Dataset Information

Impaired Recognition of Mycobacterium tuberculosis by Alveolar Macrophages From Diabetic Mice.

ABSTRACT: Diabetes mellitus is associated with increased tuberculosis risk and severity. We previously reported that tuberculosis susceptibility in diabetic mice results from a delay in innate immune response to inhaled Mycobacterium tuberculosis, leading to delayed adaptive immune priming and, consequently, a higher plateau lung bacterial burden and greater immune pathology.?We tested the capacity of alveolar macrophages from diabetic mice to phagocytose M. tuberculosis ex vivo and promote T-cell activation in vivo.?Alveolar macrophages from diabetic mice had reduced expression of CD14 and macrophage receptor with collagenous structure (MARCO), which recognize the bacterial cell wall component trehalose 6,6'-dimycolate (TDM). Diabetic alveolar macrophages exhibited reduced phagocytosis of M. tuberculosis or TDM-coated latex beads. This alveolar macrophage phenotype was absent in peritoneal and bone marrow-derived macrophages. Transfer of infected alveolar macrophages from diabetic mice into nondiabetic recipients confirmed an intrinsic alveolar macrophage defect that hindered T-cell priming. The diabetic alveolar macrophage phenotype depended in part on expression of the receptor for advanced glycation end products.?Reduced MARCO and CD14 expression contributes to defective sentinel function of alveolar macrophages, promoting tuberculosis susceptibility in diabetic hosts at a critical early step in the immune response to aerosol infection.

SUBMITTER: Martinez N

PROVIDER: S-EPMC5144731 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Impaired Recognition of Mycobacterium tuberculosis by Alveolar Macrophages From Diabetic Mice.

Martinez Nuria N Ketheesan Natkunam N West Kim K Vallerskog Therese T Kornfeld Hardy H

The Journal of infectious diseases 20160913 11

<h4>Background</h4> Diabetes mellitus is associated with increased tuberculosis risk and severity. We previously reported that tuberculosis susceptibility in diabetic mice results from a delay in innate immune response to inhaled Mycobacterium tuberculosis, leading to delayed adaptive immune priming and, consequently, a higher plateau lung bacterial burden and greater immune pathology.<h4>Methods</h4> We tested the capacity of alveolar macrophages from diabetic mice to phagocytose M. tuberculosi ...[more]

PMID: 27630197

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Project description:Lung alveolar macrophages (AMs) are in the first line of immune defense against respiratory pathogens and play key roles in the pathogenesis of Mycobacterium tuberculosis (Mtb) in humans. Nevertheless, AMs are available only in limited amounts for in vitro studies, which hamper the detailed molecular understanding of host-Mtb interactions in these macrophages. The recent establishment of the self-renewing and primary Max Planck Institute (MPI) cells, functionally very close to lung AMs, opens unique opportunities for in vitro studies of host-pathogen interactions in respiratory diseases. Here, we investigated the suitability of MPI cells as a host cell system for Mtb infection. Bacterial, cellular, and innate immune features of MPI cells infected with Mtb were characterized. Live bacteria were readily internalized and efficiently replicated in MPI cells, similarly to primary murine macrophages and other cell lines. MPI cells were also suitable for the determination of anti-tuberculosis (TB) drug activity. The primary innate immune response of MPI cells to live Mtb showed significantly higher and earlier induction of the pro-inflammatory cytokines TNF?, interleukin 6 (IL-6), IL-1?, and IL-1?, as compared to stimulation with heat-killed (HK) bacteria. MPI cells previously showed a lack of induction of the anti-inflammatory cytokine IL-10 to a wide range of stimuli, including HK Mtb. By contrast, we show here that live Mtb is able to induce significant amounts of IL-10 in MPI cells. Autophagy experiments using light chain 3B immunostaining, as well as LysoTracker labeling of acidic vacuoles, demonstrated that MPI cells efficiently control killed Mtb by elimination through phagolysosomes. MPI cells were also able to accumulate lipid droplets in their cytoplasm following exposure to lipoproteins. Collectively, this study establishes the MPI cells as a relevant, versatile host cell model for TB research, allowing a deeper understanding of AMs functions in this pathology.

Dataset Information

Impaired Recognition of Mycobacterium tuberculosis by Alveolar Macrophages From Diabetic Mice.

Publications

Impaired Recognition of Mycobacterium tuberculosis by Alveolar Macrophages From Diabetic Mice.

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