Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The outcome of infection is determined not only by the virulence of an infecting organism, nor by the microbial burden, nor by the intensity of the innate immune response, but by the ability of the host to accommodate itself to each of these factors. Homeostatic mechanisms normally limit the intensity of an inflammatory response, maintain cardiovascular stability, and bring about the repair of damaged tissues, concurrent with the initiation of the immune response itself. We have previously identified mutations that diminish the ability of the host to survive infection, including a mutation in Kcnj8, a component of an ATP-sensitive potassium channel of the vascular endothelium. Without this channel, mice suffer myocardial infarction and cardiovascular collapse during infection with mouse cytomegalovirus, or after injection of minute quantities of lipopolysaccharide. Many other mechanisms maintain homeostasis during infection, and using a forward genetic screen for hypersensitivity to DSS-induced colitis, we have identified several of them. Mutations that limit proliferation of epithelial cells, diminish the ability to sense microbes, prevent secretion or intracellular migration of vesicles, impair the unfolded protein response, or the systemic glucocorticoid response all permit severe colitis to develop following minor septic injury to the mucosa. Some of these mutations (e.g., mutations affecting Toll-like receptors, signaling proteins downstream, and the glucocorticoid response) are of very broad importance in surviving infection, operating in many different infectious disease states. We propose to identify many more such mutations and establish a strong mechanistic model of the critical homeostatic mechanisms that allow the host to recover from a defined stress on the enteric mucosa. We will further determine whether these mutations have broad effects on susceptibility to infection, and whether they might be combined to create synthetic phenotypes that affect the course of infection.
Infection continues to account for approximately one quarter of all deaths worldwide. Not only the virulence of microbes, and not only the efficacy of the immune response, but the efficacy of host homeostatic mechanisms contribute to survival during infection. The key genes that enforce homeostasis during infection and inflammation within the gut mucosa will be discovered in the course of this project, and may be relevant not only to enteric inflammation (e.g., inflammatory bowel disease) but to many other infectious diseases as well.
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| 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 |
| Beutler, Bruce (2016) Innate immunity and the new forward genetics. Best Pract Res Clin Haematol 29:379-387 |
| Wang, Tao; Zhan, Xiaowei; Bu, Chun-Hui et al. (2015) Real-time resolution of point mutations that cause phenovariance in mice. Proc Natl Acad Sci U S A 112:E440-9 |
| Moresco, Eva Marie Y; Li, Xiaohong; Beutler, Bruce (2013) Going forward with genetics: recent technological advances and forward genetics in mice. Am J Pathol 182:1462-73 |
| Arnold, Carrie N; Barnes, Michael J; Berger, Michael et al. (2012) ENU-induced phenovariance in mice: inferences from 587 mutations. BMC Res Notes 5:577 |
| Won, Sungyong; Eidenschenk, Celine; Arnold, Carrie N et al. (2012) Increased susceptibility to DNA virus infection in mice with a GCN2 mutation. J Virol 86:1802-8 |
| Rutschmann, Sophie; Crozat, Karine; Li, Xiaohong et al. (2012) Hypopigmentation and maternal-zygotic embryonic lethality caused by a hypomorphic mbtps1 mutation in mice. G3 (Bethesda) 2:499-504 |
| Siggs, Owen M; Li, Xiaohong; Xia, Yu et al. (2012) ZBTB1 is a determinant of lymphoid development. J Exp Med 209:19-27 |
| Brandl, Katharina; Tomisato, Wataru; Li, Xiaohong et al. (2012) Yip1 domain family, member 6 (Yipf6) mutation induces spontaneous intestinal inflammation in mice. Proc Natl Acad Sci U S A 109:12650-5 |
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