title: SP110b Controls Host Immunity and Susceptibility to Tuberculosis.
abstract: BACKGROUND
  How host genetic factors affect Mycobacterium tuberculosis (Mtb) infection outcomes remains largely unknown. SP110b, an IFN-induced nuclear protein, is the nearest human homologue to the mouse Ipr1 protein that has been shown to control host innate immunity to Mtb infection. However, the function(s) of SP110b remains unclear.
  
  
  OBJECTIVE
  To elucidate the role of SP110b in controlling host immunity and susceptibility to tuberculosis (TB), as well as to identify the fundamental immunological and molecular mechanisms affected by SP110b.
  
  
  METHODS
  Using cell-based approaches and mouse models of Mtb infection, we characterized the function(s) of SP110b/Ipr1. We also performed genetic characterization of patients with TB to investigate the role of SP110 in controlling host susceptibility to TB.
  
  
  RESULTS
  SP110b modulates nuclear factor-κB (NF-κB) activity, resulting in downregulation of tumor necrosis factor-α (TNF-α) production and concomitant upregulation of NF-κB-induced antiapoptotic gene expression, thereby suppressing IFN-γ-mediated monocyte and/or macrophage cell death. After Mtb infection, TNF-α is also downregulated in Ipr1-expressing mice that have alleviated cell death, less severe necrotic lung lesions, more efficient Mtb growth control in the lungs, and longer survival. Moreover, genetic studies in patients suggest that SP110 plays a key role in modulating TB susceptibility in concert with NFκB1 and TNFα genes.
  
  
  CONCLUSIONS
  These results indicate that SP110b plays a crucial role in shaping the inflammatory milieu that supports host protection during infection by fine-tuning NF-κB activity, suggesting that SP110b may serve as a potential target for host-directed therapy aimed at manipulating host immunity against TB.
authors.affiliation: 1 Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jia-Shiun
authors.initials: JS
authors.lastname: Leu
authors.affiliation: 2 Graduate Institute of Oncology.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Chen
authors.affiliation: 3 Institute of Biochemistry and Molecular Biology, and.
authors.forename: So-Yi
authors.initials: SY
authors.lastname: Chang
authors.affiliation: 4 Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University Medical College, Taipei, Taiwan.
authors.forename: Sung-Liang
authors.initials: SL
authors.lastname: Yu
authors.affiliation: 3 Institute of Biochemistry and Molecular Biology, and.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Lin
authors.affiliation: 3 Institute of Biochemistry and Molecular Biology, and.
authors.forename: Hsuan
authors.initials: H
authors.lastname: Wang
authors.affiliation: 3 Institute of Biochemistry and Molecular Biology, and.
authors.forename: Wan-Chen
authors.initials: WC
authors.lastname: Chen
authors.affiliation: 5 Department of Medical Research.
authors.forename: Chin-Hao
authors.initials: CH
authors.lastname: Chang
authors.affiliation: 6 Department of Internal Medicine, and.
authors.forename: Jann-Yuan
authors.initials: JY
authors.lastname: Wang
authors.affiliation: 7 Department of Laboratory Medicine, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan; and.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Lee
authors.affiliation: 6 Department of Internal Medicine, and.
authors.forename: Chong-Jen
authors.initials: CJ
authors.lastname: Yu
authors.affiliation: 8 Pulmonary Center, Department of Medicine, National Emerging Infectious Diseases Laboratory, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Igor
authors.initials: I
authors.lastname: Kramnik
authors.affiliation: 3 Institute of Biochemistry and Molecular Biology, and.
authors.forename: Bo-Shiun
authors.identifier: http://orcid.org/0000-0002-9613-4788
authors.initials: BS
authors.lastname: Yan
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004843:Epistasis, Genetic / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D051379:Mice; D046228:Microarray Analysis; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D034961:Antigens, Nuclear; D001324:Autoantigens; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D009687:Nuclear Proteins; C000598498:Sp110 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C066642:SP100 protein, human
keywords: Mycobacterium tuberculosis; cell death; inflammation; nuclear factor-κB; tumor necrosis factor-α