The effect of n-3 polyunsaturated fatty acids on the immune response to Mycobacterium tuberculosis : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
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[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2009]
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| Subjects: |
| Abstract: | ABSTRACT: Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), infects almost one third of the human population and kills almost 2 million people each year worldwide. Although great advances have been made in understanding the host-pathogen interaction in TB, enhanced knowlege of the factors that influence the host immune response again this pathogen, including nutritional components, would facilitate the development of new approaches to control the disease. Besides their health benefits, dietary omega-3 polyunsaturated fatty acids (n-3 PUFA) can impair host resistance to intracellular infections by creating an immunosuppressive environment. We hypothesized that n-3 PUFA impair host resistent Mtb, in part, by suppressing the activation of macrophage antimicrobial responses. We demonstrated that the incorporation of the n-3 PUFA docosahexaenoic acid (DHA) into membranes of murine J774A.1 macrophages reduced the ability to control Mtb, in part, by suppressing the activation of antibacterial responses induced by IFNy. Incorporation of DHA resulted in defective macrophage activation, as characterized by reduced production of pro-inflammatory cytokines, lower expression of co-stimulatory molecules, impaired oxidative metabolism, reduced phagolysosome maturation and increased bacterial survival. Furthermore, we showed that the endogenous production of n-3 PUFA in transgenic fat-1 mice increased their susceptibility to pulmonary TB. Bacteriological and histological analysis of lungs revealed that fat-1 mice were more susceptible to TB, as demonstrated by higher bacterial loads and poorly-organized inflammatory responses. We also observed reduced ability to control the infection in fat-1 macrophages infected ex vivo, as demonstrated by increased bacterial survival, reduced pro-inflammatory cytokine production (TNF[alpha], IL-6, Il-1[beta] and MCP-1), impaired oxidative metabolism and diminished Mtb-lysotracker colocalization within phagosomes. The impaired immunity was explained, in part, by diminished activation and antimycobacterial response in fat-1 macrophages. These data suggest that n-3 PUFA-supplemented diets could have a detrimental effect on host immunity to Mtb in humans, by interfering with protective cellular mechanisms. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Office of Research and Graduate Studies of The Texas A&M University System Health Science Center in partial fulfillment for the requirements for the degree of Doctor of Philosophy May 2009." Approved as to style and content by: David N. McMurray, Robert S. Chapkin, Vernon L. Tesh, James E. Samuel, John M. Quarles. |
| Physical Description: | xi, 110 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 92-108). |