Immunosuppression is a conserved driver of tuberculosis susceptibility
Mycobacterium tuberculosis ( Mtb ) causes 1.6 million deaths a year 1 . However, no individual mouse model fully recapitulates the hallmarks of human tuberculosis disease. Here we report that a comparison across three different susceptible mouse models identifies Mtb -induced gene signatures that predict active TB disease in humans significantly better than a signature from the standard C57BL/6 mouse model. An increase in lung myeloid cells, including neutrophils, was conserved across the susceptible mouse models, mimicking the neutrophilic inflammation observed in humans 2,3 . Myeloid cells in the susceptible models and non-human primates exhibited high expression of immunosuppressive molecules including the IL-1 receptor antagonist, which inhibits IL-1 signaling. Prior reports have suggested that excessive IL-1 signaling impairs Mtb control 4-6 . By contrast, we found that enhancement of IL-1 signaling via deletion of IL-1 receptor antagonist promoted bacterial control in all three susceptible mouse models. IL-1 signaling enhanced cytokine production by lymphoid and stromal cells, suggesting a mechanism for IL-1 signaling in promoting Mtb control. Thus, we propose that myeloid cell expression of immunosuppressive molecules is a conserved mechanism exacerbating Mtb disease in mice, non-human primates, and humans.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2023) vom: 01. Nov. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kotov, Dmitri I [VerfasserIn] |
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| Anmerkungen: |
Date Revised 03.01.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2023.10.27.564420 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM364530839 |
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| 520 | |a Mycobacterium tuberculosis ( Mtb ) causes 1.6 million deaths a year 1 . However, no individual mouse model fully recapitulates the hallmarks of human tuberculosis disease. Here we report that a comparison across three different susceptible mouse models identifies Mtb -induced gene signatures that predict active TB disease in humans significantly better than a signature from the standard C57BL/6 mouse model. An increase in lung myeloid cells, including neutrophils, was conserved across the susceptible mouse models, mimicking the neutrophilic inflammation observed in humans 2,3 . Myeloid cells in the susceptible models and non-human primates exhibited high expression of immunosuppressive molecules including the IL-1 receptor antagonist, which inhibits IL-1 signaling. Prior reports have suggested that excessive IL-1 signaling impairs Mtb control 4-6 . By contrast, we found that enhancement of IL-1 signaling via deletion of IL-1 receptor antagonist promoted bacterial control in all three susceptible mouse models. IL-1 signaling enhanced cytokine production by lymphoid and stromal cells, suggesting a mechanism for IL-1 signaling in promoting Mtb control. Thus, we propose that myeloid cell expression of immunosuppressive molecules is a conserved mechanism exacerbating Mtb disease in mice, non-human primates, and humans | ||
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| 700 | 1 | |a Suliman, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Gabay, Cem |e verfasserin |4 aut | |
| 700 | 1 | |a Vance, Russell E |e verfasserin |4 aut | |
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