A major challenge for mammalian hosts is to maintain symbiotic relationships with the vast bacterial communities that colonize the intestines. The intestinal epithelium is the primary barrier between the intestinal microbiota and internal host tissues, yet little is known about how epithelial cells control bacterial interactions with the mucosal surface and limit microbial penetration of the intestinal barrier. We have discovered a novel antibacterial factor, RegIIIg, which is produced by small intestinal epithelial cells. RegIIIg is a member of the C-type lectin family of carbohydrate-binding proteins that is discharged into the gut lumen. RegIIIg has direct bactericidal activity against Gram-positive bacteria and binds its bacterial targets via interactions with peptidoglycan carbohydrate. RegIIIg thus represents a previously unappreciated mechanism of mucosal defense and a new biological function for C-type lectins. Intestinal bacteria regulate RegIIIg transcription through direct activation of epithelial cell Toll-like receptors, revealing a direct dialog between enteric bacteria and the intestinal epithelium that regulates antimicrobial activity. As several other Reg family C-type lectins are produced by gut epithelia, directly bactericidal C-type lectins likely represent an important general mechanism of gut epithelial defense. The overall goal of this proposal is to extend our understanding of lectin- mediated antimicrobial defense of the intestinal mucosal surface. This work will involve three Specific Aims. First, we will use in vitro biochemical approaches to determine the molecular mechanism of lectin-mediated bactericidal activity. Second, we will use RegIIIg knockout mice to delineate how RegIIIg contributes to intestinal host-microbial homeostasis in vivo. Third, we will analyze other Reg proteins in vitro and in vivo in order to explore whether directly bactericidal lectins constitute a general mechanism of mucosal defense. Together, these studies should lead to fundamental insights into immune control of bacterial-mucosal associations, and will provide new perspectives on symbiotic host-microbial associations.

Public Health Relevance

A major challenge for humans is to maintain symbiotic relationships with the vast bacterial communities that colonize the intestines. Intestinal epithelial cells produce abundant quantitites of RegIIIg, a carbohydrate binding protein that has a remarkable capacity to kill bacteria. In this grant we propose to explore the mechanism that RegIIIg uses to kill bacteria, and to understand how this protein functions to protect deeper host tissues from invasion by the intestine's normal microbial inhabitants. The results from these studies should yield new strategies for designing novel antimicrobial therapeutics, and could lead to new approaches to treating inflammatory bowel disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Grey, Michael J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
Zip Code
Mukherjee, Sohini; Zheng, Hui; Derebe, Mehabaw G et al. (2014) Antibacterial membrane attack by a pore-forming intestinal C-type lectin. Nature 505:103-7
Mirpuri, Julie; Raetz, Megan; Sturge, Carolyn R et al. (2014) Proteobacteria-specific IgA regulates maturation of the intestinal microbiota. Gut Microbes 5:28-39
Derebe, Mehabaw G; Zlatkov, Clare M; Gattu, Sureka et al. (2014) Serum amyloid A is a retinol binding protein that transports retinol during bacterial infection. Elife 3:e03206
Yu, Xiaofei; Wang, Yuhao; Deng, Mi et al. (2014) The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor. Elife 3:
Raetz, Megan; Hwang, Sun-Hee; Wilhelm, Cara L et al. (2013) Parasite-induced TH1 cells and intestinal dysbiosis cooperate in IFN-ýý-dependent elimination of Paneth cells. Nat Immunol 14:136-42
Benjamin, Jamaal L; Sumpter Jr, Rhea; Levine, Beth et al. (2013) Intestinal epithelial autophagy is essential for host defense against invasive bacteria. Cell Host Microbe 13:723-34
Duerkop, Breck A; Hooper, Lora V (2013) Resident viruses and their interactions with the immune system. Nat Immunol 14:654-9
Yu, Xiaofei; Rollins, Darcy; Ruhn, Kelly A et al. (2013) TH17 cell differentiation is regulated by the circadian clock. Science 342:727-30
Ismail, Anisa S; Severson, Kari M; Vaishnava, Shipra et al. (2011) Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. Proc Natl Acad Sci U S A 108:8743-8
Vaishnava, Shipra; Yamamoto, Miwako; Severson, Kari M et al. (2011) The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science 334:255-8

Showing the most recent 10 out of 19 publications