title: S100A12 Is Part of the Antimicrobial Network against Mycobacterium leprae in Human Macrophages.
abstract: Triggering antimicrobial mechanisms in macrophages infected with intracellular pathogens, such as mycobacteria, is critical to host defense against the infection. To uncover the unique and shared antimicrobial networks induced by the innate and adaptive immune systems, gene expression profiles generated by RNA sequencing (RNAseq) from human monocyte-derived macrophages (MDMs) activated with TLR2/1 ligand (TLR2/1L) or IFN-γ were analyzed. Weighed gene correlation network analysis identified modules of genes strongly correlated with TLR2/1L or IFN-γ that were linked by the "defense response" gene ontology term. The common TLR2/1L and IFN-γ inducible human macrophage host defense network contained 16 antimicrobial response genes, including S100A12, which was one of the most highly induced genes by TLR2/1L. There is limited information on the role of S100A12 in infectious disease, leading us to test the hypothesis that S100A12 contributes to host defense against mycobacterial infection in humans. We show that S100A12 is sufficient to directly kill Mycobacterium tuberculosis and Mycobacterium leprae. We also demonstrate that S100A12 is required for TLR2/1L and IFN-γ induced antimicrobial activity against M. leprae in infected macrophages. At the site of disease in leprosy, we found that S100A12 was more strongly expressed in skin lesions from tuberculoid leprosy (T-lep), the self-limiting form of the disease, compared to lepromatous leprosy (L-lep), the progressive form of the disease. These data suggest that S100A12 is part of an innate and adaptive inducible antimicrobial network that contributes to host defense against mycobacteria in infected macrophages.
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
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, Los Angeles, California, United States of America.
authors.forename: Kindra M
authors.initials: KM
authors.lastname: Kelly-Scumpia
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Angeline Tilly
authors.initials: AT
authors.lastname: Dang
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Division of Dermatology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Rosane
authors.initials: R
authors.lastname: Teles
authors.affiliation: UCLA/Orthopedic Hospital Department of Orthopedic Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Philip T
authors.initials: PT
authors.lastname: Liu
authors.affiliation: Division of Dermatology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schenk
authors.affiliation: Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Ernest Y
authors.identifier: 0000-0001-5144-2552
authors.initials: EY
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Schmidt
authors.affiliation: Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Gerard C L
authors.initials: GC
authors.lastname: Wong
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
authors.forename: Euzenir N
authors.initials: EN
authors.lastname: Sarno
authors.affiliation: Department of Dermatology, University of Southern California School of Medicine, Los Angeles, California, United States of America.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rea
authors.affiliation: Department of Dermatology, University of Southern California School of Medicine, Los Angeles, California, United States of America.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Ochoa
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.|Division of Dermatology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
mesh_terms: D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D007918:Leprosy / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D009164:Mycobacterium Infections / Q000276:immunology; D009166:Mycobacterium leprae / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D000067616:S100A12 Protein / Q000276:immunology*; D059467:Transcriptome
chemical_list: D000067616:S100A12 Protein; C090441:S100A12 protein, human