Abstract
Host innate immunity plays a pivotal role in the early detection and neutralization of invading pathogens. Here, we show that pseudokinase mixed lineage kinase-like protein (MLKL) is required for host defence against Streptococcus pluranimalium infection by enhancing NLRP3 inflammasome activation and extracellular trap formation. Notably, Mlkl deficiency leads to increased mortality, increased bacterial colonization, severe destruction of organ architecture, and elevated inflammatory cell infiltration in murine models of S. pluranimalium pulmonary and systemic infection. In vivo and in vitro data provided evidence that potassium efflux-dependent NLRP3 inflammasome signalling downstream of active MLKL confers host protection against S. pluranimalium infection and initiates bacterial killing and clearance. Moreover, Mlkl deficiency results in defects in extracellular trap-mediated bactericidal activity. In summary, this study revealed that MLKL mediates the host defence response to S. pluranimalium, and suggests that MLKL is a potential drug target for preventing and controlling pathogen infection.
Keywords:
NLRP3 inflammasome; S. pluranimalium; extracellular trap; innate immunity; mixed lineage kinase-like protein.
MeSH terms
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Animals
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Extracellular Traps*
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Inflammasomes* / metabolism
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Mice
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NLR Family, Pyrin Domain-Containing 3 Protein / genetics
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NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
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Protein Kinases / genetics
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Streptococcal Infections* / genetics
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Streptococcal Infections* / metabolism
Substances
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Inflammasomes
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MLKL protein, mouse
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NLR Family, Pyrin Domain-Containing 3 Protein
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Protein Kinases
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Nlrp3 protein, mouse
Supplementary concepts
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Streptococcus pluranimalium
Grants and funding
This work was supported by the National Natural Science Foundation of China [No. 32302886, No. 32160832], Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region of China [No. NJYT22104], Research Program of Science and Technology at Universities of Inner Mongolia Autonomous Region of China [No. NJZZ21001], Natural Science Foundation of Inner Mongolia Autonomous Region of China [No. 2021BS03003], Student Innovation and Entrepreneurship Training Programs of Inner Mongolia University [No. 21400-23269204], Inner Mongolia University Startup Foundation for Advanced Talents [No. 30500-5185139], and Inner Mongolia Engineering Technology Research Center of Germplasm Resources Conservation and Utilization [No. 21400-222526].