Abstract
ABSTRACTThe Salmonella cytolethal distending toxin (S-CDT), first described as the “typhoid toxin” in Salmonella enterica subsp. enterica serotype Typhi, induces DNA damage in eukaryotic cells. Recent studies have shown that more than 40 nontyphoidal Salmonella (NTS) serotypes carry genes that encode S-CDT, yet very little is known about the activity, function, and role of S-CDT in NTS. Here we show that deletion of genes encoding the binding subunit (pltB) and a bacteriophage muramidase predicted to play a role in toxin export (ttsA) does not abolish toxin activity in the S-CDT-positive NTS Salmonella enterica subsp. enterica serotype Javiana. However, S. Javiana strains harboring deletions of both pltB and its homolog artB, had a complete loss of S-CDT activity, suggesting that S. Javiana carries genes encoding two variants of the binding subunit. S-CDT-mediated DNA damage, as determined by phosphorylation of histone 2AX (H2AX), producing phosphorylated H2AX (γH2AX), was restricted to epithelial cells in S and G2/M phases of the cell cycle and did not result in apoptosis or cell death. Compared to mice infected with a ΔcdtB strain, mice infected with wild-type S. Javiana had significantly higher levels of S. Javiana in the liver, but not in the spleen, ileum, or cecum. Overall, we show that production of active S-CDT by NTS serotype S. Javiana requires different genes (cdtB, pltA, and either pltB or artB) for expression of biologically active toxin than those reported for S-CDT production by S. Typhi (cdtB, pltA, pltB, and ttsA). However, as in S. Typhi, NTS S-CDT influences the outcome of infection both in vitro and in vivo.
Highlights
IMPORTANCE Nontyphoidal Salmonella (NTS) are a major cause of bacterial foodborne illness worldwide; our understanding of virulence mechanisms that determine the outcome and severity of nontyphoidal salmonellosis is incompletely understood
We show that Salmonella cytolethal distending toxin (S-CDT) produced by NTS plays a significant role in the outcome of infection both in vitro and in vivo, highlighting S-CDT as an important virulence factor for nontyphoidal Salmonella serotypes
Del Bel Belluz et al showed that genetically engineered S-CDT-positive S. enterica subsp. enterica serotype Typhimurium persisted for a longer period of time in vivo than the S-CDT-negative parent strain did, which suggests that S-CDT alters the host-pathogen interaction in vivo, enabling S-CDT-positive Salmonella to persist in the host [13]
Summary
IMPORTANCE Nontyphoidal Salmonella (NTS) are a major cause of bacterial foodborne illness worldwide; our understanding of virulence mechanisms that determine the outcome and severity of nontyphoidal salmonellosis is incompletely understood. In vitro characterizations have shown that these S-CDT-positive NTS serotypes produce active toxin [6, 8, 9]. The majority of studies characterizing S-CDT activity have been performed using Salmonella serotype Typhi, which has several important genotypic and phenotypic differences from NTS serotypes [15,16,17]. Previous characterizations in vitro [3, 8, 9, 12, 18, 19], which were critical for asserting the activity of NTS S-CDT, were conducted using tumor-derived (cancerous) cell lines, which often have an altered DNA damage response [20]. Use of a nontransformed cell line is necessary to accurately reflect how infection with S-CDT-positive NTS impacts the cellular outcome of infection
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