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

Abstract

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.

• 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
• Journal: PLoS neglected tropical diseases (PLoS Negl Trop Dis) Vol. 8 Issue 9 Pg. e3178 (Sep 2014) ISSN: 1935-2735 [Electronic] United States
• PMID: 25232720 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Calcium-Binding Proteins
• Carrier Proteins
• Ipaf protein, mouse
• Toll-Like Receptor 5
• Flagellin

Topics

• Animals
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Burkholderia pseudomallei (immunology)
• Calcium-Binding Proteins (genetics, metabolism)
• Carrier Proteins (metabolism)
• Flagellin (immunology)
• Humans
• Melioidosis (immunology)
• Mice
• Respiratory Tract Infections (immunology, microbiology)
• Toll-Like Receptor 5 (genetics, metabolism)