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.
Genetic models of latent tuberculosis in mice reveal differential influence of adaptive immunity
Disclosures: The authors declare no competing interests exist.
D. Tiwari’s present address is Centre for Global Health, Barts, and The London School of Medicine and Dentistry, Queen Mary University of London, Whitechapel, London, UK.
C. Healy’s present address is School of Medicine, Trinity College Dublin, Dublin, Ireland.
- Award Group:
- Funder(s): National Institutes of Health
- Award Ids(s): U19 AI111143
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Hongwei Su, Kan Lin, Divya Tiwari, Claire Healy, Carolina Trujillo, Yao Liu, Thomas R. Ioerger, Dirk Schnappinger, Sabine Ehrt; Genetic models of latent tuberculosis in mice reveal differential influence of adaptive immunity. J Exp Med 6 September 2021; 218 (9): e20210332. doi: https://doi.org/10.1084/jem.20210332
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