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

Sci Transl Med 20 August 2014: 
Vol. 6, Issue 250, p. 250ra114 
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3009546

• RESEARCH ARTICLE

TUBERCULOSIS

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

1. Dennis Montoya1, 
2. Megan S. Inkeles2, 
3. Phillip T. Liu1,3, 
4. Susan Realegeno1,4, 
5. Rosane M. B. Teles1,
6. Poorva Vaidya1, 
7. Marcos A. Munoz1, 
8. Mirjam Schenk1, 
9. William R. Swindell5, 
10. Rene Chun3,
11. Kathryn Zavala3, 
12. Martin Hewison3, 
13. John S. Adams3, 
14. Steve Horvath6,7, 
15. Matteo Pellegrini2,
16. Barry R. Bloom8 and 
17. Robert L. Modlin1,4,*

+Author Affiliations

1. ¹Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA.
2. ²Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, CA 90095, USA.
3. ³UCLA/Orthopaedic Hospital, Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
4. ⁴Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA 90095 USA.
5. ⁵Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
6. ⁶Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
7. ⁷Biostatistics, School of Public Health, UCLA, Los Angeles, CA 90095, USA.
8. ⁸Harvard School of Public Health, Boston, MA 02115, USA.

1. ↵*Corresponding author. E-mail: rmodlin@mednet.ucla.edu

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.

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

Citation: D. Montoya, M. S. Inkeles, P. T. Liu, S. Realegeno, R. M. B. Teles, P. Vaidya, M. A. Munoz, M. Schenk, W. R. Swindell, R. Chun, K. Zavala, M. Hewison, J. S. Adams, S. Horvath, M. Pellegrini, B. R. Bloom, R. L. Modlin, IL-32 is a molecular marker of a host defense network in human tuberculosis. Sci. Transl. Med. 6, 250ra114 (2014).

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