title: Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis.
abstract: Silencing of interleukin-32 (IL-32) in a differentiated human promonocytic cell line impairs killing of Mycobacterium tuberculosis (MTB) but the role of IL-32 in vivo against MTB remains unknown. To study the effects of IL-32 in vivo, a transgenic mouse was generated in which the human IL-32γ gene is expressed using the surfactant protein C promoter (SPC-IL-32γTg). Wild-type and SPC-IL-32γTg mice were infected with a low-dose aerosol of a hypervirulent strain of MTB (W-Beijing HN878). At 30 and 60 d after infection, the transgenic mice had 66% and 85% fewer MTB in the lungs and 49% and 68% fewer MTB in the spleens, respectively; the transgenic mice also exhibited greater survival. Increased numbers of host-protective innate and adaptive immune cells were present in SPC-IL-32γTg mice, including tumor necrosis factor-alpha (TNFα) positive lung macrophages and dendritic cells, and IFN-gamma (IFNγ) and TNFα positive CD4(+) and CD8(+) T cells in the lungs and mediastinal lymph nodes. Alveolar macrophages from transgenic mice infected with MTB ex vivo had reduced bacterial burden and increased colocalization of green fluorescent protein-labeled MTB with lysosomes. Furthermore, mouse macrophages made to express IL-32γ but not the splice variant IL-32β were better able to limit MTB growth than macrophages capable of producing both. The lungs of patients with tuberculosis showed increased IL-32 expression, particularly in macrophages of granulomas and airway epithelial cells but also B cells and T cells. We conclude that IL-32γ enhances host immunity to MTB.
authors.affiliation: Denver Veterans Affairs Medical Center, Denver, CO 80206; Departments of Medicine and Academic Affairs, Divisions of Pulmonary Sciences and Critical Care Medicine and cdinare333@aol.com BaiX@NJHealth.org ChanE@NJHealth.org.
authors.forename: Xiyuan
authors.initials: X
authors.lastname: Bai
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO 80523;
authors.forename: Shaobin
authors.initials: S
authors.lastname: Shang
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO 80523;
authors.forename: Marcela
authors.initials: M
authors.lastname: Henao-Tamayo
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO 80523;
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Basaraba
authors.affiliation: Denver Veterans Affairs Medical Center, Denver, CO 80206; Departments of Medicine and Academic Affairs, Divisions of Pulmonary Sciences and Critical Care Medicine and.
authors.forename: Alida R
authors.initials: AR
authors.lastname: Ovrutsky
authors.affiliation: Departments of Medicine and Academic Affairs.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Matsuda
authors.affiliation: Pediatrics, and.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Departments of Medicine and Academic Affairs.
authors.forename: Mallory M
authors.initials: MM
authors.lastname: Chan
authors.affiliation: Pediatrics, and.
authors.forename: Azzeddine
authors.initials: A
authors.lastname: Dakhama
authors.affiliation: Departments of Medicine and Academic Affairs.
authors.forename: William H
authors.initials: WH
authors.lastname: Kinney
authors.affiliation: Departments of Medicine and Academic Affairs.
authors.forename: Jessica
authors.initials: J
authors.lastname: Trostel
authors.affiliation: Departments of Medicine and Academic Affairs.
authors.forename: An
authors.initials: A
authors.lastname: Bai
authors.affiliation: Departments of Medicine and Academic Affairs, Divisions of Pulmonary Sciences and Critical Care Medicine and.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Honda
authors.affiliation: Pathology, National Jewish Health, Denver, CO 80206;
authors.forename: Rosane
authors.initials: R
authors.lastname: Achcar
authors.affiliation: Departments of Medicine and Academic Affairs.
authors.forename: John
authors.initials: J
authors.lastname: Hartney
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands;
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department Biomedical Science and Technology, Konkuk University, Seoul, Korea; and.
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO 80523;
authors.forename: Ian
authors.initials: I
authors.lastname: Orme
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Infectious Diseases, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045-2539 cdinare333@aol.com BaiX@NJHealth.org ChanE@NJHealth.org.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Department of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO 80523;
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Ordway
authors.affiliation: Denver Veterans Affairs Medical Center, Denver, CO 80206; Departments of Medicine and Academic Affairs, Divisions of Pulmonary Sciences and Critical Care Medicine and cdinare333@aol.com BaiX@NJHealth.org ChanE@NJHealth.org.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Chan
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007371:Interferon-gamma; D007378:Interleukins / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C / Q000378:metabolism; D022821:RNA Splice Sites / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014162:Transfection; D019076:Transgenes; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014774:Virulence / Q000276:immunology
chemical_list: D000950:Antigens, Ly; C496971:IL32 protein, human; D007378:Interleukins; C527211:Klrb1c protein, mouse; D055651:NK Cell Lectin-Like Receptor Subfamily B; D037721:Pulmonary Surfactant-Associated Protein C; D022821:RNA Splice Sites; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: cytokine; host immunity; interleukin-32; transgenic mouse; tuberculosis
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