Date Available

11-2-2012

Year of Publication

2012

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department/School/Program

Microbiology, Immunology, and Molecular Genetics

First Advisor

Dr. Charlotte S. Kaetzel

Abstract

The gastrointestinal tract houses one of the most dense and diverse communities of bacteria on the planet. The mutualistic relationship between the host and commensal microbe permits the microbe an ideal environment to grow and provides the host with increased caloric intake, maturation of the adaptive immune system, and resistance against invading pathogens. To maintain a system in which both parties benefit, the epithelium has evolved numerous strategies to ensure epithelial cells respond to microbes appropriately and that potentially hazardous commensals remain distanced from the soma proper. Breakdown of these propitiating mechanisms elicits unchecked inflammation and can lead to pathology and reduction of host fitness. We show that oral and intestinal epithelial cells respond to the circulating hormone adiponectin in the presence of bacterial constituents, and that adiponectin has the potential to downregulate NF-κB signaling. We also show many commensal bacteria have no effect on TNF or IL-8 proinflammatory gene expression in intestinal cells. Commensals within the family Enterobacteriaceae can increase TNF and IL-8 expression, but also expression of the NF-κB regulator A20 and MAPK phosphatase MKP-1. Importantly, Enterobacteriaceae also increased expression of the IgA transporter pIgR. In the mouse model, we show pIgR expression along the intestinal epithelium is necessary for SIgA accumulation in the outer mucus layer where commensal bacteria reside. Loss of the mucus layer, but not pIgR is sufficient to allow direct bacterial-epithelial cell contact and induce spontaneous inflammation along the colon. Secretory IgA is supplied maternally through breast milk early in life to compensate for the neonate’s inability to produce sufficient endogenous amounts. By utilizing a breeding scheme in which mouse dams were unable to provide their offspring with SIgA, we show the necessity of maternally-supplied SIgA to control bacterial invasion to mesenteric lymph nodes before weaning. In addition, 8-10 week old adult offspring not receiving SIgA as neonates showed both a unique intestinal microbiota and different patterns of intestinal epithelial cell gene expression with and without chemically-induced acute colitis. In summary, we reveal new mechanisms the mammalian host utilizes in order to maintain peace between the commensal microbe and host immune system.

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