Activation of an NLRP3 Inflammasome Restricts Mycobacterium Kansasii Infection

PLoS One. 2012;7(4):e36292. doi: 10.1371/journal.pone.0036292. Epub 2012 Apr 30.

Abstract

Mycobacterium kansasii has emerged as an important nontuberculous mycobacterium pathogen, whose incidence and prevalence have been increasing in the last decade. M. kansasii can cause pulmonary tuberculosis clinically and radiographically indistinguishable from that caused by Mycobacterium tuberculosis infection. Unlike the widely-studied M. tuberculosis, little is known about the innate immune response against M. kansasii infection. Although inflammasome activation plays an important role in host defense against bacterial infection, its role against atypical mycobacteria remains poorly understood. In this report, the role of inflammasome activity in THP-1 macrophages against M. kansasii infection was studied. Results indicated that viable, but not heat-killed, M. kansasii induced caspase-1-dependent IL-1β secretion in macrophages. The underlying mechanism was found to be through activation of an inflammasome containing the NLR (Nod-like receptor) family member NLRP3 and the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD). Further, potassium efflux, lysosomal acidification, ROS production and cathepsin B release played a role in M. kansasii-induced inflammasome activation. Finally, the secreted IL-1β derived from caspase-1 activation was shown to restrict intracellular M. kansasii. These findings demonstrate a biological role for the NLRP3 inflammasome in host defense against M. kansasii.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / metabolism*
  • Caspase 1 / metabolism
  • Cathepsin B / metabolism
  • Cell Line, Tumor
  • Cytoskeletal Proteins / metabolism
  • Enzyme Activation / immunology
  • Humans
  • Hydrogen-Ion Concentration
  • Immunity, Innate
  • Inflammasomes / metabolism*
  • Interleukin-1beta / metabolism
  • Intracellular Space / immunology
  • Intracellular Space / metabolism
  • Intracellular Space / microbiology
  • Lysosomes / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / microbiology
  • Mycobacterium kansasii / physiology*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Potassium / metabolism
  • Reactive Oxygen Species / metabolism

Substances

  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • PYCARD protein, human
  • Reactive Oxygen Species
  • Cathepsin B
  • Caspase 1
  • Potassium