title: Pyroptosis of Salmonella Typhimurium-infected macrophages was suppressed and elimination of intracellular bacteria from macrophages was promoted by blocking QseC.
abstract: QseC is a membrane-bound histidine sensor kinase found in Gram-negative pathogens and is involved in the regulation of bacterial virulence. LED209, a QseC-specific inhibitor, significantly inhibits the virulence of several pathogens and partially protects infected mice from death by blocking QseC. However, the mechanism of its antibacterial effects remains unclear. In this experiment, a Salmonella Typhimurium (S. Typhimurium) and macrophage co-culture system was utilized to investigate possible mechanisms underlying the antimicrobial effects of the QseC inhibitor. QseC blockade inhibited the expression of QseC-dependent virulence genes, including flhDC, sifA, and sopB, in S. Typhimurium, leading to inhibition of swimming motility, invasion capacity, and replication capacity of the pathogens. Release of lactate dehydrogenase (LDH) from S. Typhimurium-infected macrophages was significantly inhibited by blocking QseC. Activated caspase-1 and IL-1β levels were suppressed, and intracellular bacterial count was reduced in infected macrophages. QseC blockade effectively reduced the virulence of S. Typhimurium, inhibited S. Typhimurium-induced pyroptosis of macrophages, and promoted elimination of intracellular bacteria from infected macrophages. Thus, the antibacterial effects of QseC inhibitor are mediated via enhancement of intracellular killing of S. Typhimurium in macrophages.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, P. R. China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Center of Clinical Laboratory Medicine of PLA, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, P. R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, P. R. China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, P. R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, P. R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Da
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, P. R. China.
authors.forename: Di
authors.initials: D
authors.lastname: Qu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, P. R. China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hou
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, P. R. China.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Luo
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D061251:Primary Cell Culture; D000069292:Pyroptosis / Q000187:drug effects*; D053038:Quorum Sensing / Q000187:drug effects / Q000235:genetics; D012481:Salmonella Infections, Animal / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006023:Glycoproteins; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; C531088:LED209; C421862:SifA protein, Salmonella; D013449:Sulfonamides; D015534:Trans-Activators; D007770:L-Lactate Dehydrogenase; C489224:SopB protein, Salmonella; D020170:Caspase 1