Abstract
Typhoid toxin is a virulence factor for Salmonella Typhi and Paratyphi, the cause of typhoid fever in humans. This toxin has a unique architecture in that its pentameric B subunit, made of PltB, is linked to two enzymatic A subunits, the ADP ribosyl transferase PltA and the deoxyribonuclease CdtB. Typhoid toxin is uniquely adapted to humans, recognizing surface glycoprotein sialoglycans terminated in acetyl neuraminic acid, which are preferentially expressed by human cells. The transport pathway to its cellular targets followed by typhoid toxin after receptor binding is currently unknown. Through a genome-wide CRISPR/Cas9-mediated screen we have characterized the mechanisms by which typhoid toxin is transported within human cells. We found that typhoid toxin hijacks specific elements of the retrograde transport and endoplasmic reticulum-associated degradation machineries to reach its subcellular destination within target cells. Our study reveals unique and common features in the transport mechanisms of bacterial toxins that could serve as the bases for the development of novel anti-toxin therapeutic strategies.
Highlights
Typhoid toxin is a unique virulence factor for the typhoidal Salmonella enterica serovars Typhi and Paratyphi [1,2,3,4], the cause of typhoid fever in humans, a systemic disease that remains a major global public health concern [5,6,7,8,9]
Through a genome-wide screen, we found that typhoid toxin utilizes components of the retrograde transport cellular machinery to arrive to the endoplasmic reticulum, from where it is transported to the cell cytosol by the endoplasmic reticulum-associated degradation pathway
This study provides a detailed view of the transport mechanisms that deliver typhoid toxin from the cell surface to its destination within target cells, and identifies cellular components that are unique to the transport of this toxin as well as components that are exploited for the transport of other bacterial toxins, providing the foundation for the development of novel anti toxin strategies
Summary
Typhoid toxin is a unique virulence factor for the typhoidal Salmonella enterica serovars Typhi and Paratyphi [1,2,3,4], the cause of typhoid fever in humans, a systemic disease that remains a major global public health concern [5,6,7,8,9]. Typhoid toxin can target a variety of cells by engaging specific cell surface receptors [1]. The autocrine and paracrine pathways are the only mechanism by which the toxin can reach its targets after its interaction with cell surface receptors [2]. Typhi-infected cells potentially lacking receptors for the toxin would not be susceptible to intoxication they would be competent to harbor bacteria to produce it, a mechanistic feature that may be relevant for the toxin’s proposed role during persistent infection [13]
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