Ultra-low Dose Aerosol Infection of Mice with Mycobacterium tuberculosis More Closely Models Human Tuberculosis

Courtney R. Plumlee, Fergal J. Duffy, Benjamin H. Gern, Jared L. Delahaye, Sara B. Cohen, Caleb R. Stoltzfus, Tige R. Rustad, Scott G. Hansen, Michael K. Axthelm, Louis J. Picker, John D. Aitchison, David R. Sherman, Vitaly V. Ganusov, Michael Y. Gerner, Daniel E. Zak, Kevin B. Urdahl

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Tuberculosis (TB) is a heterogeneous disease manifesting in a subset of individuals infected with aerosolized Mycobacterium tuberculosis (Mtb). Unlike human TB, murine infection results in uniformly high lung bacterial burdens and poorly organized granulomas. To develop a TB model that more closely resembles human disease, we infected mice with an ultra-low dose (ULD) of between 1–3 founding bacteria, reflecting a physiologic inoculum. ULD-infected mice exhibited highly heterogeneous bacterial burdens, well-circumscribed granulomas that shared features with human granulomas, and prolonged Mtb containment with unilateral pulmonary infection in some mice. We identified blood RNA signatures in mice infected with an ULD or a conventional Mtb dose (50–100 CFU) that correlated with lung bacterial burdens and predicted Mtb infection outcomes across species, including risk of progression to active TB in humans. Overall, these findings highlight the potential of the murine TB model and show that ULD infection recapitulates key features of human TB.

Original languageEnglish (US)
Pages (from-to)68-82.e5
JournalCell Host and Microbe
Volume29
Issue number1
DOIs
StatePublished - Jan 13 2021

Keywords

  • granuloma
  • heterogeneity
  • murine
  • pulmonary
  • transcriptional signature
  • tuberculosis
  • ultra-low dose

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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