The Role of Sirtuin 1 in the Regulation of Autophagy and Respiratory Syncytial Virus-induced Immune Responses

Abstract

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in children, and a significant source of morbidity and mortality among those susceptible, including infants, the elderly, and those with chronic lung diseases. Severe RSV infection during infancy is highly correlated with asthmatic symptoms later in life, suggesting a chronic alteration of the pulmonary immune environment even after viral clearance. Within the airways, dendritic cells (DCs) drive innate and adaptive immune responses to pathogens through the production of proinflammatory cytokines and the activation of T cell responses. Autophagy, a pathway that sequesters intracellular material within double-walled vesicles for degradation by lysosomes, enhances Toll-like receptor-dependent activation, cytokine production, and antigen presenting cell function within RSV-infected DCs. Of interest, key proteins that orchestrate autophagosome formation are targeted by SIRT1, a NAD+-dependent histone and protein deacetylase. SIRT1 impacts many areas of biology and pathophysiology, including immune function. However, the role of SIRT1 in DC biology and its subsequent impact on adaptive immunity has not been elucidated. We have demonstrated that SIRT1 regulates DC activation and autophagy-mediated processes during RSV infection, and that the absence of SIRT1 activity alters the antiviral immune response through the regulation of innate cytokine production. Upon infection, SIRT1 inhibitor (EX-527)-treated DCs, Sirt1 siRNA-treated DCs, or DCs from conditional knockout (Sirt1f/f-CD11c-Cre+) mice failed to upregulate autophagy and cytokine production, but retained the capacity to present antigen to T cells. Additionally, RSV infection of Sirt1f/f-CD11c-Cre+ mice resulted in altered lung and lymph node cytokine responses, leading to exacerbated pathology. Overall, these studies highlight the essential role of SIRT1-mediated DC cytokine production in fine-tuning the antiviral adaptive immune response, and establish SIRT1 as a promising therapeutic target for the prevention of severe RSV-induced lung disease.PHDMolecular & Cellular Path PhDUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/137127/1/aniaowcz_1.pd