Khan, N.; Chevre, R.; Sun, S. J.; Sadeghi, M.; Pernet, E.; Herrero, A.; Grant, A.; Downey, J.; Barreiro, L. B.; Yipp, B. G.; Soehnlein, O.; Divangahi, M.

Disease tolerance is an evolutionarily conserved host defence strategy that preserves tissue integrity and physiology without affecting pathogen load. Unlike host resistance, the mechanisms underlying disease tolerance remain poorly understood. In the present study, we investigated whether an adjuvant ({beta}-glucan) can reprogram innate immunity to provide protection against Influenza A virus (IAV) infection. Here we observe that {beta}-glucan treatment reduced the morbidity and mortality against IAV infection, independent of host resistance (viral load). Increased survival of {beta}-glucan treated mice against IAV is associated with the accumulation of neutrophils via RoR{gamma}t+ T cells in the lung tissue. Using gain-and-loss-of-function approaches, we demonstrate that {beta}-glucan reprogrammed neutrophils are essential for promoting disease tolerance, limiting pulmonary tissue damage, and enhancing survival against IAV infection. {beta}-glucan treatment promotes granulopoiesis in a type 1 interferon-dependent manner that leads to the generation of a unique subset of neutrophils, which are less mature with higher mitochondrial mass utilizing mitochondrial oxidative (OXPHOS) metabolism. Collectively, our data indicate that {beta}-glucan reprograms hematopoietic stem cells (HSCs) to generate neutrophils with a novel \'regulatory\' function, which is required for promoting disease tolerance and maintaining lung tissue integrity against viral infection.