A multi-cohort study of the immune factors associated with M. tuberculosis infection outcomes

Roshni Roy Chowdhury, Francesco Vallania, Qianting Yang, Cesar Joel Lopez Angel, Fatoumatta Darboe, Adam Penn-Nicholson, Virginie Rozot, Elisa Nemes, Stephanus T. Malherbe, Katharina Ronacher, Gerhard Walzl, Willem Hanekom, Mark M. Davis, Jill Winter, Xinchun Chen, Thomas J. Scriba, Purvesh Khatri () and Yueh-hsiu Chien ()
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Roshni Roy Chowdhury: Stanford University School of Medicine
Francesco Vallania: Stanford University School of Medicine
Qianting Yang: Shenzhen Third People’s Hospital
Cesar Joel Lopez Angel: Stanford University School of Medicine
Fatoumatta Darboe: University of Cape Town
Adam Penn-Nicholson: University of Cape Town
Virginie Rozot: University of Cape Town
Elisa Nemes: University of Cape Town
Stephanus T. Malherbe: Stellenbosch University
Katharina Ronacher: Stellenbosch University
Gerhard Walzl: Stellenbosch University
Willem Hanekom: University of Cape Town
Mark M. Davis: Stanford University School of Medicine
Jill Winter: Catalysis Foundation for Health
Xinchun Chen: Shenzhen University School of Medicine
Thomas J. Scriba: University of Cape Town
Purvesh Khatri: Stanford University School of Medicine
Yueh-hsiu Chien: Stanford University School of Medicine

Nature, 2018, vol. 560, issue 7720, 644-648

Abstract: Abstract Most infections with Mycobacterium tuberculosis (Mtb) manifest as a clinically asymptomatic, contained state, known as latent tuberculosis infection, that affects approximately one-quarter of the global population1. Although fewer than one in ten individuals eventually progress to active disease2, tuberculosis is a leading cause of death from infectious disease worldwide3. Despite intense efforts, immune factors that influence the infection outcomes remain poorly defined. Here we used integrated analyses of multiple cohorts to identify stage-specific host responses to Mtb infection. First, using high-dimensional mass cytometry analyses and functional assays of a cohort of South African adolescents, we show that latent tuberculosis is associated with enhanced cytotoxic responses, which are mostly mediated by CD16 (also known as FcγRIIIa) and natural killer cells, and continuous inflammation coupled with immune deviations in both T and B cell compartments. Next, using cell-type deconvolution of transcriptomic data from several cohorts of different ages, genetic backgrounds, geographical locations and infection stages, we show that although deviations in peripheral B and T cell compartments generally start at latency, they are heterogeneous across cohorts. However, an increase in the abundance of circulating natural killer cells in tuberculosis latency, with a corresponding decrease during active disease and a return to baseline levels upon clinical cure are features that are common to all cohorts. Furthermore, by analysing three longitudinal cohorts, we find that changes in peripheral levels of natural killer cells can inform disease progression and treatment responses, and inversely correlate with the inflammatory state of the lungs of patients with active tuberculosis. Together, our findings offer crucial insights into the underlying pathophysiology of tuberculosis latency, and identify factors that may influence infection outcomes.

Keywords: Mass Cytometry; Cell Type Deconvolution; TB Latency; Latent Tuberculosis Infection (LTBI); Cytometry By Time-of-flight (CyTOF) (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0439-x

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