SP110b Controls Host Immunity and Susceptibility to Tuberculosis

Am J Respir Crit Care Med. 2017 Feb 1;195(3):369-382. doi: 10.1164/rccm.201601-0103OC.

Abstract

Rationale: 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.

Objectives: 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.

Measurements and main 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.

Keywords: Mycobacterium tuberculosis; cell death; inflammation; nuclear factor-κB; tumor necrosis factor-α.

MeSH terms

  • Animals
  • Antigens, Nuclear* / genetics
  • Antigens, Nuclear* / immunology
  • Apoptosis / genetics
  • Apoptosis / immunology
  • Autoantigens* / genetics
  • Autoantigens* / immunology
  • Disease Models, Animal
  • Epistasis, Genetic / immunology*
  • Gene Expression Regulation / immunology
  • Genetic Predisposition to Disease*
  • Humans
  • Immunity, Innate / genetics*
  • Mice
  • Microarray Analysis
  • Minor Histocompatibility Antigens* / genetics
  • Minor Histocompatibility Antigens* / immunology
  • Mycobacterium tuberculosis / genetics*
  • Mycobacterium tuberculosis / immunology*
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Nuclear Proteins* / genetics
  • Nuclear Proteins* / immunology
  • Polymorphism, Single Nucleotide
  • Tuberculosis / genetics*
  • Tuberculosis / immunology*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Antigens, Nuclear
  • Autoantigens
  • Minor Histocompatibility Antigens
  • NF-kappa B
  • Nuclear Proteins
  • Sp110 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Sp100 protein, human