NOD1, but not NOD2, provides protection from systemic Listeria monocytogenes infection 2260383

Abstract Introduction Listeria monocytogenes (Lm) is a foodborne pathogen that can breach intestinal barriers and disseminate systemically, leading to sepsis and death in vulnerable hosts. Hospitalized cases of listeriosis carry mortality rates approaching 50%. While adaptive immunity to Lm has been well characterized, early cytosolic sensing mechanisms that limit bacterial spread remain poorly understood. The innate immune receptors NOD1 and NOD2, along with their adaptor kinase RIPK2, detect bacterial peptidoglycan and initiate protective signaling. Although individual studies have implicated NOD1, NOD2, or RIPK2 in Listeria infection, their relative contributions and interdependence during systemic disease remain unclear. Methods We used C57BL/6 mice lacking NOD1, NOD2, RIPK2, or its kinase activity to evaluate survival, bacterial burden, and cytokine responses after systemic Listeria infection. Macrophage signaling and infection-induced cell death were assessed by immunoblotting and flow cytometry. Results Our findings show NOD1 is required for survival during systemic Lm infection, whereas NOD2 is dispensable but aids recovery. Both RIPK2 KO and RIPK2 kinase-dead mice are highly susceptible to systemic Lm infection and phenocopy NOD1 KO mice. In macrophages, NOD1 and NOD2 were required for optimal activation of signaling pathways during Lm infection. Interestingly, the deficiency of NOD1 or NOD2 led to increased Lm-induced cell death in macrophages. Collectively, our results show that NOD1 and NOD2 cooperate to promote optimal innate immune responses to Lm, but NOD1 has additional nonredundant functions in vivo that are critical for host survival. Conclusion We propose that NOD1 plays distinct roles in non-immune cells, which are essential for protection, and that NOD1 regulates type I interferon production during Lm infection, a process detrimental to the host. In summary, our findings identify the NOD1—RIPK2 pathway as a dominant cytosolic sensor axis conferring protection against systemic Listeria infection. Funding Source n/a Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)