The intestine of animals is colonized by a large number of commensal microorganisms that contribute to many host physiological processes. An important role of the intestinal microbiota is to protect the host against colonization and invasio by pathogens that often enter the intestinal tract. However, the interaction between the microbiota and the host immune system that mediates protection against enteric pathogens remains poorly understood. Furthermore, the mechanisms that enteric pathogens employ to overcome the presence of the microbiota remain poorly understood. We find that the commensal microbiota is critical for the elimination of Citrobacter rodentium, an enteric mouse pathogen that models human infection by diarrheagenic enterohemorrhagic (EHEC) and enteropathogenic (EPEC) Escherichia coli. EHEC and EPEC are important causes of watery diarrhea and mortality worldwide. These Gram-negative bacteria are food- and waterborne non-invasive pathogens which attach to and colonize the intestinal tract by inducing characteristic attaching- and-effacing (A/E) lesions on the intestinal epithelium, leading to transient enteritis r colitis in humans. The genome of EPEC and EPEC and related pathogens harbor the locus for enterocyte effacement (LEE) which is critical for bacterial colonization and the ability to cause pathology. LEE virulence factors are controlled by Ler, a transcription factor that acts as a globa regulator of LEE virulence genes. We plan in this proposal to use the Citrobacter rodentium model to test several hypotheses raised by our Preliminary Results. The goal of this proposal is to gain a better understanding of the interactions among the pathogen, the host immune system and the indigenous microbiota that are critical in controlling the colonization and eradication of enteric pathogens. In addition, we propose to develop novel therapeutic strategies to treat C. rodentium-induced colitis based on the ability of the indigenous microbiota to outcompete the pathogen with reduced Ler-mediated virulence. Given that A/E pathogens are a major cause of death and morbidity in human populations, this proposal is expected to have a significant and broad impact in the medical field

Public Health Relevance

The intestine of animals is colonized by a large number of commensal microorganisms that play an important role in protection against enteric bacterial pathogens, but the mechanisms involved remain poorly understood. The goal of this proposal is to gain a better understanding of the interactions among the enteric pathogen C. rodentium, the host immune system and the intestinal microbiota that regulate the colonization and clearance of the pathogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK095782-01A1
Application #
8495692
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Grey, Michael J
Project Start
2013-05-20
Project End
2018-04-30
Budget Start
2013-05-20
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$338,213
Indirect Cost
$120,713
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zeng, Melody Y; Cisalpino, Daniel; Varadarajan, Saranyaraajan et al. (2016) Gut Microbiota-Induced Immunoglobulin G Controls Systemic Infection by Symbiotic Bacteria and Pathogens. Immunity 44:647-58
Coll, Rebecca C; Robertson, Avril A B; Chae, Jae Jin et al. (2015) A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med 21:248-55
Seo, Sang-Uk; Kamada, Nobuhiko; Muñoz-Planillo, Raúl et al. (2015) Distinct Commensals Induce Interleukin-1β via NLRP3 Inflammasome in Inflammatory Monocytes to Promote Intestinal Inflammation in Response to Injury. Immunity 42:744-55
Seo, Sang-Uk; Kuffa, Peter; Kitamoto, Sho et al. (2015) Intestinal macrophages arising from CCR2(+) monocytes control pathogen infection by activating innate lymphoid cells. Nat Commun 6:8010
Kamada, Nobuhiko; Sakamoto, Kei; Seo, Sang-Uk et al. (2015) Humoral Immunity in the Gut Selectively Targets Phenotypically Virulent Attaching-and-Effacing Bacteria for Intraluminal Elimination. Cell Host Microbe 17:617-27
De la Fuente, Marjorie; Franchi, Luigi; Araya, Daniela et al. (2014) Escherichia coli isolates from inflammatory bowel diseases patients survive in macrophages and activate NLRP3 inflammasome. Int J Med Microbiol 304:384-92
Kim, Yun-Gi; Udayanga, Kankanam Gamage Sanath; Totsuka, Naoya et al. (2014) Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGEâ‚‚. Cell Host Microbe 15:95-102
Kamada, Nobuhiko; Núñez, Gabriel (2014) Regulation of the immune system by the resident intestinal bacteria. Gastroenterology 146:1477-88
Hasegawa, Mizuho; Yada, Shoko; Liu, Meng Zhen et al. (2014) Interleukin-22 regulates the complement system to promote resistance against pathobionts after pathogen-induced intestinal damage. Immunity 41:620-32
Kamada, Nobuhiko; Núñez, Gabriel (2013) Role of the gut microbiota in the development and function of lymphoid cells. J Immunol 190:1389-95

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