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Escherichia coli is a major constituent of the gut microbiota of mammals. Despite this frequent symbiosis, some strains of E. coli are pathogenic. According to the World Health Organization (WHO), foodborne Shiga toxin-producing Escherichia coli (STEC) caused more than 1,000,000 illnesses, leading to more than 100 deaths and approximately 13,000 disability-adjusted life years (DALYs) in 2020. Shiga toxins (Stxs) are primary virulence factors produced by Stx-producing Escherichia coli (STEC). Stxs are multi-functional ribosome-inactivating proteins primarily responsible for developing the hemolytic uremic syndrome (HUS) and central nervous system (CNS) impairment. Current therapeutic options for diseases caused by Stxs are few, including peritoneal dialysis. However, the precise reasons for dialysis of the peritoneum to treat HUS are unknown. It has become increasingly apparent that Stx-activated immune cells release increased amounts of biologically active molecules that function as paracrine factors and may exacerbate adverse effects on primary target organs. Besides, it has been shown that Stx induces phosphorylation of GSK-3β, which accelerates the biogenesis of Wnts and may lead to paracrine effects of neighboring cells. Wnts are highly-conserved lipid-modified secreted proteins that regulate the tight junction of recipient cells. Wnts are highly-conserved lipid-modified secreted proteins that regulate the tight junction of recipient cells. Here, we identify Stx-activated peritoneal immune cells that produce Wnt along with elevated levels of calcium, which disrupts the tight junction of the kidney, leading to exacerbating the lethality in a host. Notably, we observed that the depletion of Wnt-producing peritoneal macrophage/B cells ameliorates the development of HUS in vivo. Given the capacity of Stxs to subvert the tight- junction of the target organ in a host by Wnt, inhibition of Wnt production successfully ameliorates the pathogenesis of HUS.
Acknowledgment: This work was supported by the KRIBB Research Initiative Program (KGM9942213, KGM5322214) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI23C0041) and also by the Basic Science Research Program through the National Research Foundation of Korea (NRF) (2022R1A2C1003699)
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| Keywords | Escherichia coli,Shiga toxins, GSK-3β, Wnt |
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