IL-32 is a molecular marker of a host defense network in human tuberculosis

Dennis Montoya, Megan S Inkeles, Phillip T Liu, Susan Realegeno, Rosane M B Teles, Poorva Vaidya, Marcos A Munoz, Mirjam Schenk, William R Swindell, Rene Chun, Kathryn Zavala, Martin Hewison, John S Adams, Steve Horvath, Matteo Pellegrini, Barry R Bloom, Robert L Modlin

Research output: Contribution to journalArticlepeer-review

73 Citations (Scopus)

Abstract

Tuberculosis is a leading cause of infectious disease-related death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease. Factors that contribute to protection could prove to be promising targets for M. tuberculosis therapies. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify potential human candidate markers of host defense by studying gene expression profiles of macrophages, cells that, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene coexpression network analysis revealed an association between the cytokine interleukin-32 (IL-32) and the vitamin D antimicrobial pathway in a network of interferon-γ- and IL-15-induced "defense response" genes. IL-32 induced the vitamin D-dependent antimicrobial peptides cathelicidin and DEFB4 and to generate antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. In addition, the IL-15-induced defense response macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent compared with active tuberculosis or healthy controls and a coexpression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15-induced gene network. As maintaining M. tuberculosis in a latent state and preventing transition to active disease may represent a form of host resistance, these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis.

Original languageEnglish
Article number250ra114
Number of pages11
JournalScience Translational Medicine
Volume6
Issue number250
DOIs
Publication statusPublished - 20 Aug 2014

Bibliographical note

Copyright © 2014, American Association for the Advancement of Science.

Keywords

  • Antimicrobial Cationic Peptides
  • Biological Markers
  • Cell Differentiation
  • Gene Expression Profiling
  • Humans
  • Interferon-gamma
  • Interleukin-15
  • Interleukins
  • Macrophages
  • Mycobacterium tuberculosis
  • Tuberculosis
  • Vitamin D

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