Mutation of hilD in a Salmonella Derby lineage linked to swine adaptation and reduced risk to human health

Abstract

Salmonella enterica variants exhibit diverse host adaptation, outcome of infection, and associated risk to food safety. Analysis of the distribution of Salmonella enterica serovar Derby (S. Derby) subtypes in human and swine identified isolates with a distinct PFGE profile that were significantly under-represented in human infections, consistent with further host adaptation to swine. Here we show that isolates with this PFGE profile form a distinct phylogenetic sub-clade within S. Derby and exhibit a profound reduction in invasion of human epithelial cells, and a relatively small reduction in swine epithelial cells. A single missense mutation in hilD, that encodes the master-regulator of the Salmonella Pathogenicity Island 1 (SPI-1), was present in the adapted lineage. The missense mutation resulted in a loss of function of HilD that accounted for reduced invasion in human epithelial cells. The relatively small impact of the mutation on interaction with swine cells was consistent with an alternative mechanism of invasion in this pathogen-host combination.

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

“…1A ). This hilC stop and sipA stop -carrying lineage included the 15 isolates carrying also the loss-of-function mutation in hilD previously characterized ( 5 ). The logistic regression performed on the occurrence of the genomes carrying sipA stop and hilC stop in the ST40 population from swine as a function of time (considering also the continent of isolation) showed a significant increase of the fraction of mutation-carrying genomes over time, both in Europe and North America ( Fig.…”

“…In a previous study, we identified a specialized case of host adaptation to swine by a specific S . Derby lineage, featuring even further decreased pathogenicity to humans while maintaining high prevalence in pigs ( 5 ). We found that the lineage carries a single loss-of-function mutation in hilD , encoding the master activator of Salmonella Pathogenicity Island 1 (SPI-1) ( 6 ), and demonstrated that the hilD mutation was responsible for impaired interaction with human cells much more than with swine cells, potentially explaining the negligible presence of this lineage in humans despite its circulation in swine.…”

Automated Analysis of Intracellular Phenotypes of <em>Salmonella</em> Using ImageJ

“…The strains were selected in order to represent the phenotype diversity covered by the protocol. In particular, these strains were chosen because their behavior inside epithelial cells was already known to differ in terms of invasion or replication 9 ; therefore, they were valuable controls to test whether the protocol allowed to quantitatively distinguish differences in intracellular Salmonella phenotypes. In particular, S. Tm and S. Derby wt were included because we had previously demonstrated that S. Tm has higher invasion and intracellular replication efficiency than S. Derby wt 9 while S. Derby ΔsipA was added as a hyper-replication impaired strain since the virulence effector SipA plays a crucial role in the onset of hyper-replication 10 , 11 .…”

Cooperative virulence can emerge via horizontal gene transfer but is stabilized by transmission

“…The target of selection is the transcriptional regulation of virulence expression via HilD 12 . Such hilD mutants have been isolated from patients 25 and swine 26 , and are under niche-specific positive selection according to comparative genomic analyses of more than 100 000 natural isolates of Salmonella enterica 27 . Therefore, division of labour alone cannot explain the maintenance of cooperative virulence in S .Tm and much less its emergence.…”