Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control

  • Biology
  • Cell Atlas
  • Genomics
  • Immunology
  • Infectious Disease
  • Microbiology
  • Travis Hughes
  • Constantine Tzouanas
  • Marc Wadsworth II
  • Conner Kummerlowe
  • Sarah Nyquist
  • Samira Ibrahim
  • José Ordovas-Montañes
  • Alex K. Shalek
  • Gideon et al.▾
    Gideon, H.P.*, Hughes, T.K.*, Tzouanas, C.N.*, Wadsworth II, M.H., Tu, A.A., Gierahn, T.M., Peters, J.M., Hopkins, F.F., Wei, J.-R., Kummerlowe, C., Grant, N.L., Nargan, K., Phuah, J.Y., Borish, H.J., Maiello, P., White, A.G., Winchell, C.G., Nyquist, S.K., Ganchua, S.K.C., Myers, A., Patel, K.V., Ameel, C.L., Cochran, C.T., Ibrahim, S., Tomko, J.A., Frye, L.J., Rosenberg, J.M., Shih, A., Chao, M., Klein, E., Scanga, C.A., Ordovas-Montanes, J., Berger, B., Mattila, J.T., Madansein, R., Love, J.C., Lin, P.L., Leslie, A., Behar, S.M., Bryson, B., Flynn, J.L.#, Fortune, S.M.#, Shalek, A.K.#
  • Immunity
  • April, 2022
Biology
Cell Atlas
Genomics
Immunology
Infectious Disease
Microbiology
Travis Hughes
Constantine Tzouanas
Marc Wadsworth II
Conner Kummerlowe
Sarah Nyquist
Samira Ibrahim
José Ordovas-Montañes
Alex K. Shalek

Abstract

Mycobacterium tuberculosis lung infection results in a complex multicellular structure: the granuloma. In some granulomas, immune activity promotes bacterial clearance, but in others, bacteria persist and grow. We identified correlates of bacterial control in cynomolgus macaque lung granulomas by co-registering longitudinal positron emission tomography and computed tomography imaging, single-cell RNA sequencing, and measures of bacterial clearance. Bacterial persistence occurred in granulomas enriched for mast, endothelial, fibroblast, and plasma cells, signaling amongst themselves via type 2 immunity and wound-healing pathways. Granulomas that drove bacterial control were characterized by cellular ecosystems enriched for type 1-type 17, stem-like, and cytotoxic T cells engaged in pro-inflammatory signaling networks involving diverse cell populations. Granulomas that arose later in infection displayed functional characteristics of restrictive granulomas and were more capable of killing Mtb. Our results define the complex multicellular eco- systems underlying (lack of) granuloma resolution and highlight host immune targets that can be leveraged to develop new vaccine and therapeutic strategies for TB.

Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control