1. Heterogeneous GM-CSF signaling in macrophages is associated with control of Mycobacterium tuberculosis.
- Author
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Bryson BD, Rosebrock TR, Tafesse FG, Itoh CY, Nibasumba A, Babunovic GH, Corleis B, Martin C, Keegan C, Andrade P, Realegeno S, Kwon D, Modlin RL, and Fortune SM
- Subjects
- Blood Buffy Coat cytology, Cells, Cultured, Gene Expression Profiling, Granulocyte-Macrophage Colony-Stimulating Factor immunology, HIV immunology, HIV pathogenicity, HIV Infections immunology, HIV Infections microbiology, Humans, Interferon-gamma immunology, Interferon-gamma metabolism, Macrophages microbiology, Mycobacterium tuberculosis pathogenicity, Primary Cell Culture, Sequence Analysis, RNA, Tuberculosis microbiology, Vitamin D immunology, Vitamin D metabolism, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Macrophages immunology, Mycobacterium tuberculosis immunology, Signal Transduction immunology, Tuberculosis immunology
- Abstract
Variability in bacterial sterilization is a key feature of Mycobacterium tuberculosis (Mtb) disease. In a population of human macrophages, there are macrophages that restrict Mtb growth and those that do not. However, the sources of heterogeneity in macrophage state during Mtb infection are poorly understood. Here, we perform RNAseq on restrictive and permissive macrophages and reveal that the expression of genes involved in GM-CSF signaling discriminates between the two subpopulations. We demonstrate that blocking GM-CSF makes macrophages more permissive of Mtb growth while addition of GM-CSF increases bacterial control. In parallel, we find that the loss of bacterial control that occurs in HIV-Mtb coinfected macrophages correlates with reduced GM-CSF secretion. Treatment of coinfected cells with GM-CSF restores bacterial control. Thus, we leverage the natural variation in macrophage control of Mtb to identify a critical cytokine response for regulating Mtb survival and identify components of the antimicrobial response induced by GM-CSF.
- Published
- 2019
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