Dataset Information

Infant Alveolar Macrophages Are Unable to Effectively Contain Mycobacterium tuberculosis.

ABSTRACT: Infants are more likely to develop lethal disseminated forms of tuberculosis compared with older children and adults. The reasons for this are currently unknown. In this study we test the hypothesis that antimycobacterial function is impaired in infant alveolar macrophages (AM?s) compared with those of adults. We develop a method of obtaining AM?s from healthy infants using rigid bronchoscopy and incubate the AM?s with live virulent Mycobacterium tuberculosis (Mtb). Infant AM?s are less able to restrict Mtb replication compared with adult AM?s, despite having similar phagocytic capacity and immunophenotype. RNA-Seq showed that infant AM?s exhibit lower expression of genes involved in mycobactericidal activity and IFN?-induction pathways. Infant AM?s also exhibit lower expression of genes encoding mononuclear cell chemokines such as CXCL9. Our data indicates that failure of AM?s to contain Mtb and recruit additional mononuclear cells to the site of infection helps to explain the more fulminant course of tuberculosis in early life.

SUBMITTER: Goenka A

PROVIDER: S-EPMC7107672 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Infant Alveolar Macrophages Are Unable to Effectively Contain <i>Mycobacterium tuberculosis</i>.

Goenka Anu A Prise Ian E IE Connolly Emma E Fernandez-Soto Paulina P Morgan David D Cavet Jennifer S JS Grainger John R JR Nichani Jaya J Arkwright Peter D PD Hussell Tracy T

Frontiers in immunology 20200324

Infants are more likely to develop lethal disseminated forms of tuberculosis compared with older children and adults. The reasons for this are currently unknown. In this study we test the hypothesis that antimycobacterial function is impaired in infant alveolar macrophages (AMϕs) compared with those of adults. We develop a method of obtaining AMϕs from healthy infants using rigid bronchoscopy and incubate the AMϕs with live virulent <i>Mycobacterium tuberculosis</i> (Mtb). Infant AMϕs are less a ...[more]

PMID: 32265931

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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

Infant Alveolar Macrophages Are Unable to Effectively Contain Mycobacterium tuberculosis.

Publications

Infant Alveolar Macrophages Are Unable to Effectively Contain <i>Mycobacterium tuberculosis</i>.

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