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Title: NLRC4 and TLR5 Each Contribute to Host Defense in Respiratory Melioidosis
Authors: T. Eoin West
Nicolle D. Myers
Narisara Chantratita
Wirongrong Chierakul
Direk Limmathurotsakul
Vanaporn Wuthiekanun
Edward A. Miao
Adeline M. Hajjar
Sharon J. Peacock
H. Denny Liggitt
Shawn J. Skerrett
University of Washington School of Medicine
University of Washington, Seattle
Mahidol University
The University of North Carolina at Chapel Hill
University of Cambridge
Keywords: Medicine
Issue Date: 1-Sep-2014
Citation: PLoS Neglected Tropical Diseases. Vol.8, No.9 (2014)
Abstract: © 2014 West et al. 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.
ISSN: 19352735
Appears in Collections:Scopus 2011-2015

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