Authors: Celeste Brady, Future Science Group
Researchers at the University of Toronto (Canada) have published a study in Cell revealing the receptor for the bacterial toxin produced by Paeniclostridium sordellii, which causes toxic shock syndrome. Through comparing its receptor binding activity with that of Clostridium difficile toxins, the researchers have discovered a mechanism by which pathogen activity can evolve to infect different organs.
P. sordellii lives in the gut and the female reproductive tract and can cause serious or even fatal disease if it enters the bloodstream and reaches the lungs. The closely related C. difficile resides in the gut and can cause diarrhea, and its toxin binds to the cell surface receptor Frizzled, which is active in tissue regeneration. Although the toxins released by the two bacteria are very similar in structure, the P. sordellii toxin does not bind to Frizzled: its action was previously unknown.
The researchers systematically switched off genes in human cells to determine which receptor was targeted by the P. sordellii toxin. Cells that survived exposure to the toxin lacked cell surface receptors of the semaphorin class, specifically Semaphorin6A and Semaphorin6B.
The paper, which provides a novel understanding of the action of the P. sordellii toxin, could lead the way to finding new treatments for toxic shock syndrome. The researchers found that injections of semaphorin fragments successfully neutralized the toxin in mice, preventing their interaction with the cell surface receptors.
Semaphorin6A and Semaphorin6B are present in the lungs. Although their specific actions are unknown, this class of receptors plays an important role in the developing nervous system by guiding nerve fiber growth. Surprisingly, despite the similarity of their substrates, semaphorins bear no structural resemblance to Frizzled. “Here we have two toxins that are so similar to each other, but they use completely different receptors,” noted Mikko Taipale (University of Toronto), co-lead author of the study. “We did not expect to find that.”
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Using cryo electron microscopy, the researchers discovered that the crucial difference between the proteins lies in the center of their structures, where they bind to their receptors. The team was able to swap the binding affinities of the two toxins by altering only 15 amino acids.
“We were floored when we saw that the toxins shared a surface each evolved to uniquely interact with distinct cells,” commented Jean-Philippe Julien (University of Toronto), another co-first author of the study.
The diverse action of two highly similar toxins is an important adaptation in many pathogens. Evolutionarily stable components are highly preserved while small changes allow the infectious agent to target new receptors and tissues.
“This is a nice example of how viruses and bacteria – from completely different domains of life – have found similar molecular tactics to change their receptor targets in human cells,” Taipale highlighted.
Sources: Lee H, Beilhartz GL, Kucharska I et al., Recognition of Semaphorin Proteins by P. sordellii Lethal Toxin Reveals Principles of Receptor Specificity in Clostridial Toxins. Cell doi:10.1016/j.cell.2020.06.005; www.eurekalert.org/pub_releases/2020-06/uot-wbt062220.php