Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 1; pp. 385 - 390
• Main Authors: Zaki, Md. Hasan, Man, Si Ming, Vogel, Peter, Lamkanfi, Mohamed, Kanneganti, Thirumala-Devi
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07-01-2014; National Acad Sciences
• Subjects: Animals; Bacterial infections; Biological Sciences; Bone Marrow Cells - immunology; Bone Marrow Cells - microbiology; Cytokines; Digestive system; Extracellular Signal-Regulated MAP Kinases - metabolism; Food contamination & poisoning; Host-Pathogen Interactions; Immunity (Disease); Immunity, Innate; Infections; Inflammation; Intracellular Signaling Peptides and Proteins - metabolism; Liver; Liver - metabolism; Macrophages; Macrophages - microbiology; Male; Mice; Mice, Transgenic; Models, Biological; Molecules; NF-kappa B - metabolism; Nitric Oxide - chemistry; Nucleotides - chemistry; Pathogens; Phosphorylation; Protein Structure, Tertiary; Receptors; Salmonella; Salmonella enterica; Salmonella infections; Salmonella Infections, Animal - immunology; Salmonella Infections, Animal - microbiology; Salmonella typhimurium; Salmonella typhimurium - metabolism; Signal Transduction; Time Factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1317643111

The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 12 (NLRP12) plays a protective role in intestinal inflammation and carcinogenesis, but the physiological function of this NLR during microbial infection is largely unexplored. Salmonella enterica serovar Typhimurium (S. typhimurium) is a leading cause of food poisoning worldwide. Here, we show that NLRP12-deficient mice were highly resistant to S. typhimurium infection. Salmonella- infected macrophages induced NLRP12-dependent inhibition of NF-κB and ERK activation by suppressing phosphorylation of IκBα and ERK. NLRP12-mediated down-regulation of proinflammatory and antimicrobial molecules prevented efficient clearance of bacterial burden, highlighting a role for NLRP12 as a negative regulator of innate immune signaling during salmonellosis. These results underscore a signaling pathway defined by NLRP12-mediated dampening of host immune defenses that could be exploited by S. typhimurium to persist and survive in the host.