Salmonella Derby adaptation to swine and simultaneous attenuation for humans go through decay of Salmonella Pathogenicity Island I

Abstract

ABSTRACT We report the identification, within the global population of Salmonella Derby, of a lineage highly diffused and expanding in swine while being significantly under-represented in humans which carries stop mutations in the Salmonella Pathogenicity Island 1 (SPI-1) genes sipA and hilC . Single-cell analysis of invasion, vacuolar load, and cytosolic hyper-replication show that these mutations attenuate S . Derby virulence in human intestinal cells. Identification of this lineage follows the previous detection of another lineage over-represented in swine compared with humans which carries a loss-of-function mutation in hilD , the major SPI-1 regulator, responsible for reduced infection of human cells. Notably, this hilD -mutated lineage represents a sub-population of the wider sipA and hilC- mutated lineages identified in this study, indicating that SPI-1 is subjected to genetic decay in this part of the Salmonella Derby population adapted to swine. Virulence assessment on swine intestinal cells showed drastically lower levels for both wild-type and mutant S . Derby compared with human cells. Still, S . Derby with impaired sipA and hilC showed further attenuation also in swine cells compared with the wild type. These data suggest that invasion of swine intestinal epithelium is not needed by S . Derby to circulate in pigs, leading to the decay of SPI-1, which in turn determines attenuation for humans. Accordingly, a further S . Derby lineage under-represented in humans compared with pigs was found carrying truncated or missing SPI-1 genes, indicating that the S . Derby population is undergoing converging evolution in its adaptation to swine while attenuating for humans through loss of SPI-1 function. IMPORTANCE This study integrated population data with in vitro assessment of virulence phenotypes to unveil that a considerable part of the global population of Salmonella Derby is evolving to enhance its host adaptation to the swine host and that this evolution is simultaneously increasing its attenuation for humans. The study shows that the fixation of deleterious mutations in SPI-1 has a role in this process. This evidence indicates that SPI-1 has a key role for S . Derby virulence in humans but not for its circulation in swine. The results show that genes generally considered essential for Salmonella pathogenesis do not play the same key role for all Salmonella serovars or lineages and/or all hosts. The study helps in understanding the molecular mechanisms underlying the ecology and host adaptation of Salmonella showing that the adaptation process can vary for different types of Salmonella and hosts.