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NLRC4 and TLR5 each contribute to host defense in respiratory melioidosis
T Eoin West1, Nicolle D Myers2, Narisara Chantratita3
1Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America; International Respiratory and Severe Illness Center, University of Washington, Seattle, Washington, United States of America; Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
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.
Insights
Toll-like receptor 5 (TLR5) and NLR family CARD domain-containing protein 4 (NLRC4) are crucial for host defense against Burkholderia pseudomallei, the bacterium causing melioidosis. These pathways are vital for controlling respiratory infections and improving patient survival.
Area of Science:
- Infectious Diseases
- Immunology
- Microbiology
Background:
- Melioidosis, caused by Burkholderia pseudomallei, is a tropical infection with high pneumonia-related mortality.
- Host defense mechanisms against B. pseudomallei are not fully understood, hindering therapeutic development.
- B. pseudomallei utilizes flagella and type III secretion systems, potentially activating host pathogen recognition receptors like TLR5 and NLRC4.
Purpose of the Study:
- To investigate the roles of Toll-like receptor 5 (TLR5) and NLR family CARD domain-containing protein 4 (NLRC4) in host defense against respiratory melioidosis.
- To determine the contribution of flagellin sensing pathways to survival and bacterial control in a murine model of melioidosis.
- To explore the clinical relevance of NLRC4 and TLR5 polymorphisms in melioidosis patient outcomes.
Main Methods:
- Utilized a murine model of respiratory melioidosis.
- Employed knockout mice deficient in Tlr5, Nlrc4, and Casp1/Casp11.
- Assessed bacterial burden in lungs and spleens, pulmonary inflammation, and survival rates.
- Analyzed human NLRC4 and TLR5 polymorphisms in relation to melioidosis patient survival.
Main Results:
- Both Tlr5 and Nlrc4 individually contributed to survival in a murine model of respiratory melioidosis.
- Mice deficient in both Tlr5 and Nlrc4 showed no increased susceptibility compared to single knockouts.
- Casp1/Casp11 deficiency led to impaired bacterial control and more severe pulmonary inflammation, with NLRC4 playing a significant role.
- The human NLRC4 polymorphism rs6757121 and functional TLR5 polymorphisms were associated with improved survival in melioidosis patients.
Conclusions:
- NLRC4 and TLR5 are critical components of host defense against respiratory melioidosis.
- These flagellin sensing pathways contribute significantly to bacterial control and survival.
- Genetic variations in NLRC4 and TLR5 may influence clinical outcomes in melioidosis patients, suggesting therapeutic potential.
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