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

Hannah P Gideon; Travis K Hughes; Constantine N Tzouanas; Marc H Wadsworth 2nd; Ang Andy Tu; Todd M Gierahn; Joshua M Peters; Forrest F Hopkins; Jun-Rong Wei; Conner Kummerlowe; Nicole L Grant; Kievershen Nargan; Jia Yao Phuah; H Jacob Borish; Pauline Maiello; Alexander G White; Caylin G Winchell; Sarah K Nyquist; Sharie Keanne C Ganchua; Amy Myers; Kush V Patel; Cassaundra L Ameel; Catherine T Cochran; Samira Ibrahim; Jaime A Tomko; Lonnie James Frye; Jacob M Rosenberg; Angela Shih; Michael Chao; Edwin Klein; Charles A Scanga; Jose Ordovas-Montanes; Bonnie Berger; Joshua T Mattila; Rajhmun Madansein; J Christopher Love; Philana Ling Lin; Alasdair Leslie; Samuel M Behar; Bryan Bryson; JoAnne L Flynn; Sarah M Fortune; Alex K Shalek

doi:10.1016/j.immuni.2022.04.004

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

Immunity. 2022 May 10;55(5):827-846.e10. doi: 10.1016/j.immuni.2022.04.004. Epub 2022 Apr 27.

Authors

Hannah P Gideon¹, Travis K Hughes², Constantine N Tzouanas², Marc H Wadsworth 2nd³, Ang Andy Tu⁴, Todd M Gierahn⁴, Joshua M Peters⁵, Forrest F Hopkins⁶, Jun-Rong Wei⁶, Conner Kummerlowe⁷, Nicole L Grant⁸, Kievershen Nargan⁹, Jia Yao Phuah⁸, H Jacob Borish⁸, Pauline Maiello⁸, Alexander G White⁸, Caylin G Winchell¹⁰, Sarah K Nyquist¹¹, Sharie Keanne C Ganchua⁸, Amy Myers⁸, Kush V Patel⁸, Cassaundra L Ameel⁸, Catherine T Cochran⁸, Samira Ibrahim², Jaime A Tomko⁸, Lonnie James Frye⁸, Jacob M Rosenberg¹², Angela Shih¹³, Michael Chao⁶, Edwin Klein¹⁴, Charles A Scanga¹, Jose Ordovas-Montanes¹⁵, Bonnie Berger¹⁶, Joshua T Mattila¹⁷, Rajhmun Madansein¹⁸, J Christopher Love¹⁹, Philana Ling Lin²⁰, Alasdair Leslie²¹, Samuel M Behar²², Bryan Bryson⁵, JoAnne L Flynn²³, Sarah M Fortune²⁴, Alex K Shalek²⁵

Affiliations

¹ Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA.
² Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁶ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁷ Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁹ Africa Health Research Institute, Durban, South Africa.
¹⁰ Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA; Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹ Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹² Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA.
¹³ Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Division of Laboratory Animal Research, University of Pittsburgh, Pittsburgh PA, USA.
¹⁵ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁶ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁷ Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA; Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁸ Department of Cardiothoracic Surgery, University of KwaZulu Natal, Durban, South Africa.
¹⁹ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
²⁰ Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pediatrics, University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
²¹ Africa Health Research Institute, Durban, South Africa; School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa; Department of Infection and Immunity, University College London, London, UK.
²² Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
²³ Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: joanne@pitt.edu.
²⁴ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: sfortune@hsph.harvard.edu.
²⁵ Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA; The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: shalek@mit.edu.

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 ecosystems underlying (lack of) granuloma resolution and highlight host immune targets that can be leveraged to develop new vaccine and therapeutic strategies for TB.

Keywords: Mycobacterium tuberculosis; PET-CT; immunology; intercellular interactions; scRNA-seq; single-cell RNA sequencing; type 1-type 17; type 2 responses.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Ecosystem
Granuloma
Lung
Macaca fascicularis
Mycobacterium tuberculosis*
Pulmonary Fibrosis* / pathology
Tuberculosis*

Abstract

Publication types

MeSH terms

Grants and funding