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Impact of Pulmonary Surfactant on Human Macrophage Susceptibility to Mycobacterium tuberculosis

Dodd, Claire Elizabeth

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Microbiology.
Mycobacterium tuberculosis (M.tb) is an extremely salient pathogen and causes a human death every twenty seconds. M.tb is also capable of enduring for decades inside of the human body and therefore a substantial reservoir of latently infected individuals exists as a lurking threat to global health. A historical scourge of the human species, M.tb is now highly adapted to the lung environment and is capable of intracellular survival within alveolar macrophages (AMs). As the immunological guardians of the alveolar airspace, AMs not only phagocytose inhaled microbes and particulate matter but are also crucial in the catabolism of lung surfactant, a lipid-protein complex which lines the tissue. Macrophage phenotype and behavior is regulated by surfactant and M.tb can utilize host lipids as a carbon source during infection. We therefore investigated which receptor(s) contribute to surfactant uptake and whether the presence of those surfactant lipids within human macrophages prior to infection with M.tb enhances bacterial survival. We show that preformed scavenger receptor CD36 is redistributed from an intracellular pool to the cell membrane following exposure to lipids and proteins found in lung surfactant. Over days in culture with surfactant components, CD36 transcript and protein levels are increased relative to resting macrophages. siRNA knockdown of CD36 inhibits the ability of human macrophages to acquire the most abundant lipid species in surfactant, dipalmitoylphosphatidylcholine (DPPC). DPPC uptake is specifically mediated by CD36, as acquisition of another surfactant lipid, phophatidylglycerol, is unaffected by CD36 knockdown. Furthermore, Scavenger Receptor-A knockdown macrophages retain the ability to acquire DPPC. When human macrophages are cultured in surfactant lipids prior to infection with M.tb, bacterial growth is increased significantly. This surfactant-mediated growth advantage does not occur if CD36 is knocked down prior to culturing macrophages in surfactant. Finally, pre-exposure of macrophages to surfactant lipids results in decreased production of TNFa and a delay in the switching time to a host-protective macrophage metabolic program. We conclude that CD36 contributes to surfactant lipid uptake by human macrophages and that M.tb is able to exploit this function, resulting in enhanced M.tb growth in the first few days of infection.
Larry Schlesinger (Advisor)
215 p.

Recommended Citations

Citations

  • Dodd, C. E. (2017). Impact of Pulmonary Surfactant on Human Macrophage Susceptibility to Mycobacterium tuberculosis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1491747880967301

    APA Style (7th edition)

  • Dodd, Claire. Impact of Pulmonary Surfactant on Human Macrophage Susceptibility to Mycobacterium tuberculosis. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1491747880967301.

    MLA Style (8th edition)

  • Dodd, Claire. "Impact of Pulmonary Surfactant on Human Macrophage Susceptibility to Mycobacterium tuberculosis." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1491747880967301

    Chicago Manual of Style (17th edition)