Chemokines are small secreted proteins that induce chemotaxis in various cell types. This proposal focuses on CCL28, one of the most widely expressed mucosal chemokines. CCL28 is strongly expressed in the salivary gland and it therefore normally coats the digestive tract. It is also expressed by mucosal epithelial cells, exhibits antimicrobial activity, and its expression is induced in the mammary gland upon the onset of lactation. Its receptor is GPR2/CCR10, and a Ccr10-/- mouse cannot recruit IgA plasmablasts to the mammary gland. In the gut, CCL28 expression is induced in colonocytes in response to pro-inflammatory cytokines, suggesting that it could play an important role in colitis. CCL28 is therefore a Dual (homeostatic/inflammatory) chemokine. In this proposal, we have studied the phenotype of a Ccl28-/- mouse. Importantly, our preliminary data indicates that the Ccl28-/- mouse is extremely sensitive to infection with the enteric pathogen Salmonella enterica serotype Typhimurium. Salmonella enterica is a leading cause of morbidity and mortality worldwide. Serotype Typhimurium is one the most common isolates of Salmonella, causing inflammatory diarrhea in immunocompetent patients but also bacteremia in immunocompromised individuals. The main objective of our proposal is to study the mechanism through which CCL28 plays a role against infection with mucosal pathogens like S. Typhimurium. Our central hypothesis is that CCL28 plays a critical role in the protective response to S. Typhimurium infection, either through the recruitment of specific subsets of immune cells, or through direct antimicrobial activity. Our hypothesis is based on preliminary data indicating that a Ccl28-/- mouse shows dramatic mortality and increased bacterial load in lymphoid tissues following infection with S. Typhimurium. Accordingly, we will test our hypothesis through the following Specific Aims:
In Specific Aim 1, we will confirm that CCL28 plays a protective role during S. Typhimurium infection, and will obtain more data on the conditions under which this susceptibility is observed.
In Specific Aim 2, we will investigate the mechanism through which CCL28 exerts a protective effect during infection. We hypothesize that it can be due to a failure (in the Ccl28-/- mouse) to recruit certain leukocyte populations critical for controlling Salmonella infection, or alternatively, because the antimicrobial activityof Ccl28 is an important factor in natural resistance against Salmonella. To address these possibilities, we will analyze the leukocyte populations in the gut of Ccl28-/- mice compared to wild-type littermates. We will also study the potential susceptibility of a Ccr10-/- mouse to Salmonella infection. Successful implementation of this study will open a new field of research, namely, the role of CCL28 in the control of bacterial infections and host-pathogen interactions.

Public Health Relevance

Non-typhoidal Salmonella causes 1.4 million infections in the United States each year. Here we will investigate the interplay between Salmonella and CCL28, a mucosal chemokine, with a focus on the mechanisms by which this chemokine controls Salmonella infection. Based on our results, our goal is to design new strategies to treat and prevent infection with Salmonella.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Alexander, William A
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University of California Irvine
Schools of Medicine
United States
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