Environmental Enteric Dysfunction (EED) is a disease of the gastrointestinal (GI) tract that contributes to malnutrition and growth stunting and 150 million children worldwide are at risk. EED is associated with both a diet low in protein/fat and an invasion of the microbiota with inflammatory bacteria of the family Enterobacteriaceae. One of the symptoms of the disease is dysfunction of the GI immune response, as in areas where the disease is endemic, the efficacy of oral vaccination is severely compromised. Why EED leads to a disruption of the mucosal immune response is not clear and is a critical question because failure of oral vaccination will hinder worldwide efforts to eradicate important GI pathogens such as poliovirus, rotavirus and Cholera. To define the mechanisms that disrupt oral vaccination during EED we have developed a murine model of the disease that is dependent upon low protein/fat diet and introduction of a single strain of adherent-invasive E. coli. Murine EED was characterized by growth stunting and damage to the intestinal barrier/permeability which is characteristic of human disease. We have also developed novel MHC class II tetramers and ?retrogenic? T cells to measure the CD4 T cell response to an attenuated Heat Labile Toxin (dmLT) that induces large CD4 T cell responses without significant intestinal pathology. Critically, when mice were orally immunized with dmLT we observed a profound defect in the accumulation of dmLT-specific CD4 T cells in the GI tract. T cell responses in the secondary lymphoid tissue were unaffected, indicating that systemic immune responses are relatively intact and that EED mice have a specific defect in GI tract immunity. Analysis of the GI tract of EED-affected animals revealed that they had a significant increase in cells known to regulate tissue T cell responses; macrophages and Tregs. The failure of oral vaccination and increase in macrophages/Tregs requires both a low protein/fat diet and addition of E. coli to the intestinal microbiota. Our hypothesis is that shifts in the microbiota caused by EED modify intestinal macrophages and Tregs leading to the disruption of the local CD4 T cell response to oral vaccination. We propose to test this hypothesis in two aims focused on the murine model of EED. First, using a combination of genetic mouse models we will define the role of intestinal Tregs and macrophages in controlling local T cell responses to oral vaccination. Second, we will define the ileal and fecal microbiota of EED mice by 16S rRNA analysis and determine if changes to the microbiota are necessary and sufficient to reduce the efficacy of oral vaccination via fecal transfers into gnotobiotic mice. All of the reagents have been prepared and validated uniquely by our lab, including a novel tetramer and retroviruses that express TCR genes specific to dmLT. The anticipated results will enable future research towards a mechanistic understanding of EED and the critical cellular factors necessary for effective oral vaccination. These findings will be broadly significant to worldwide efforts to curb infectious disease with vaccination.

Public Health Relevance

Environmental Enteric Dysfunction (EED) is disease common to children of resource-poor countries that causes stunting and cognitive defects and is associated with the failure of oral vaccination protocols. EED is associated with shifts in the composition of both the intestinal microbiota and local immune response. Here, using a novel animal model we propose to test how the microbiota associated with EED induces shifts in immune cells of the intestine to reduce the efficacy of oral vaccination.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Immunity and Host Defense (IHD)
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Rothermel, Annette L
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University of Pittsburgh
Schools of Medicine
United States
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