Infectious Salmonella typhimurium serovars are a substantial health burden in the United States with an estimated 76 million cases of food borne illness and 5,000 associated deaths annually. Acute enteritis caused by Salmonella strains is manifested clinically by severe cramping and secretory diarrhea, and is the most common cause of infectious gastroenteritis in the United States. Certain Salmonella strains establish themselves within the host cells with no outward signs of disease because they have evolved sophisticated mechanisms to evade host innate immunity. Many infected patients become chronic pathogen carriers and continue to shed Salmonella in stools and urine for prolonged periods following initial invasion and acute gastroenteritis. These patients are a major public health concern because they are pathogen reservoirs. An extensive body of literature is devoted to identifying candidate molecules facilitating Salmonella survival, dissemination and persistence within the host. We have previously shown that some Salmonella strains secrete the preformed AvrA effector protein that potently inhibits the innate immune JNK and NF-kB signaling pathways, thus blocking cytokine production, neutrophil recruitment, and activation of apoptosis during the invasion stage of infection. However, the function of AvrA in mediating Salmonella dissemination and persistence within the host not been addressed, and will be the focus of this proposal. Intriguing preliminary data presented here demonstrate that concurrent AvrA expression and cytokine stimulation force proliferation of immune cells within the Drosophila animal model. We hypothesis that AvrA is responsible for skewing innate immune pathways, influencing Salmonella dissemination and/or chronic persistence. We propose to examine the mechanisms of AvrA mediated cell proliferation in 1) primary bone marrow derived leukocytes infected with nonreplicating adenovirus expressing AvrA, and 2) a murine salmonellosis infection model. In both aims, we will identify the proliferating leukocyte sub-sets using cell specific markers and FACS analysis. As an outcome of the study, we will advance current knowledge of bacterial strategies for survival during dissemination or in the chronic carrier state.
The research is significant because it will contribute to a full understanding of the evasion strategies evolved by enteric pathogens to escape the immune response and persist within the host. The positive impact of this study on advancing our knowledge of host/pathogen interactions will have relevance in human disease, allowing better understanding and potential treatment for chronic Salmonella infection.
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