Journal
INFECTION AND IMMUNITY
Volume 90, Issue 7, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/iai.00663-21
Keywords
ASC; CASP4; NAIP; NLRC4; NLRP3; Salmonella; human innate immunity; inflammasome; intestinal epithelial cell
Categories
Funding
- NIH/NIAID [AI128520, AI139102]
- Linda Pechenik Montague Investigator Award from the University of Pennsylvania Perelman School of Medicine
- Burroughs-Wellcome Fund Investigators in the Pathogenesis of Infectious Disease Award
- OHSU
- NIH [R01-AI130055]
- N.L. Tartar Trust (OHSU)
- Medical Research Foundation of Oregon (OHSU)
- OHSU School of Medicine Faculty Innovation Fund
- American Heart Association Predoctoral Fellowship [19PRE34380315]
- FWF-Immunity in Cancer & Allergy PhD program of the University of Salzburg
- Austrian Marshall Plan Foundation Scholarship
- NIH/NIAID Microbial Pathogenesis and Genomics training grant [5T32AI141393-03]
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Salmonella enterica serovar Typhimurium is a pathogen that causes various diseases. It uses a type III secretion system to inject effectors into host cells, triggering immune responses. While murine intestinal epithelial cells rely on one inflammasome to combat Salmonella, human intestinal epithelial cells primarily use another inflammasome.
Salmonella enterica serovar Typhimurium is a Gram-negative pathogen that causes diseases ranging from gastroenteritis to systemic infection and sepsis. Salmonella uses type III secretion systems (T3SS) to inject effectors into host cells. While these effectors are necessary for bacterial invasion and intracellular survival, intracellular delivery of T3SS products also enables detection of translocated Salmonella ligands by cytosolic immune sensors. Some of these sensors form multimeric complexes called inflammasomes, which activate caspases that lead to interleukin-1 (IL-1) family cytokine release and pyroptosis. In particular, the Salmonella T3SS needle, inner rod, and flagellin proteins activate the NAIP/NLRC4 inflammasome in murine intestinal epithelial cells (IECs), which leads to restriction of bacterial replication and extrusion of infected IECs into the intestinal lumen, thereby preventing systemic dissemination of Salmonella. While these processes are quite well studied in mice, the role of the NAIP/NLRC4 inflammasome in human IECs remains unknown. Unexpectedly, we found the NAIP/NLRC4 inflammasome is dispensable for early inflammasome responses to Salmonella in both human IEC lines and enteroids. Additionally, NLRP3 and the adaptor protein ASC are not required for inflammasome activation in Caco-2 cells. Instead, we observed a necessity for caspase-4 and gasdermin D pore-forming activity in mediating inflammasome responses to Salmonella in Caco-2 cells. These findings suggest that unlike murine IECs, human IECs do not rely on NAIP/NLRC4 or NLRP3/ASC inflammasomes and instead primarily use caspase-4 to mediate inflammasome responses to Salmonella pathogenicity island 1 (SPI-1)-expressing Salmonella.
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