The intestinal epithelium regulates the development of adaptive immunity to gut microorganisms, yet little is known about the underlying mechanisms. Filling this knowledge gap is crucial, as many human intestinal diseases arise from dysregulated intestinal immunity. Dietary vitamin A absorbed by the intestinal epithelium is essential for key adaptive immune responses to the microbiota. These include the homing of CD4+ T cells to the intestine and the development of B cells that produce immunoglobulin A. These responses depend on specialized intestinal dendritic cells (DCs) that enzymatically convert the vitamin A derivative retinol to retinoic acid (RA). A major unanswered question is how RA-producing DCs acquire their retinol. Retinol's lipid-like chemical nature necessitates its transport by proteins that protect the retinol from the aqueous environment. However, the protein(s) that mobilize retinol from the intestinal epithelium to DCs as substrate for RA production remain unknown. We have gained insight into this question by studying serum amyloid A (SAA) proteins, which are produced by the intestinal epithelium in response to the microbiota. This R01 renewal application will explore the hypothesis that serum amyloid A (SAA) proteins mobilize retinol to RA-producing DCs and thus shape intestinal adaptive immunity. In the previous project period, we discovered that SAAs are retinol-binding proteins that circulate with bound retinol during acute systemic infection. Further preliminary findings indicate that intestinal SAAs promote retinol acquisition by RA-producing DCs. We propose to build on these findings during the next project period to gain a deeper mechanistic understanding of how SAAs shape intestinal DC function and the development of intestinal adaptive immunity.
In Aim 1, we will delineate the role of SAAs in retinol acquisition and retinoic acid production by intestinal dendritic cells.
In Aim 2, we will identify the cellular receptor for retinol-bound SAAs.
In Aim 3, we will determine the physiological relevance of SAAs for the development of vitamin A-dependent adaptive immunity in the intestine. These studies will provide mechanistic insight into how vitamin A is mobilized to intestinal immune cells and advance our understanding of how microbiota-epithelial interactions shape adaptive immunity. Understanding how the microbiota controls vitamin A-dependent immunity will promote the design of new therapeutics for inflammatory disorders and vaccines against infections.
Vitamin A plays an essential role in promoting the development of adaptive immunity in the intestine. This project will illuminate how dietary vitamin A is taken up and delivered to differentiating immune cells, and how this process affects the development of adaptive immunity. The findings from the proposed project could reveal new targets for pharmacologic and dietary manipulation of intestinal immunity.
| 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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