Role of the Alteration in Calcium Homeostasis in Cell Death Induced by Clostridioides difficile Toxin A and Toxin B

SIMPLE SUMMARY: Clostridioides difficile (C. difficile) infections represent a major health risk and a high cost to health-care systems. C. difficile causes pathogenic activity in the colon through the production of two toxins, A and B, which provoke cell death. Several studies conducted on the mechanisms by which these two toxins induce various types of cell death in the intestinal mucosa cells and in the immune system cells failed to identify a common basic event. Since calcium is an important regulator of cellular physiology, here we propose a new point of view in which the alteration in physiological intracellular calcium levels by the two toxins may be the key common event responsible for the activation of cell death. Further exploration of this issue with in vivo studies could be important for possible pharmacological interventions aimed at antagonizing the Ca(2+) homeostasis alterations that could tone down the C. difficile pathogenicity until specific antibiotic therapy has brought the infection under control. ABSTRACT: Clostridioides difficile (C. difficile), responsible for 15–25% of gastrointestinal infections, causes health problems mainly due to the toxic activity of toxins A and B (Tcds). These are responsible for its clinical manifestations, including diarrhea, pseudomembranous colitis, toxic megacolon and death, with a mortality of 5–30% in primary infection, that increase following relapses. Studies on Tcd-induced cell death have highlighted a key role of caspases, calpains, and cathepsins, with involvement of mitochondria and reactive oxygen species (ROS) in a complex signaling pathway network. The complex response in the execution of various types of cell death (apoptosis, necrosis, pyroptosis and pyknosis) depends on the amount of Tcd, cell types, and Tcd receptors involved, and could have as initial/precocious event the alterations in calcium homeostasis. The entities, peculiarities and cell types involved in these alterations will decide the signaling pathways activated and cell death type. Calcium homeostasis alterations can be caused by calcium influx through calcium channel activation, transient intracellular calcium oscillations, and leakage of calcium from intracellular stores. These increases in cytoplasmic calcium have important effects on all calcium-regulated molecules, which may play a direct role in several cell death types and/or activate other cell death effectors, such as caspases, calpains, ROS and proapoptotic Bcl-2 family members. Furthermore, some support for the possible role of the calcium homeostasis alteration in Tcd-induced cell death originates from the similarity with cytotoxic effects that cause pore-forming toxins, based mainly on calcium influx through plasma membrane pores.