Bacillus anthracis, the causative agent of anthrax, secretes lethal toxin that down-regulates immune functions. Translocation of B. anthracis across mucosal epithelia is key for its dissemination and pathogenesis. Group 3 innate lymphocytes (ILC3s) are important in mucosal barrier maintenance due to their expression of the cytokine IL-22, a critical regulator of tissue responses and repair during homeostasis and inflammation. We found that B. anthracis lethal toxin perturbed ILC3 function in vitro and in vivo, revealing an unknown IL-23-mediated MAPK signaling pathway. Lethal toxin had no effects on the canonical STAT3-mediated IL-23 signaling pathway. Rather lethal toxin triggered the loss of several MAP2K kinases, which correlated with reduced activation of downstream ERK1/2 and p38, respectively. Inhibition studies showed the importance of MAPK signaling in IL-23-mediated production of IL-22. Our finding that MAPK signaling is required for optimal IL-22 production in ILC3s may lead to new approaches for targeting IL-22 biology. Bacillus anthracis, the bacterium that causes the deadly disease anthrax, is commonly known for its use in bioterrorism. We have used B. anthracis to study the effect of MAPK signaling pathways in group 3 innate immune lymphocytes (ILC3s). B. anthracis enters the host through the lungs or gastrointestinal (GI) tract. To cause disease, the pathogen requires translocation across barrier tissue layers to disseminate. During this infection process, the bacterium produces many virulence factors, including a lethal toxin, that allow it to subvert the host immune response. In many immune cells, lethal toxin turns off signaling events through degradation of intermediate signaling components. In this study, we show that lethal toxin interferes in a specific signaling pathway, MAPK, which is significant because it is not usually associated with IL-23-mediated signaling. We specifically studied the interference of MAPK in ILC3s, rare immune cells found in the lungs and GI tract. These cells secrete high levels of interleukin-22 (IL-22), a key cytokine for maintaining barrier tissues during inflammation. Lethal toxin significantly reduced in vitro IL-23-mediated IL-22 production in mouse and human ILC3s. Furthermore, in vivo administration of lethal toxin reduced IL-22 production in ILC3s. This negative effect on IL-22 implicated MAPK signaling as one of the required pathways in ILC3s for IL-22 production, which means that B. anthracis may inhibit ILC3 function during infection, potentially aiding its bacterial dissemination. These findings increase our understanding of the molecular factors that control IL-22 regulation in ILC3s and aid in development of immune therapeutics and preventive measures.

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