NLRC4 and TLR5 each contribute to host defense in respiratory melioidosis.

Journal Article (Journal Article)

Burkholderia pseudomallei causes the tropical infection melioidosis. Pneumonia is a common manifestation of melioidosis and is associated with high mortality. Understanding the key elements of host defense is essential to developing new therapeutics for melioidosis. As a flagellated bacterium encoding type III secretion systems, B. pseudomallei may trigger numerous host pathogen recognition receptors. TLR5 is a flagellin sensor located on the plasma membrane. NLRC4, along with NAIP proteins, assembles a canonical caspase-1-dependent inflammasome in the cytoplasm that responds to flagellin (in mice) and type III secretion system components (in mice and humans). In a murine model of respiratory melioidosis, Tlr5 and Nlrc4 each contributed to survival. Mice deficient in both Tlr5 and Nlrc4 were not more susceptible than single knockout animals. Deficiency of Casp1/Casp11 resulted in impaired bacterial control in the lung and spleen; in the lung much of this effect was attributable to Nlrc4, despite relative preservation of pulmonary IL-1β production in Nlrc4(-/-) mice. Histologically, deficiency of Casp1/Casp11 imparted more severe pulmonary inflammation than deficiency of Nlrc4. The human NLRC4 region polymorphism rs6757121 was associated with survival in melioidosis patients with pulmonary involvement. Co-inheritance of rs6757121 and a functional TLR5 polymorphism had an additive effect on survival. Our results show that NLRC4 and TLR5, key components of two flagellin sensing pathways, each contribute to host defense in respiratory melioidosis.

Full Text

Duke Authors

Cited Authors

  • West, TE; Myers, ND; Chantratita, N; Chierakul, W; Limmathurotsakul, D; Wuthiekanun, V; Miao, EA; Hajjar, AM; Peacock, SJ; Liggitt, HD; Skerrett, SJ

Published Date

  • September 18, 2014

Published In

Volume / Issue

  • 8 / 9

Start / End Page

  • e3178 -

PubMed ID

  • 25232720

Pubmed Central ID

  • PMC4169243

Electronic International Standard Serial Number (EISSN)

  • 1935-2735

International Standard Serial Number (ISSN)

  • 1935-2727

Digital Object Identifier (DOI)

  • 10.1371/journal.pntd.0003178

Language

  • eng