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

doi:10.1016/j.chom.2020.10.003

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

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58 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 language	English (US)
Pages (from-to)	68-82.e5
Journal	Cell Host and Microbe
Volume	29
Issue number	1
DOIs	https://doi.org/10.1016/j.chom.2020.10.003
State	Published - 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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Plumlee, C. R., Duffy, F. J., Gern, B. H., Delahaye, J. L., Cohen, S. B., Stoltzfus, C. R., Rustad, T. R., Hansen, S. G., Axthelm, M. K., Picker, L. J., Aitchison, J. D., Sherman, D. R., Ganusov, V. V., Gerner, M. Y., Zak, D. E., & Urdahl, K. B. (2021). Ultra-low Dose Aerosol Infection of Mice with Mycobacterium tuberculosis More Closely Models Human Tuberculosis. Cell Host and Microbe, 29(1), 68-82.e5. https://doi.org/10.1016/j.chom.2020.10.003

Plumlee, CR, Duffy, FJ, Gern, BH, Delahaye, JL, Cohen, SB, Stoltzfus, CR, Rustad, TR, Hansen, SG , Axthelm, MK , Picker, LJ, Aitchison, JD, Sherman, DR, Ganusov, VV, Gerner, MY, Zak, DE & Urdahl, KB 2021, 'Ultra-low Dose Aerosol Infection of Mice with Mycobacterium tuberculosis More Closely Models Human Tuberculosis', Cell Host and Microbe, vol. 29, no. 1, pp. 68-82.e5. https://doi.org/10.1016/j.chom.2020.10.003

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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.",

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AU - Rustad, Tige R.

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AU - Axthelm, Michael K.

AU - Picker, Louis J.

AU - Aitchison, John D.

AU - Sherman, David R.

AU - Ganusov, Vitaly V.

AU - Gerner, Michael Y.

AU - Zak, Daniel E.

AU - Urdahl, Kevin B.

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N2 - 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.

AB - 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.

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

Abstract

Keywords

ASJC Scopus subject areas

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