Symbiotic bacteria control intestinal infection by directing lysozyme sorting in Paneth cells

▸ Zhang Q, Pan Y, Yan R, et al. Commensal bacteria direct selective cargo sorting to promote symbiosis. Nat Immunol 2016;16:918–26.

The symbiotic interaction between the mucosal immune system and intestinal microbiota is critical for intestinal homeostasis. When this homeostasis is disrupted, IBD arises. Mutations in NOD2 and LRRK2 have been associated with Crohn's disease (CD). Paneth cells, secretory cells located at the bottom of small intestinal crypts, are responsible for maintaining the epithelial barrier by secreting antimicrobial proteins (AMPs) into the intestinal lumen. Within Paneth cells, the various AMPs are sorted after synthesis into specialised secretory granules called dense core vesicles (DCVs). Many studies have indicated a role for Paneth cells in intestinal disease; however, the underlying mechanisms are unknown. In this study, Zhang and colleagues investigate how LRRK2 and Nod2 may act within the same pathway to regulate Paneth cell function. The authors discovered that symbiotic bacteria direct a DCV cargo-sorting process to promote symbiosis. High LRRK2 expression was found in Paneth cells, and LRRK2 deficiency caused decreased lysozyme in Paneth cells, which made Lrrk2^−/− mice more susceptible to intestinal, but not systemic, Listeria monocytogenes infection. The lysozyme defect in Lrrk2^−/− Paneth cells was a result of failed recruitment of Rab2a, a small GTPase, onto the DCV surface. Also, the presence of luminal biota was required for DCV sorting of lysozyme. In germ-free mice, lysozyme was targeted for lysosomal degradation rather than secretion in Paneth cells. The authors also found that Nod2 was responsible for sensing commensal bacteria to direct lysozyme sorting in Paneth cells. Altogether, the data demonstrate that commensal bacteria direct lysozyme sorting in Paneth cells through a Nod2-LRRK2-Rab2a axis, which is critical for controlling intestinal infection. Additional studies are required to understand the role of these CD-associated proteins in Paneth cell function, how …