NLRP3 inflammasome activation by mycobacterial ESAT-6 and dsRNA in intraocular tuberculosis

Microb Pathog. 2018 Jan;114:219-224. doi: 10.1016/j.micpath.2017.11.044. Epub 2017 Nov 24.

Abstract

The molecular basis of intraocular tuberculosis (TB) is not well understood. In this study, we investigated the role of two constituents of viable Mycobacterium tuberculosis - Early Secreted Antigenic Target-6 (ESAT-6), and mycobacterial RNA- in inflammasome activation in the retinal pigment epithelium (RPE), a key site of inflammation in intraocular TB. We found that ESAT-6 induced caspase-1 activation and inflammasome priming in mouse RPE cells, substantially more in wild-type than in Tlr2/3/4/7/9-/-, Myd88-/- or Nlrp3-/- RPE cells. Sub-retinal ESAT-6 injection resulted in greater RPE degeneration in wild-type than in Nlrp3-/- mice. In human ocular TB tissue sections, NLRP3 staining was noted in retina as well as RPE. Mycobacterial RNA, specifically its double stranded component, also induced caspase-1 activation, and the double stranded RNA was immunolocalized to human ocular TB sections. Our observations suggest that inflammasome activation in RPE by viable M. tuberculosis could potentially contribute to human intraocular TB.

Keywords: ESAT-6; Inflammasome; Intraocular tuberculosis; NLRP3; RNA.

MeSH terms

  • Animals
  • Antigens, Bacterial / genetics
  • Antigens, Bacterial / immunology*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / immunology*
  • Caspase 1 / genetics
  • Caspase 1 / immunology
  • Host-Parasite Interactions
  • Humans
  • Inflammasomes / genetics
  • Inflammasomes / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / immunology*
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
  • RNA, Bacterial / genetics
  • RNA, Bacterial / immunology*
  • RNA, Double-Stranded / genetics
  • RNA, Double-Stranded / immunology*
  • Retinal Pigment Epithelium / immunology
  • Retinal Pigment Epithelium / microbiology
  • Tuberculosis, Ocular / genetics
  • Tuberculosis, Ocular / immunology*
  • Tuberculosis, Ocular / microbiology

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • ESAT-6 protein, Mycobacterium tuberculosis
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • RNA, Bacterial
  • RNA, Double-Stranded
  • Caspase 1