Macrophage-specific responses to human -and animal- adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation

Christophe J. Queval, Antony Fearns, Laure Botella, Alicia Smyth, Laura Schnettger, Morgane Mitermite, Esen Wooff, Bernardo Villarreal-Ramos, Waldo Garcia-Jimenezi, Tiaan Heunis, Matthias Trosti, Dir Werlingi, Francisco J. Salguero, Stephen V. Gordon, Maximiliano G. Gutierrez*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (SciVal)
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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 languageEnglish
Article numbere1009410
Number of pages31
JournalPLOS Pathogens
Volume17
Issue number3
Early online date15 Mar 2021
DOIs
Publication statusPublished - 15 Mar 2021

Keywords

  • Research Article
  • Biology and life sciences
  • Medicine and health sciences
  • Research and analysis methods
  • Macrophages/microbiology
  • Viral Tropism/physiology
  • Mycobacterium bovis
  • Humans
  • Host-Pathogen Interactions/physiology
  • Animals
  • Mycobacterium tuberculosis
  • Tuberculosis/microbiology
  • Cattle
  • Giant Cells

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