| 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 knowledge 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. Beside 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 resistance to 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 IFNgamma. 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 (TNFalpha, IL-6, IL-1beta 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. |
