A Naturally Occurring Single Nucleotide Polymorphism in the Salmonella SPI-2 Type III Effector srfH/sseI Controls Early Extraintestinal Dissemination

Abstract

CD18 expressing phagocytes associated with the gastro-intestinal (GI) epithelium can shuttle Salmonella directly into the bloodstream within a few minutes following microbial ingestion. We have previously demonstrated that Salmonella controls the CD18 pathway to deeper tissue, manipulating the migratory properties of infected cells as an unappreciated component of its pathogenesis. We have observed that one type III effector, SrfH (also called SseI) that Salmonella secretes into infected phagocytes manipulates the host protein TRIP6 to stimulate their migration. Paradoxically, SrfH was shown in another study to subvert a different host protein, IQGAP1, in a manner that inhibits the productive motility of such cells, perhaps to avoid interactions with T cells. Here, we resolve the discrepancy. We report that one naturally occurring allele of srfH promotes the migration of infected phagocytes into the bloodstream, while another naturally occurring allele that differs by only a single nucleotide polymorphism (SNP) does not. This SNP determines if the protein contains an aspartic acid or a glycine residue at position 103 and may determine if SrfH binds TRIP6. SrfH Gly103 is a rare allele, but is present in the highly invasive strain Salmonella enterica serovar Typhimurium UK-1 (stands for universal killer). It is also present in the genome of the only sequenced strain belonging to the emerging pandemic Salmonella enterica serovar 4, [5],12,i:-, which is frequently associated with septicemia. Finally, we present evidence that suggests that Gifsy-2, the bacteriophage upon which srfH resides, is present in a clinical isolate of the human-specific pathogen, Salmonella enterica serovar Typhi. These observations may have interesting implications for our understanding of Salmonella pathogenesis.

The Salmonella Effector SpvD Is a Cysteine Hydrolase with a Serovar-specific Polymorphism Influencing Catalytic Activity, Suppression of Immune Responses, and Bacterial Virulence

“…There are very few descriptions of single amino acid polymorphisms influencing the potency of bacterial effectors. A naturally occurring polymorphism within S. typhimurium SseI at position 103 was shown to affect binding to the cell migration adaptor protein TRIP6 in a yeast two-hybrid assay and bacterial dissemination in mice (27). However, the position of the SseI polymorphism in relation to the catalytic site is unknown as only partial SseI (amino acids 145–313) structure is currently available (15).…”

Impact ofSalmonella entericaType III Secretion System Effectors on the Eukaryotic Host Cell

“…This second role could be critical during later stages of infection and could explain the attenuation of the sseI mutant in long-term, but not short-term, systemic infections [207,343]. The discrepancy between these two roles (stimulation or inhibition of cell migration) has been recently resolved: a naturally occurring allele of sseI/srfH promotes the migration of infected phagocytes into the bloodstream, while another naturally occurring allele that differs by only a single nucleotide polymorphism does not [344]. Upon infection of polarized epithelial cells, SseI is targeted to the plasma membrane in a manner dependent on S-palmitoylation of a conserved cysteine residue within its N-terminal domain.…”

Identification of Novel Host Interactors of Effectors Secreted by Salmonella and Citrobacter

“…Whereas SrfH binding to TRIP6 has been reported to promote phagocyte mobility and systemic dissemination, IQGAP1 interactions were shown to suppress Salmonella migration to the spleen ( 34 , 35 ). These contradictory phenotypes might be due to a single nucleotide polymorphism that dictates SrfH binding to TRIP6 ( 37 ). SrfH from Salmonella Typhimurium 14028s bears a glycine residue at position 103, whereas the allele from serovar SL1344 has an aspartic acid residue at the same position which abolishes the binding to TRIP6 ( 37 ).…”