title: IL-32 is a molecular marker of a host defense network in human tuberculosis.
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.
authors.affiliation: Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Montoya
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Inkeles
authors.affiliation: Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA. UCLA/Orthopaedic Hospital, Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Phillip T
authors.initials: PT
authors.lastname: Liu
authors.affiliation: Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA. Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA 90095 USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Realegeno
authors.affiliation: Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Rosane M B
authors.initials: RM
authors.lastname: Teles
authors.affiliation: Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Poorva
authors.initials: P
authors.lastname: Vaidya
authors.affiliation: Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Marcos A
authors.initials: MA
authors.lastname: Munoz
authors.affiliation: Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schenk
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Swindell
authors.affiliation: UCLA/Orthopaedic Hospital, Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Chun
authors.affiliation: UCLA/Orthopaedic Hospital, Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Zavala
authors.affiliation: UCLA/Orthopaedic Hospital, Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
authors.affiliation: UCLA/Orthopaedic Hospital, Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Adams
authors.affiliation: Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Biostatistics, School of Public Health, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Bloom
authors.affiliation: Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA. Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, CA 90095 USA. rmodlin@mednet.ucla.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D019409:Interleukin-15 / Q000378:metabolism; D007378:Interleukins / Q000235:genetics* / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000502:physiology; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology; D014807:Vitamin D / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D015415:Biomarkers; C496971:IL32 protein, human; D019409:Interleukin-15; D007378:Interleukins; D014807:Vitamin D; D007371:Interferon-gamma