Caspase-1 and -11 defend against environmental but not host-adapted pathogens in genetically complex mice
- 1Duke University School of Medicine
Abstract
Caspase-1 and -11 are inflammatory caspases that trigger pyroptosis, yet in most infection models they confer only a modest survival benefit. We have proposed that caspase-1 and -11 evolved primarily to defend against ubiquitous environmental microbes that have not been under selective pressure to evade them, whereas host-adapted pathogens have evolved evasion strategies. Testing this idea is complicated because the inbred mouse strains used in most infection studies carry mutations in innate immune genes: i.e., C57BL/6 (B6) mice carry a loss-of-function Nramp1 allele, and 129 mice lack functional caspase-11. Here we generated B6 x 129 F1 hybrid mice, which are gene-sufficient at both Nramp1 and Casp11, and used them to measure the fold change in lethal dose ({triangleup}LD100) caused by caspase-1 and -11 deficiency for four pathogens on the B6, 129, and F1 backgrounds. Caspase-1 and -11 conferred little or no survival benefit against the host-adapted pathogens Listeria monocytogenes and Salmonella Typhimurium on any of the three backgrounds, apart from a modest benefit at the lowest S. Typhimurium inoculum in F1 mice. In contrast, caspase-1 and -11 were required to survive infection with the environmental pathogens Burkholderia thailandensis and Chromobacterium violaceum, where caspase-1 and -11 deficiency lowered the lethal dose by up to six orders of magnitude. The failure of caspase-1 and -11 against host-adapted pathogens therefore persists on a genetically robust hybrid background, supporting the view that a major evolutionary role of caspase-1 and -11 is defense against environmental microbes that have not been selected to evade them.
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BibTeX
@misc{li2026caspase1,
title = {{Caspase-1 and -11 defend against environmental but not host-adapted pathogens in genetically complex mice}},
author = {L. Li and B. D. McGlaughon and H. N. Larson and B. H. Koller and E. A. Miao},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.30.763184},
url = {https://www.biorxiv.org/content/10.64898/2026.10.30.763184v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Caspase-1 and -11 defend against environmental but not host-adapted pathogens in genetically complex mice
AU - L. Li
AU - B. D. McGlaughon
AU - H. N. Larson
AU - B. H. Koller
AU - E. A. Miao
PY - 2026
DA - 2026/10/30
PB - bioRxiv
DO - 10.64898/2026.10.30.763184
UR - https://www.biorxiv.org/content/10.64898/2026.10.30.763184v1
AB - Caspase-1 and -11 are inflammatory caspases that trigger pyroptosis, yet in most infection models they confer only a modest survival benefit. We have proposed that caspase-1 and -11 evolved primarily to defend against ubiquitous environmental microbes that have not been under selective pressure to evade them, whereas host-adapted pathogens have evolved evasion strategies. Testing this idea is complicated because the inbred mouse strains used in most infection studies carry mutations in innate immune genes: i.e., C57BL/6 (B6) mice carry a loss-of-function Nramp1 allele, and 129 mice lack functional caspase-11. Here we generated B6 x 129 F1 hybrid mice, which are gene-sufficient at both Nramp1 and Casp11, and used them to measure the fold change in lethal dose ({triangleup}LD100) caused by caspase-1 and -11 deficiency for four pathogens on the B6, 129, and F1 backgrounds. Caspase-1 and -11 conferred little or no survival benefit against the host-adapted pathogens Listeria monocytogenes and Salmonella Typhimurium on any of the three backgrounds, apart from a modest benefit at the lowest S. Typhimurium inoculum in F1 mice. In contrast, caspase-1 and -11 were required to survive infection with the environmental pathogens Burkholderia thailandensis and Chromobacterium violaceum, where caspase-1 and -11 deficiency lowered the lethal dose by up to six orders of magnitude. The failure of caspase-1 and -11 against host-adapted pathogens therefore persists on a genetically robust hybrid background, supporting the view that a major evolutionary role of caspase-1 and -11 is defense against environmental microbes that have not been selected to evade them.
ER -