Sequential inflammatory processes define human progression from M. tuberculosisinfection to tuberculosis disease

PLoS Pathogens

Mzwandile Erasmus¹  Tom Hraha²  Urs A. Ochsner²  David Sterling²  Alan Aderem²  Wendy Whatney³  Fatoumatta Darboe³  Adam Penn-Nicholson³  Sara Suliman³  Daniel E. Zak³  Hassan Mahomed³  Thomas J. Scriba³  Elisa Nemes³  John L. Johnson³  Joe Valvo³  Lynn M. Amon⁴  Mary Ann De Groote⁴  Ethan G. Thompson⁴  other members of the ACS cohort study team⁴  Smitha Shankar⁴  Willem A. Hanekom⁴  Mark Hatherill⁵  W. Henry Boom⁵ 

[1] Now at Metro District Health Services, Western Cape Government: Health and Division of Public Health and Health Systems, Department of Global Health, Faculty of Health Sciences and Medicine, Stellenbosch University, Cape Town, South Africa;Somalogic Inc, Boulder, CO, United States of America;South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine & Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa;The Center for Infectious Disease Research, Seattle, WA, United States of America;Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University and University Hospitals Case Cleveland Medical Center, Cleveland, OH, United States of America

关键词: Tuberculosis;    Blood;    T cells;    Tuberculosis diagnosis;    management;    Monocytes;    Interferons;    Gene expression;    Inflammatory diseases;   

DOI  :  10.1371/journal.ppat.1006687

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Our understanding of mechanisms underlying progression from Mycobacterium tuberculosis infection to pulmonary tuberculosis disease in humans remains limited. To define such mechanisms, we followed M. tuberculosis-infected adolescents longitudinally. Blood samples from forty-four adolescents who ultimately developed tuberculosis disease (“progressors”) were compared with those from 106 matched controls, who remained healthy during two years of follow up. We performed longitudinal whole blood transcriptomic analyses by RNA sequencing and plasma proteome analyses using multiplexed slow off-rate modified DNA aptamers. Tuberculosis progression was associated with sequential modulation of immunological processes. Type I/II interferon signalling and complement cascade were elevated 18 months before tuberculosis disease diagnosis, while changes in myeloid inflammation, lymphoid, monocyte and neutrophil gene modules occurred more proximally to tuberculosis disease. Analysis of gene expression in purified T cells also revealed early suppression of Th17 responses in progressors, relative to M. tuberculosis-infected controls. This was confirmed in an independent adult cohort who received BCG re-vaccination; transcript expression of interferon response genes in blood prior to BCG administration was associated with suppression of IL-17 expression by BCG-specific CD4 T cells 3 weeks post-vaccination. Our findings provide a timeline to the different immunological stages of disease progression which comprise sequential inflammatory dynamics and immune alterations that precede disease manifestations and diagnosis of tuberculosis disease. These findings have important implications for developing diagnostics, vaccination and host-directed therapies for tuberculosis.

【 授权许可】

CC BY