Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation.
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...
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Public Library of Science (PLoS)
2021-03-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009410&type=printable |
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| author | Christophe J Queval Antony Fearns Laure Botella Alicia Smyth Laura Schnettger Morgane Mitermite Esen Wooff Bernardo Villarreal-Ramos Waldo Garcia-Jimenez Tiaan Heunis Matthias Trost Dirk Werling Francisco J Salguero Stephen V Gordon Maximiliano G Gutierrez |
| author_facet | Christophe J Queval Antony Fearns Laure Botella Alicia Smyth Laura Schnettger Morgane Mitermite Esen Wooff Bernardo Villarreal-Ramos Waldo Garcia-Jimenez Tiaan Heunis Matthias Trost Dirk Werling Francisco J Salguero Stephen V Gordon Maximiliano G Gutierrez |
| author_sort | Christophe J Queval |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e727828c479d4e6498c48e899a7a91d6 |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2021-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-e727828c479d4e6498c48e899a7a91d62025-08-20T02:55:27ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-03-01173e100941010.1371/journal.ppat.1009410Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation.Christophe J QuevalAntony FearnsLaure BotellaAlicia SmythLaura SchnettgerMorgane MitermiteEsen WooffBernardo Villarreal-RamosWaldo Garcia-JimenezTiaan HeunisMatthias TrostDirk WerlingFrancisco J SalgueroStephen V GordonMaximiliano G GutierrezThe 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009410&type=printable |
| spellingShingle | Christophe J Queval Antony Fearns Laure Botella Alicia Smyth Laura Schnettger Morgane Mitermite Esen Wooff Bernardo Villarreal-Ramos Waldo Garcia-Jimenez Tiaan Heunis Matthias Trost Dirk Werling Francisco J Salguero Stephen V Gordon Maximiliano G Gutierrez Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation. PLoS Pathogens |
| title | Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation. |
| title_full | Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation. |
| title_fullStr | Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation. |
| title_full_unstemmed | Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation. |
| title_short | Macrophage-specific responses to human- and animal-adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation. |
| title_sort | macrophage specific responses to human and animal adapted tubercle bacilli reveal pathogen and host factors driving multinucleated cell formation |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1009410&type=printable |
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