Elucidating the role of autophagic protein Atg5 in dendritic cells against respiratory syncytial virus infection

Abstract

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants, young children, and the elderly that often leads to patient hospitalization. Generating new therapeutic agents or vaccines against RSV is an important worldwide public health endeavor. Autophagy is a highly-conserved cellular process during which cytoplasmic contents are enveloped in a double-walled membrane and degraded upon fusion with lysosomes. Autophagy is important for maintaining cellular homeostasis and is specifically associated with eukaryotic immunity against some invading pathogens. However, the role of autophagy in promoting an innate immune response during RSV infection and its impact on adaptive T cell activity are poorly understood. Here, we present the role of Atg5, a protein essential for autophagosome formation, in innate and adaptive immune responses against RSV. Infection with RSV induced autophagosome formation in wild type dendritic cells, while Atg5-deficient dendritic cells produced more innate immunity cytokines against RSV and limited its replication. In vivo Atg5-knockout studies using hematopoietic cell-specific mice revealed significantly increased innate response cytokine production in $Atg5^{-/-}$ chimeric mice after RSV infection. These phenotypes also appeared in dendritic cell-specific CD11c-$Atg5^{-/-}$ mice, suggesting that Atg5 in dendritic cells plays a critical role in modulating proinflammatory cytokine production against RSV. Moreover, mice with Atg5-deficient dendritic cells showed greater glycolytic capacity than wild type mice, and Atg5 deficiency induced glycolytic reprogramming in dendritic cells sufficient to enhance proinflammatory cytokine production against RSV. However, maximal aerobic respiration was decreased in Atg5-deficient dendritic cells due to mitochondrial dysfunction. During adaptive immunity, Atg5 deficiency promoted increased responses of cytotoxic $CD8^+$ T lymphocytes, but not of Th1 or Th17 cells. We surmise that because Atg5-deficient dendritic cells display more surface MHC class I molecules than wild type cells, RSV-specific cytotoxic $CD8^+$ T cell responses are more efficiently stimulated during infection. Our results suggest that metabolic changes and elevated MHC class I expression in dendritic cells induced by Atg5 deficiency promotes antiviral immune responses against RSV. The impact of these findings may have significant therapeutic implications for severe RSV-associated diseases and may enable the development of novel RSV vaccines.