Molecular mechanisms of shiga toxin-mediated cell death

The National Institute of Allergy and Infectious Diseases awarded the University of Connecticut Health Center $616,782 on August 17, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to support molecular mechanisms research on Shiga toxin-mediated cell death.

The funded research investigates how Shiga toxin produced by enterohemorrhagic Escherichia coli kills human cells through apoptotic, pyroptotic, or necroptotic pathways. The work aims to characterize the intracellular signaling mechanisms underlying toxin-induced cell death and downstream inflammatory responses, with potential applications toward identifying new therapeutic targets for hemolytic uremic syndrome and other Shiga toxin diseases. Antibiotics are ineffective for toxin-mediated disease, creating a critical need for alternative treatments that mechanistic understanding of cell death pathways may reveal.

Performance occurs in Farmington, Connecticut. The award period runs from August 17, 2026, through July 31, 2027.

Abstract

Bacterial exotoxins encompass one of the most prominent and well-characterized microbial virulence factors. Exotoxins efficiently target the host cells and exert damage via a variety of potent mechanisms including damaging the host cell membrane and modifying key cellular enzymes. Toxin- mediated damage alone is sufficient to cause disease in several bacterial infections. One major mechanism of exotoxin damage is the direct killing of cells that are susceptible to the toxin primarily due to the expression of toxin receptor on the cell surface. Depending on the intracellular signaling pathways activated by its biological activity, the toxin can induce apoptotic, pyroptotic, or necroptotic cell death. Apoptosis is a relatively less inflammatory form of cell death whereas pyroptosis, the lytic form of cell death, can lead to release of alarmins into the surrounding environment leading to exaggerated inflammation. Consequently, the nature of toxin-induced cell death is a key determinant of the outcome of a bacterial toxin-mediated disease. Therefore, an in-depth understanding of the molecular signaling pathways driving the toxin-mediated cell death, the exact type of cell death, and the downstream effector responses is critical for gaining insights into the mechanisms of bacterial diseases. However, these mechanisms are poorly characterized for several bacterial toxins. One such toxin is shiga toxin (STX), a cytotoxin produced by enterohemorrhagic escherichia coli (ehec), that causes severe intestinal damage and a life-threatening kidney disease, hemolytic uremic syndrome (HUS). Antibiotics are not advised as a treatment for STX disease and there is a critical need for new treatments for HUS. Understanding the mechanisms by which STX kills human cells may reveal new therapeutic targets. IT is well established that during ehec infection, STX enters systemic circulation, interacts with multiple cell types and kills cells expressing STX receptor, GB3, via protein synthesis inhibition and ribotoxic stress response. However, how STX-induced ribotoxic stress response results in cell death, the molecules that control this cell death, and the exact nature of STX-mediated cells death are not known. The studies proposed in three specific aims of this proposal employing multiple STX-sensitive human cells as well as 3D human intestine and mouse infection models will systematically characterize the signaling events triggered by shiga toxin leading to cell death, the precise nature of cell death, and the effector responses initiated by STX-induced cell death that may influence the course of ehec disease. The findings from this study will provide critical insights into the mechanisms underlying the extensive host tissue damage observed in a clinically relevant bacterial infection.