title: Inflammatory signaling in human tuberculosis granulomas is spatially organized.
abstract: Granulomas are the pathological hallmark of tuberculosis (TB). However, their function and mechanisms of formation remain poorly understood. To understand the role of granulomas in TB, we analyzed the proteomes of granulomas from subjects with tuberculosis in an unbiased manner. Using laser-capture microdissection, mass spectrometry and confocal microscopy, we generated detailed molecular maps of human granulomas. We found that the centers of granulomas have a pro-inflammatory environment that is characterized by the presence of antimicrobial peptides, reactive oxygen species and pro-inflammatory eicosanoids. Conversely, the tissue surrounding the caseum has a comparatively anti-inflammatory signature. These findings are consistent across a set of six human subjects and in rabbits. Although the balance between systemic pro- and anti-inflammatory signals is crucial to TB disease outcome, here we find that these signals are physically segregated within each granuloma. From the protein and lipid snapshots of human and rabbit lesions analyzed here, we hypothesize that the pathologic response to TB is shaped by the precise anatomical localization of these inflammatory pathways during the development of the granuloma.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Mohlopheni J
authors.identifier: 0000-0001-7476-1652
authors.initials: MJ
authors.lastname: Marakalala
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Ravikiran M
authors.initials: RM
authors.lastname: Raju
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Kirti
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Yanjia J
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Newark, New Jersey, USA.|Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Eliseo A
authors.initials: EA
authors.lastname: Eugenin
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Prideaux
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Isaac B
authors.identifier: 0000-0001-7967-1162
authors.initials: IB
authors.lastname: Daudelin
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Program in Immunology, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Matthew G
authors.identifier: 0000-0002-0835-3439
authors.initials: MG
authors.lastname: Booty
authors.affiliation: National Masan TB Hospital, Changwon, Republic of Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: International Tuberculosis Research Center, Changwon, Republic of Korea.
authors.forename: Seok Yong
authors.initials: SY
authors.lastname: Eum
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland.|Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Rondebosch, Republic of South Africa.|Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Rondebosch, Republic of South Africa.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Via
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Behar
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland.|Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Rondebosch, Republic of South Africa.|Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Rondebosch, Republic of South Africa.
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Newark, New Jersey, USA.|Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dartois
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Rubin
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D015777:Eicosanoids / Q000276:immunology* / Q000378:metabolism; D006099:Granuloma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D061346:Laser Capture Microdissection; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D040901:Proteomics; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D015777:Eicosanoids; D017382:Reactive Oxygen Species; D016718:Arachidonic Acid