Diverse infection models demonstrate robust resistance of Mycobacterium tuberculosis to innate immunity
4 affiliations
- 1Department of Molecular and Cell Biology, Division of Immunology and Molecular Medicine, University of California, Berkeley, California, United States of America.
- 2Howard Hughes Medical Institute, University of California, Berkeley, California, United States of America.
- 3Cancer Research Laboratory, University of California, Berkeley, California, United States of America.
- 4Center for Emerging and Neglected Diseases, University of California, Berkeley, California, United States of America.
Abstract
Mycobacterium tuberculosis (Mtb) is a robust activator of innate immunity. While innate immune activation of macrophages can impact Mtb replication in vitro, there is little in vivo evidence that the innate immune system controls Mtb before the onset of adaptive immunity. Prior work has generally used specific pathogen-free (SPF) mouse models and relatively large infectious doses, which may obscure the capacity of innate immunity to control Mtb. Here, we performed ultra-low dose Mtb infections and found that the initial innate immune response was unable to curb even minimal Mtb infectious doses. Additionally, we primed the immune systems of C57BL/6 mice by co-housing with “pet shop” mice prior to Mtb exposure. Co-housed mice were as susceptible to Mtb infection as SPF mice. To pre-activate innate immunity at the site of Mtb infection more specifically, we also infected the lungs of mice with Legionella pneumophila (Lp) prior to Mtb. Innate immunity alone can clear large doses (>100,000 CFU) of Lp from the lung within a few days. However, priming the mouse lung by pre-infection with Lp only modestly reduced Mtb CFU compared to mice infected with only Mtb, indicating that Mtb can robustly replicate even in the presence of a strong anti-bacterial innate response. We performed single-cell RNA-sequencing on myeloid cells from mice either infected with Mtb alone or mice primed with Lp. We found that Lp priming before Mtb infection induced measurable changes in myeloid cells responding to Mtb, but these changes had little effect on innate control of Mtb. Together, these data demonstrate the robust resistance of Mtb to innate immune clearance under diverse experimental conditions. Author summary: Mycobacterium tuberculosis (Mtb) causes more human mortality than any other single pathogen. Despite over 140 years of research, fundamental questions remain about how Mtb interacts with the immune system during early infection. Interestingly, Mtb is highly immunostimulatory, yet replicates robustly during the innate phase of infection (prior to the onset of adaptive immunity). Using ultra-low dose infections, we observed that the innate immune system failed to control infections seeded by even a single bacterium, and that innate immune pathways which aid in control during later disease stages fail to exert control during the early innate phase. To test whether the lack of innate control of Mtb is due to insufficient inflammation during the critical early days of infection, we primed the innate immune system using pet shop mouse co-housing and Legionella pneumophila co-infections. However, priming failed to inhibit early Mtb growth. Our results suggest that Mtb exhibits potent intrinsic resistance to anti-bacterial innate immune responses.
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BibTeX
@article{fairgrieve2026diverse,
title = {{Diverse infection models demonstrate robust resistance of Mycobacterium tuberculosis to innate immunity}},
author = {Marian R Fairgrieve and Ella C Brydon and Roberto A Chavez and Dmitri I Kotov and Russell E Vance},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014713},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014713},
note = {CC BY},
}
RIS
TY - JOUR
TI - Diverse infection models demonstrate robust resistance of Mycobacterium tuberculosis to innate immunity
AU - Marian R Fairgrieve
AU - Ella C Brydon
AU - Roberto A Chavez
AU - Dmitri I Kotov
AU - Russell E Vance
PY - 2026
DA - 2026/10/21
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014713
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014713
AB - Mycobacterium tuberculosis (Mtb) is a robust activator of innate immunity. While innate immune activation of macrophages can impact Mtb replication in vitro, there is little in vivo evidence that the innate immune system controls Mtb before the onset of adaptive immunity. Prior work has generally used specific pathogen-free (SPF) mouse models and relatively large infectious doses, which may obscure the capacity of innate immunity to control Mtb. Here, we performed ultra-low dose Mtb infections and found that the initial innate immune response was unable to curb even minimal Mtb infectious doses. Additionally, we primed the immune systems of C57BL/6 mice by co-housing with “pet shop” mice prior to Mtb exposure. Co-housed mice were as susceptible to Mtb infection as SPF mice. To pre-activate innate immunity at the site of Mtb infection more specifically, we also infected the lungs of mice with Legionella pneumophila (Lp) prior to Mtb. Innate immunity alone can clear large doses (>100,000 CFU) of Lp from the lung within a few days. However, priming the mouse lung by pre-infection with Lp only modestly reduced Mtb CFU compared to mice infected with only Mtb, indicating that Mtb can robustly replicate even in the presence of a strong anti-bacterial innate response. We performed single-cell RNA-sequencing on myeloid cells from mice either infected with Mtb alone or mice primed with Lp. We found that Lp priming before Mtb infection induced measurable changes in myeloid cells responding to Mtb, but these changes had little effect on innate control of Mtb. Together, these data demonstrate the robust resistance of Mtb to innate immune clearance under diverse experimental conditions. Author summary: Mycobacterium tuberculosis (Mtb) causes more human mortality than any other single pathogen. Despite over 140 years of research, fundamental questions remain about how Mtb interacts with the immune system during early infection. Interestingly, Mtb is highly immunostimulatory, yet replicates robustly during the innate phase of infection (prior to the onset of adaptive immunity). Using ultra-low dose infections, we observed that the innate immune system failed to control infections seeded by even a single bacterium, and that innate immune pathways which aid in control during later disease stages fail to exert control during the early innate phase. To test whether the lack of innate control of Mtb is due to insufficient inflammation during the critical early days of infection, we primed the innate immune system using pet shop mouse co-housing and Legionella pneumophila co-infections. However, priming failed to inhibit early Mtb growth. Our results suggest that Mtb exhibits potent intrinsic resistance to anti-bacterial innate immune responses.
SN - 1553-7374
SN - 1553-7366
ER -