Ancient familial Mediterranean fever mutations in human pyrin and resistance toYersinia pestis

Familial Mediterranean fever is an autoinflammatory disease caused by gain-of-function mutations in the pyrin inflammasome. Kastner and colleagues show that mutant pyrin better resists suppression by the plague bacteriumYersinia pestisand may have been positively selected in human Middle Eastern populations. Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations inMEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multipleMEFVmutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly withYersinia pestisvirulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1 beta suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1 beta specifically in response toY. pestis.Y. pestis-infectedMefv(M680I/M680I)FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance toY. pestis.