IL-33 Controls IL-22-Dependent Antibacterial Defense by Modulating the Microbiota

Abstract

Infections of the lower respiratory tract represent the fifth most common cause of death worldwide. This study describes a mechanism that influences the course of pneumococcal pneumonia based on genetic determinants as well as environmental factors. Previous experiments have shown that animals deficient in IL-33 or its receptor ST2 exhibit an enhanced bacterial defense against Streptococcus pneumoniae. Initially, associations between the susceptibility to human pneumococcal pneumonia and single nucleotide polymorphisms (SNPs) in the genes coding for IL-33 and ST2 were demonstrated. Furthermore, IL-33-deficient animals were shown to produce increased amounts of IL-22, and experiments using Il33-/- Il22-/- animals as well as recombinant IL-22 revealed that enhanced IL-22 production was responsible for the increased resistance of Il33-/- mice to Streptococcus pneumoniae. Classical type 2 immune responses driven by type 2 innate lymphoid cells (ILC2s) or IL-4/IL-13 signaling cascades were not involved in the IL-33-dependent regulation, while ST2-negative ILCs, most likely representing ILC3s, were identified as the main differential producers of IL-22. Additionally, an association between bacterial defense and animal housing conditions was revealed. The IL-33-dependent negative regulation of pneumococcal pneumonia could only be reproduced in facilities with specific individual hygiene conditions. This effect was accompanied by differences in the composition of the intestinal microbiota of the animals, where increased abundance of Lactobacillus spp. correlated with a protective phenotype in Il33-/- mice. Finally, microbiota depletion and co-housing experiments resulted in equilibration of bacterial burden, while a fecal microbiota transplant was able to rescue the observed phenotype in microbiota-depleted animals. Taken together it was demonstrated, that the intestinal microbiota influences pneumococcal pneumonia. The results presented in this study enhance our understanding of the bidirectional communication between microbiota and the immune system and demonstrate that genetic as well as environmental factors infl uence the defense against Streptococcus pneumoniae.