Bacillus anthracis Lethal Toxin (LT) is a determinant for deadly anthrax. Its function in myeloid cells is required for bacterial dissemination, and LT itself can directly cause dysfunction of the cardiovascular system. The interplay between LT and host responses is important for pathogenesis, yet our understanding of this interaction remains limited. Tumor necrosis factor-α (TNF-α) is a pleiotropic proinflammatory cytokine induced by bacterial infections. It drives cytokine production/survival or cell death and is therefore involved in many processes, including embryonic development and sepsis. It has been reported that LT sensitizes TNF-induced activation of the NLRP3 inflammasome (NACHT, LRR, and PYD domain-containing protein 3) and Caspase-8-dependent apoptosis in macrophages. Furthermore, TNF-activated apoptosis contributes to the lethal effects of anthrax toxins.
Recently, researchers from Yingying Zhang’s group attempted to further investigate the effect of TNF + LT treatment in vivo. They used simultaneous TNF + LT treatment in mice under in vivo conditions to mimic the function of LT in inflamed hosts. Using bone marrow transplants and genetically modified mice, they unexpectedly found that the death of intestinal epithelial cells (IECs), and not that of hematopoietic cells, led to LT + TNF-induced lethality, i.e., intestinal epithelial cells (IECs) were targets of LT-induced death in the presence of TNF, and resulting intestinal damage played a crucial role in mouse lethality.
Both necroptotic and apoptotic pathways were involved in the TNF + LT-induced IEC deaths and mouse deaths. Inhibition of p38α mitogen-activated protein kinase (MAPK) signaling by LT in IECs promoted TNF-induced apoptosis and necroptosis of IECs, leading to intestinal damage and mouse death. Consistently, inhibition of p38α by LT enhanced TNF-mediated cell death in human colonic epithelial HT-29 cells, supporting the role of p38α inactivation in anthrax pathology. Therefore, preventing TNF-induced apoptosis and necroptosis, combined with controlling bacterial proliferation, may be an effective prevention against anthrax-induced fatalities.
One conclusion from the data is that impairment of p38α, and potentially other MAPK signaling pathways, in IECs would naturally make animals susceptible to inflammation-induced tissue damage and animal deaths. Since intestinal damage is one of the most common causes of death in anthrax patients, LT + TNF-induced IEC damage is highly likely to be a mechanism underlying this clinical manifestation and could be a target for interventions.
Gao, X., et al. (2023). Anthrax Lethal Toxin and Tumor Necrosis Factor-α Act on Intestinal Epithelia Together and Induce Mouse Death. Protein & Cell. doi.org/10.1093/procel/pwad050.