
We determined that multiple phosphoinositide-3 kinase (PI3K) isoforms contributed to responses to human rhinovirus (HRV) infection, and we suggest a role of mTOR in the regulation of responses to HRV
The HRVs are an important family of human pathogens, and the dominant viral pathogen accounting for exacerbations of asthma and COPD
Summary
Rhinoviruses are a leading cause of exacerbations of asthma and chronic obstructive pulmonary disease (COPD) [1]. TLR3 recognises double-stranded viral RNA (dsRNA), generated during HRV replication. Autophagy delivers viral replication products from the cytoplasm to TLR7-containing endosomes [8]. Autophagy has not yet been shown to be a major mechanism delivering double-stranded RNA intermediates to TLR3-containing endosomes. HRV infection has been associated with autophagosome formation [10] and recent work has suggested that autophagy is necessary for maximal viral replication of HRV-2 and HRV-14 [11]. Dissecting the roles of PI3K and autophagy in responses to HRV infection is complicated by the recent finding that the main class III PI3K inhibitor traditionally used to selectively target the autophagic pathway, 3methyladenine (3-MA), has been shown to inhibit other pathways such as class I PI3K [12, 13]. We determined that multiple PI3K isoforms contributed to responses to HRV infection, and we suggest a role of mTOR in the regulation of responses to HRV
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