Caspase-1 and -11 defend against environmental but not host-adapted pathogens in genetically complex mice

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 × 129 F1 hybrid mice, which are gene-sufficient at both Nramp1 and Casp11 , and used them to measure the fold change in lethal dose (ΔLD ₁₀₀ ) 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.