Genetic models of latent tuberculosis in mice reveal differential influence of adaptive immunity

J Exp Med. 2021 Sep 6;218(9):e20210332. doi: 10.1084/jem.20210332. Epub 2021 Jul 16.


Studying latent Mycobacterium tuberculosis (Mtb) infection has been limited by the lack of a suitable mouse model. We discovered that transient depletion of biotin protein ligase (BPL) and thioredoxin reductase (TrxB2) results in latent infections during which Mtb cannot be detected but that relapse in a subset of mice. The immune requirements for Mtb control during latency, and the frequency of relapse, were strikingly different depending on how latency was established. TrxB2 depletion resulted in a latent infection that required adaptive immunity for control and reactivated with high frequency, whereas latent infection after BPL depletion was independent of adaptive immunity and rarely reactivated. We identified immune signatures of T cells indicative of relapse and demonstrated that BCG vaccination failed to protect mice from TB relapse. These reproducible genetic latency models allow investigation of the host immunological determinants that control the latent state and offer opportunities to evaluate therapeutic strategies in settings that mimic aspects of latency and TB relapse in humans.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptive Immunity / physiology*
  • Animals
  • Antitubercular Agents / pharmacology
  • BCG Vaccine / pharmacology
  • Carbon-Nitrogen Ligases / genetics
  • Carbon-Nitrogen Ligases / metabolism
  • Dexamethasone / pharmacology
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Bacterial
  • Latent Tuberculosis / etiology
  • Latent Tuberculosis / immunology*
  • Latent Tuberculosis / prevention & control
  • Lung / drug effects
  • Lung / microbiology
  • Mice, Inbred C57BL
  • Mycobacterium tuberculosis / genetics*
  • Mycobacterium tuberculosis / pathogenicity
  • Reproducibility of Results
  • Thioredoxin Reductase 2 / genetics
  • Thioredoxin Reductase 2 / metabolism
  • Tuberculosis / immunology*
  • Tuberculosis / microbiology
  • Tuberculosis / pathology


  • Antitubercular Agents
  • BCG Vaccine
  • Dexamethasone
  • Thioredoxin Reductase 2
  • Carbon-Nitrogen Ligases