Salmonella Typhoid Toxin PltB Subunit and Its Non-typhoidal Salmonella Ortholog Confer Differential Host Adaptation and Virulence

Abstract

Typhoidal and non-typhoidal Salmonelleae (NTS) cause typhoid fever and gastroenteritis, respectively, in humans. Salmonella typhoid toxin contributes to typhoid disease progression and chronic infection, but little is known about the role of its NTS ortholog. We found that typhoid toxin and its NTS ortholog induce different clinical presentations. The PltB subunit of each toxin exhibits different glycan-binding preferences that correlate with glycan expression profiles of host cells targeted by each bacterium at the primary infection or intoxication sites. Through co-crystal structures of PltB subunits bound to specific glycan receptor moieties, we show that they induce markedly different glycan-binding preferences and virulence outcomes. Furthermore, immunization with the NTS S. Javiana or its toxin offers cross-reactive protection against lethal-dose typhoid toxin challenge. Cumulatively, these results offer insights into the evolution of host adaptations in Salmonella AB toxins, their cell and tissue tropisms, and the design for improved typhoid vaccines and therapeutics.

The Majority of Typhoid Toxin-Positive Salmonella Serovars Encode ArtB, an Alternate Binding Subunit

“…While PltB has been reported to preferentially bind Neu5Ac-terminated glycans ( 26 ), ArtB can bind both Neu5Ac- and Neu5Gc-terminated glycans ( 26 ), suggesting that PltB and ArtB allow TT to bind to different cell types. Furthermore, Lee et al recently established that specific amino acid residues in PltB produced by S. Javiana (called Javiana toxin in that study) were associated with toxin binding to intestinal epithelial cells but not to endothelial cells of brain arterioles ( 45 ), therefore supporting the idea that PltB produced by S. Typhi and S. Javiana may have evolved to enable binding to different tissues. Given that single amino acid changes have been found to significantly dampen binding affinity to cell surface glycans ( 45 ), collectively, this suggests that encoding two different subunits may provide an evolutionary advantage, as it likely enables TT-positive Salmonella to affect a wider range of cell types, tissues, and possibly hosts.…”

“…Furthermore, Lee et al recently established that specific amino acid residues in PltB produced by S. Javiana (called Javiana toxin in that study) were associated with toxin binding to intestinal epithelial cells but not to endothelial cells of brain arterioles ( 45 ), therefore supporting the idea that PltB produced by S. Typhi and S. Javiana may have evolved to enable binding to different tissues. Given that single amino acid changes have been found to significantly dampen binding affinity to cell surface glycans ( 45 ), collectively, this suggests that encoding two different subunits may provide an evolutionary advantage, as it likely enables TT-positive Salmonella to affect a wider range of cell types, tissues, and possibly hosts. Therefore, future studies examining the sequence variants of ArtB and PltB among a broader range of Salmonella serovars, as well as the binding affinities for these variants for a panel of different cells representing different tissues and hosts, will provide a more complete picture of the potential role of the TT binding subunit in facilitating tissue and or host tropism.…”

Enteric Fever Diagnosis: Current Challenges and Future Directions

“…Similarly, type IVb pilus has a role in the invasion of human cells [ 120 ]. In the case of noninvasive NTS, these interactions lead to the activation of proinflammatory responses localized in the intestine, with the consequence of rapid onset of diarrhea within 12–72 h. However, typhoidal salmonellae typically do not trigger a proinflammatory response [ 121 ], where Vi CPS and the typhoid toxin play a role in inhibiting host immune responses by hindering the PAMPs, such as LPS O-antigen, and altering recruited immune cell function and/or depleting those cells, respectively [ 108 , 118 , 122 , 123 , 124 ]. The absence of profound inflammatory responses in infection with typhoidal Salmonella is also likely associated with only a transient presence in the circulation while maintaining its intracellular lifecycle in the reticuloendothelial system for most of its infectious cycle [ 118 , 125 ].…”

“…IgM-CdtB has also been detected but at a lower level using standard ELISA methods [ 151 ]. While typhoid toxin orthologs are encoded in the genomes of some NTS serovars, their target host cells are intestinal epithelial cells that produce different clinical presentations [ 123 ]. Amino acid sequence variations on glycan receptor binding pockets of typhoid toxin orthologs are responsible for a narrow host cell tropism [ 123 ].…”

“…While typhoid toxin orthologs are encoded in the genomes of some NTS serovars, their target host cells are intestinal epithelial cells that produce different clinical presentations [ 123 ]. Amino acid sequence variations on glycan receptor binding pockets of typhoid toxin orthologs are responsible for a narrow host cell tropism [ 123 ]. To make this biomarker a more reliable diagnostic method, some changes should be made to improve the detection limit and/or use it as part of signatures that can be combined with other biomarkers, such as Vi polysaccharides [ 152 ], LPS, and other membrane components [ 142 ].…”