Abstract
The Mycobacterium tuberculosis complex (MTBC) is a group of related pathogens that cause tuberculosis (TB) in mammals. MTBC species are distinguished by their ability to sustain in distinct host populations. While Mycobacterium bovis (Mbv) sustains transmission cycles in cattle and wild animals and causes zoonotic TB, M. tuberculosis (Mtb) affects human populations and seldom causes disease in cattle. The host and pathogen determinants underlying host tropism between MTBC species are still unknown. Macrophages are the main host cell that encounters mycobacteria upon initial infection, and we hypothesised that early interactions between the macrophage and mycobacteria influence species-specific disease outcome. To identify factors that contribute to host tropism, we analysed blood-derived primary human and bovine macrophages (hMϕ or bMϕ, respectively) infected with Mbv and Mtb. We show that Mbv and Mtb reside in different cellular compartments and differentially replicate in hMϕ whereas both Mbv and Mtb efficiently replicate in bMϕ. Specifically, we show that out of the four infection combinations, only the infection of bMϕ with Mbv promoted the formation of multinucleated giant cells (MNGCs), a hallmark of tuberculous granulomas. Mechanistically, we demonstrate that both MPB70 from Mbv and extracellular vesicles released by Mbv-infected bMϕ promote macrophage multinucleation. Importantly, we extended our in vitro studies to show that granulomas from Mbv-infected but not Mtb-infected cattle contained higher numbers of MNGCs. Our findings implicate MNGC formation in the contrasting pathology between Mtb and Mbv for the bovine host and identify MPB70 from Mbv and extracellular vesicles from bMϕ as mediators of this process.
Original language | English |
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Article number | 1009410 |
Number of pages | 31 |
Journal | PLoS Pathogens |
Volume | 17 |
Issue number | 3 |
DOIs | |
Publication status | Published - 15 Mar 2021 |
Bibliographical note
Funding Information: This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (10092 to MGG), the UK Medical Research Council (10092 to MGG), and the Wellcome Trust (10092 to MGG) and by the Biotechnology and Biological Sciences Research Council (BB/N004574/1 to MGG and SVG), Science Foundation Ireland (SFI/15/IA/3154 to SVG) and a Wellcome Trust PhD studentship (109166/Z/15/A to MM), and EU FP7 Research Infrastructures grant agreement No. FP7-228394 (NADIR to SVG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Open Access: This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Publisher Copyright: © 2021 Queval et al.
Citation: Queval CJ, Fearns A, Botella L, Smyth A, Schnettger L, Mitermite M, et al. (2021) Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation. PLoS Pathog 17(3): e1009410.
DOI: https://doi.org/10.1371/journal.ppat.1009410