Heterogeneous GM-CSF signaling in macrophages is associated with control of Mycobacterium tuberculosis

Bryan D. Bryson, Tracy R. Rosebrock, Fikadu G. Tafesse, Christopher Y. Itoh, Armel Nibasumba, Gregory H. Babunovic, Bjorn Corleis, Constance Martin, Caroline Keegan, Priscila Andrade, Susan Realegeno, Douglas Kwon, Robert L. Modlin and Sarah M. Fortune ()
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Bryan D. Bryson: Harvard T. H. Chan School of Public Health
Tracy R. Rosebrock: Harvard T. H. Chan School of Public Health
Fikadu G. Tafesse: Oregon Health and Science University
Christopher Y. Itoh: Harvard T. H. Chan School of Public Health
Armel Nibasumba: Harvard T. H. Chan School of Public Health
Gregory H. Babunovic: Harvard T. H. Chan School of Public Health
Bjorn Corleis: Ragon Institute of MGH, MIT, and Harvard
Constance Martin: Harvard T. H. Chan School of Public Health
Caroline Keegan: David Geffen School of Medicine at University of California
Priscila Andrade: David Geffen School of Medicine at University of California
Susan Realegeno: David Geffen School of Medicine at University of California
Douglas Kwon: Ragon Institute of MGH, MIT, and Harvard
Robert L. Modlin: David Geffen School of Medicine at University of California
Sarah M. Fortune: Harvard T. H. Chan School of Public Health

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10065-8

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