Chitinase 3-like-1 Promotes Streptococcus pneumoniae Killing and Augments Host Tolerance to Lung Antibacterial Responses

Host antibacterial responses include mechanisms that kill bacteria, but also those that protect or tolerize the host to potentially damaging antibacterial effects. We determined that Chitinase 3-like-1 (Chi3l1), a conserved prototypic chitinase-like protein, is induced by Streptococcus pneumoniae and plays central roles in promoting bacterial clearance and mediating host tolerance. S. pneumoniae-infected Chi3l1 null mice exhibit exaggerated lung injury, inflammation and hemorrhage, more frequent bacterial dissemination, decreased bacterial clearance, and enhanced mortality compared to controls. Chi3l1 augments macrophage bacterial killing by inhibiting caspase-1-dependent macrophage pyroptosis and augments host tolerance by controlling inflammasome activation, ATP accumulation, expression of ATP receptor P2X7R, and production of thymic stromal lymphopoietin and type 1, type 2, and type 17 cytokines. These data demonstrate that Chi3l1 is induced during infection, where it promotes bacterial clearance while simultaneously augmenting host tolerance, and that these roles likely contributed to the retention of Chi3l1 over species and evolutionary time.