Skip to content
DraconiticResearch
Search Sources API
203,234 studies31 sourcesUpdated 3 min ago
Peer-reviewedCC BY 4.0Antimicrobial Agents and Chemotherapy

Adaptive immunity shapes baseline physiology of M. tuberculosis in high-dose versus low-dose infection BALB/c mouse drug treatment models

  • Jo Hendrix1,2,3
  • Reem Al Mubarak1,2,3
  • Karen Rossmassler1,2,3,4
  • Holly Nielsen1,2,3
  • Elizabeth Wynn3,5,6
  • Camile Moore3,5,6
  • Isabelle L. Jones3,7
  • Martin I. Voskuil3,8
  • Brendan K. Podell3,7
  • Gregory T. Robertson3,7
  • Chuangqi Wang8
  • Nicholas D. Walter1,2,3
8 affiliations
  1. 1Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
  2. 2Rocky Mountain Regional VA Medical Center, Aurora, Colorado, USA
  3. 3Consortium for Applied Microbial Metrics, Aurora, Colorado, USA
  4. 4Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
  5. 5Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA
  6. 6Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
  7. 7Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA
  8. 8Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
Read full textPDFDOICite

Abstract

Preclinical tuberculosis (TB) drug evaluation relies heavily on mouse infection models. Drug efficacy varies depending on inoculum and the timing of treatment initiation. These differences reflect, in part, physiological adaptations of Mycobacterium tuberculosis (Mtb) to host immune pressure. We used novel molecular markers of pathogen health (RS ratio and SEARCH-TB) to contrast Mtb phenotypes in the BALB/c high dose aerosol (HDA) subacute TB and low dose aerosol (LDA) chronic TB infection models, focusing on the onset of adaptive immunity. We found that the onset of adaptive immunity coincided with a rapid reprogramming of Mtb physiology, characterized by suppressed respiration, metabolism, and biosynthesis, together with induction of stress and nutrient acquisition pathways. Changes in key Mtb processes were concordant with changes in host expression of canonical features of adaptive immunity. Our results also explain key model-specific differences in drug efficacy: when used for drug evaluation, the HDA model begins treatment during the innate immune phase when Mtb are metabolically active, whereas the LDA model initiates therapy after host adaptive immunity has already activated and the bacterial population is immune-constrained. The HDA model is shown to be a mixed model, spanning immune phases with initial treatment acting on replicating bacteria and later treatment acting on immune-constrained populations. Together, the two models offer complementary perspectives on therapeutic activity across the spectrum of bacterial states and provide a framework for designing regimens that are effective against both active and immune-constrained Mtb.

Related

  1. Determinants of willingness to accept Tuberculosis Preventive Treatment (TPT) among close contacts with Tuberculosis Infection (TBI) in Xinjiang, China
    Senlu Wang, Baozhen Peng, Mingzhe Wang +12
    BMC Public HealthPeer-reviewedCC BY-NC-ND 4.0Infectious diseaseCrossref
  2. Preferences for treatment for latent tuberculosis infection in primary care among people in the USA at increased risk of tuberculosis: a pilot survey.
    Hélène E Aschmann, Amy S Tang, Meagan Lee +11
    BMJ openPeer-reviewedCC BYFull textInfectious diseaseEurope PMCCrossref
  3. Latent tuberculosis infection in focus: Evaluating public concerns, treatment perceptions, and awareness in King Sabatha Dalindyebo Local Municipality, Eastern Cape, South Africa
    Lindiwe Modest Faye, Ncomeka Sineke, Ntandazo Dlatu +3
    PLOS Global Public HealthPeer-reviewedCC BY 4.0Full textEpidemiology & public healthPLOS
  4. Defining use cases for biomarkers and tests across tuberculosis infection, disease and treatment: An international consensus and prioritisation exercise
    S. Wright, F. Fama, A. de Wilton +21
    medRxivPreprintCC BY-NC-NDFull textEpidemiology & public healthmedRxiv
  5. Determinants of infection vulnerability and health system capacity affecting tuberculosis treatment success in low- and middle-income countries: panel data analysis 2001–2023
    Emine Kübra Dindar, Burak Sayar, Osman Şenol
    Frontiers in Public HealthPeer-reviewedCC BY 4.0Epidemiology & public healthFrontiersCrossref

Cite

BibTeXRIS
BibTeX
@article{hendrix2026adaptive,
  title = {{Adaptive immunity shapes baseline physiology of M. tuberculosis in high-dose versus low-dose infection BALB/c mouse drug treatment models}},
  author = {Jo Hendrix and Reem Al Mubarak and Karen Rossmassler and Holly Nielsen and Elizabeth Wynn and Camile Moore and Isabelle L. Jones and Martin I. Voskuil and Brendan K. Podell and Gregory T. Robertson and Chuangqi Wang and Nicholas D. Walter},
  journal = {Antimicrobial Agents and Chemotherapy},
  year = {2026},
  month = jul,
  doi = {10.1128/aac.00421-26},
  url = {https://doi.org/10.1128/aac.00421-26},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Adaptive immunity shapes baseline physiology of M. tuberculosis in high-dose versus low-dose infection BALB/c mouse drug treatment models
AU  - Jo Hendrix
AU  - Reem Al Mubarak
AU  - Karen Rossmassler
AU  - Holly Nielsen
AU  - Elizabeth Wynn
AU  - Camile Moore
AU  - Isabelle L. Jones
AU  - Martin I. Voskuil
AU  - Brendan K. Podell
AU  - Gregory T. Robertson
AU  - Chuangqi Wang
AU  - Nicholas D. Walter
PY  - 2026
DA  - 2026/07/31
JO  - Antimicrobial Agents and Chemotherapy
DO  - 10.1128/aac.00421-26
UR  - https://doi.org/10.1128/aac.00421-26
AB  - Preclinical tuberculosis (TB) drug evaluation relies heavily on mouse infection models. Drug efficacy varies depending on inoculum and the timing of treatment initiation. These differences reflect, in part, physiological adaptations of Mycobacterium tuberculosis (Mtb) to host immune pressure. We used novel molecular markers of pathogen health (RS ratio and SEARCH-TB) to contrast Mtb phenotypes in the BALB/c high dose aerosol (HDA) subacute TB and low dose aerosol (LDA) chronic TB infection models, focusing on the onset of adaptive immunity. We found that the onset of adaptive immunity coincided with a rapid reprogramming of Mtb physiology, characterized by suppressed respiration, metabolism, and biosynthesis, together with induction of stress and nutrient acquisition pathways. Changes in key Mtb processes were concordant with changes in host expression of canonical features of adaptive immunity. Our results also explain key model-specific differences in drug efficacy: when used for drug evaluation, the HDA model begins treatment during the innate immune phase when Mtb are metabolically active, whereas the LDA model initiates therapy after host adaptive immunity has already activated and the bacterial population is immune-constrained. The HDA model is shown to be a mixed model, spanning immune phases with initial treatment acting on replicating bacteria and later treatment acting on immune-constrained populations. Together, the two models offer complementary perspectives on therapeutic activity across the spectrum of bacterial states and provide a framework for designing regimens that are effective against both active and immune-constrained Mtb.
SN  - 0066-4804
SN  - 1098-6596
ER  -