IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota [scRNA-seq]

IL-22 plays a critical role in defending against mucosal infections, but how IL-22 production is regulated is incompletely understood. Here, we show that mice lacking IL-33 or its receptor ST2 (IL-1RL1) were more resistant to Streptococcus pneumoniae lung infection than wild-type animals, and that single nucleotide polymorphisms in IL33 and IL1RL1 were associated with pneumococcal pneumonia in humans. The effect of IL-33 on S. pneumoniae infection was mediated by negative regulation of IL-22 production by innate lymphoid cells (ILCs), but independent of ILC2s as well as IL-4 and IL-13 signaling. Moreover, IL-33´s influence on antibacterial defense was dependent on housing conditions of the mice, and mediated by the modulatory effect of IL-33 on the intestinal microbiota. Collectively, we reveal that IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota. Our study thus provides insight into the bidirectional crosstalk between the innate immune system and the microbiota and how it shapes susceptibility to bacterial infection. Overall design: Infection of mice with S.pn., lung digestion to single cells, sorting for CD90+ CD127+ ILCs with a quarter of the lung and spiked back into whole lung digest. 10x protocol scRNAseq. 60hpi animals abx treatment from 30hpi on.