The mucosal surfaces are often the first interface between the host, the normal flora, and pathogenic bacteria. The mucosal epithelium is involved in maintaining the homeostasis with the normal flora and in constituting the mucosal barrier against pathogens. One host strategy in response to bacterial infection is to inhibit bacterial growth by limiting availability of essential nutrients and metals, like iron and zinc. The role of metal withholding responses in the gut mucosa in response to pathogens and in the dynamics with the microbiota is not well understood. Our long-range goal is to understand the mechanisms by which epithelial cells constitute the mucosal barrier by interacting with the resident microbiota and responding to mucosal pathogens. The objectives of this application are to investigate the role of metal withholding in the gut mucosa and how it is triggered in response to bacterial infection. Our central hypothesis is that in response to bacterial infection intestinal epithelial cells secrete lipocalin-2 and calprotectin, two antimicrobial peptides that sequester iron and zinc, respectively. While mucosal pathogens are resistant to metal withholding and thus colonize the gut, growth of the resident microbiota is suppressed. We plan to test our hypothesis and fulfill the objectives of this application by pursuing the following specific aims: 1. Determine how metal withholding is induced in the gut mucosa during bacterial infections. We will test the hypothesis that lipocalin-2 and calprotectin are secreted by epithelial cells in response to IL-17 and IL-22 stimulation during bacterial infection. 2. Determine the role of metal withholding responses in the gut mucosa during bacterial infections. We will test the hypothesis that resistance to lipocalin-2-mediated iron starvation and calprotectin-mediated zinc starvation in the gut facilitate bacterial colonization during inflammation. The proposed work is innovative because it establishes new concepts on the role of the epithelium as component of the mucosal barrier in its dynamics with pathogens and the resident microbiota. It is our expectation that the outcome of this study will identify the role of metal withholding responses during bacterial infections. This outcome will be significant because it will contribute to understanding the complex interplay at the mucosal surfaces between epithelial cells, commensals and pathogens. The mucosal epithelium is involved in maintaining the homeostasis with the normal flora and in constituting the mucosal barrier against pathogens. One host strategy in response to bacterial infection is to inhibit bacterial growth by limiting availability of essential nutrients and metals, like iron and zinc. The role of metal withholding responses in the gut mucosa in response to pathogens and in the dynamics with the microbiota is not well understood.
The mucosal epithelium is involved in maintaining the homeostasis with the normal flora and in constituting the mucosal barrier against pathogens. One host strategy in response to bacterial infection is to inhibit bacterial growth by limiting availability of essential nutrients and metals, like iron and zinc. The role of metal withholding responses in the gut mucosa in response to pathogens and in the dynamics with the microbiota is not well understood.
| Diaz-Ochoa, Vladimir E; Lam, Diana; Lee, Carlin S et al. (2016) Salmonella Mitigates Oxidative Stress and Thrives in the Inflamed Gut by Evading Calprotectin-Mediated Manganese Sequestration. Cell Host Microbe 19:814-25 |
| Bellet, Marina M; Deriu, Elisa; Liu, Janet Z et al. (2013) Circadian clock regulates the host response to Salmonella. Proc Natl Acad Sci U S A 110:9897-902 |
| Behnsen, Judith; Deriu, Elisa; Sassone-Corsi, Martina et al. (2013) Probiotics: properties, examples, and specific applications. Cold Spring Harb Perspect Med 3:a010074 |
| Liu, Janet Z; Jellbauer, Stefan; Poe, Adam J et al. (2012) Zinc sequestration by the neutrophil protein calprotectin enhances Salmonella growth in the inflamed gut. Cell Host Microbe 11:227-39 |
| Im, Seung-Soon; Yousef, Leyla; Blaschitz, Christoph et al. (2011) Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. Cell Metab 13:540-9 |
| Blaschitz, Christoph; Raffatellu, Manuela (2010) Th17 cytokines and the gut mucosal barrier. J Clin Immunol 30:196-203 |
| Liu, Janet Z; Pezeshki, Milad; Raffatellu, Manuela (2009) Th17 cytokines and host-pathogen interactions at the mucosa: dichotomies of help and harm. Cytokine 48:156-60 |
