Abstract
Shiga toxin-producing Escherichia coli (STEC) causes hemorrhagic colitis, hemolytic uremic syndrome, and acute encephalopathies that may lead to sudden death or severe neurologic sequelae. Current treatments, including immunoglobulin G (IgG) immunoadsorption, plasma exchange, steroid pulse therapy, and the monoclonal antibody eculizumab, have limited effects against the severe neurologic sequelae. Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative non-tumorigenic stem cells that naturally reside in the body and are currently under clinical trials for regenerative medicine. When administered intravenously, Musecells accumulate to the damaged tissue, where they exert anti-inflammatory, anti-apoptotic, anti-fibrotic, and immunomodulatory effects, and replace damaged cells by differentiating into tissue-constituent cells. Here, severely immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD-SCID) mice orally inoculated with 9 × 109 colony-forming units of STEC O111 and treated 48 h later with intravenous injection of 5 × 104 Muse cells exhibited 100% survival and no severe after-effects of infection. Suppression of granulocyte-colony-stimulating factor (G-CSF) by RNAi abolished the beneficial effects of Muse cells, leading to a 40% death and significant body weight loss, suggesting the involvement of G-CSF in the beneficial effects of Muse cells in STEC-infected mice. Thus, intravenous administration of Muse cells could be a candidate therapeutic approach for preventing fatal encephalopathy after STEC infection.
Highlights
Shiga toxin-producing Escherichia coli (STEC) is a causative agent of hemorrhagic diarrhea, hemolytic uremic syndrome (HUS), and acute encephalopathies, which occasionally lead to sudden death.[1]
All of the mice infected with O157-Sakai and O157 Tokyo survived for 2 weeks, whereas 60% of ICR mice infected with O111 survived for 2 weeks
None of the NOD-SCID mice injected with 1 Â 109 colony-forming unit (CFU) of E32511 and O111 died (100% survival; data not shown), whereas all mice inoculated with 1 Â 1010 CFU E32511 and O111 died within 108 h (Figure S1C)
Summary
Shiga toxin-producing Escherichia coli (STEC) is a causative agent of hemorrhagic diarrhea, hemolytic uremic syndrome (HUS), and acute encephalopathies, which occasionally lead to sudden death.[1] Infected individuals may develop serious neurologic complications, including apnea, seizures, coma, cortical blindness, hemiparesis, and loss of consciousness. The main Shiga toxins (Stxs) produced by STEC, Stx1a and Stx2a, comprise one A and five B subunit proteins.[3] The Stxs-B subunit binds with high affinity to globotriaosylceramide Gb3 (CD77) on the plasma membrane of some eukaryotic cells,[4] which is upregulated by lipopolysaccharide (LPS), tumor necrosis factor-a, and interleukin-1b.5,6. The Stxs-B subunit is retrogradely transported from the cell membrane to the endoplasmic reticulum (ER), and only the Stxs-A subunit enters the cytosol.[7] The Stxs-A subunit removes
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