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. Filling this knowledge gap is crucial, as many gastrointestinal diseases of humans originate with pathogenic invasions of the intestinal epithelium, or involve dysregulated interactions between the commensal microbiota and epithelial cells. In the previous project period, we showed that intestinal epithelil cell autophagy limits tissue invasion by opportunistically invasive commensals and the invasive intestinal pathogen, Salmonella typhimurium. We found that autophagy activation by S. typhimurium requires the innate immune signaling adaptor MyD88, and is regulated by interactions between the anti-autophagy factor BCL2 and the essential autophagy protein Beclin 1. Our initial findings thus identify autophagy as an important epithelial cell-autonomous mechanism of antibacterial defense and indicate that epithelial autophagy activation is tightly regulated. During the next project period, we propose to build upon these findings to gain a deeper understanding of how antibacterial autophagy is regulated in the intestinal epithelium, and to elucidate the physiological significance of epithelial autophagy for maintaining homeostasis with the microbiota.
In Aim 1, we will use in vivo mouse models to further delineate the role of BCL2 in regulating antibacterial autophagy in the intestinal epithelium.
In Aim 2, we will use in vivo approaches to determine how MyD88 regulates antibacterial autophagy in intestinal epithelial cells.
In Aim 3, we will use mice harboring epithelial cell-specific autophag defects to test the hypothesis that autophagy promotes the clearance of opportunistically-invasive commensal bacteria. These studies will significantly advance our understanding of how intestinal epithelial cells promote homeostasis with the diverse bacterial community in the intestine. Further, our findings should suggest novel strategies for enhancing intestinal epithelia cell autophagy to protect against intestinal infections and inflammatory diseases.
Humans harbor 100 trillion bacteria that make important contributions to health, but can invade host tissues and cause diseases such as inflammatory bowel disease and bacteremia. This proposal will explore how the cellular process of autophagy is regulated in intestinal epithelial cells and how epithelial autophagy promotes the clearance of bacteria that invade the intestinal barrier. Our findings should yield novel strategies for enhancing intestinal epithelial cell autophagy to protect against intestinal infections and inflammatory bowel disease.
|Gillis, Caroline C; Hughes, Elizabeth R; Spiga, Luisella et al. (2018) Dysbiosis-Associated Change in Host Metabolism Generates Lactate to Support Salmonella Growth. Cell Host Microbe 23:54-64.e6|
|Zhu, Wenhan; Winter, Maria G; Byndloss, Mariana X et al. (2018) Precision editing of the gut microbiota ameliorates colitis. Nature 553:208-211|
|Gillis, Caroline C; Hughes, Elizabeth R; Spiga, Luisella et al. (2018) Dysbiosis-Associated Change in Host Metabolism Generates Lactate to Support Salmonella Growth. Cell Host Microbe 23:570|
|Duerkop, Breck A; Kleiner, Manuel; Paez-Espino, David et al. (2018) Murine colitis reveals a disease-associated bacteriophage community. Nat Microbiol 3:1023-1031|
|Propheter, Daniel C; Chara, Andrew L; Harris, Tamia A et al. (2017) Resistin-like molecule ? is a bactericidal protein that promotes spatial segregation of the microbiota and the colonic epithelium. Proc Natl Acad Sci U S A 114:11027-11033|
|Udden, S M Nashir; Peng, Lan; Gan, Jia-Liang et al. (2017) NOD2 Suppresses Colorectal Tumorigenesis via Downregulation of the TLR Pathways. Cell Rep 19:2756-2770|
|Bel, Shai; Pendse, Mihir; Wang, Yuhao et al. (2017) Paneth cells secrete lysozyme via secretory autophagy during bacterial infection of the intestine. Science 357:1047-1052|
|Spiga, Luisella; Winter, Maria G; Furtado de Carvalho, Tatiane et al. (2017) An Oxidative Central Metabolism Enables Salmonella to Utilize Microbiota-Derived Succinate. Cell Host Microbe 22:291-301.e6|
|Wang, Yuhao; Kuang, Zheng; Yu, Xiaofei et al. (2017) The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. Science 357:912-916|
|Choi, Jin Huk; Wang, Kuan-Wen; Zhang, Duanwu et al. (2017) IgD class switching is initiated by microbiota and limited to mucosa-associated lymphoid tissue in mice. Proc Natl Acad Sci U S A 114:E1196-E1204|
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