Biology subjects

Morimoto, C.

Publications and source records attributed to Morimoto, C..

3 recordsLinked to original sources

bioRxiv2026

LRP1 is an entry receptor for the botulinum toxin complex in the gut

Botulinum neurotoxin (BoNT) is an etiologic agent of food poisoning caused by Clostridium botulinum. The large progenitor toxin complex (L-PTC) crosses the intestinal epithelial barrier to deliver BoNT to target neurons; however, it is not clearly understood how BoNT enters the host. Here, we identified low-density lipoprotein receptor-related protein 1 (LRP1) as a major enterocyte transcytosis receptor for the hyper-oral-toxic L-PTC serotype B-Okra (L-PTC/BOkra). We found that hemagglutinin (HA), a neurotoxin-associated protein within the L-PTC/BOkra complex, binds to LRP1 via N-glycans. HA/BOkra co-localized with LRP1 within the internalized vesicles in cultured cells and enterocytes. LRP1 deletion inhibited the apical-to-basal transcytosis of L-PTC/BOkra in an intestinal epithelial cell line, and this effect was rescued by LRP1 re-expression. Finally, intestinal epithelial cell-specific LRP1-deficient mice displayed reduced susceptibility to toxicity caused by oral administration of L-PTC/BOkra. Taken together, these results indicate that N-glycosylated LRP1 mediates L-PTC/BOkra transcytosis via enterocytes, enabling BoNT to traverse the intestinal epithelial barrier.

microbiology↗

bioRxiv2025

Gut mucin fucosylation dictates the entry of botulinum toxin complexes

Botulinum toxins (BoNTs) are the most potent known bacterial toxins. The BoNT complex from Clostridium botulinum B-Okra (large progenitor toxin complex (L-PTC)/BOkra, hyper-oral-toxic) exerts at least 80-fold higher oral toxicity1 in mice compared with that from serotype A1 (L-PTC/A62A, non-hyper-oral-toxic). Here, we showed that L-PTC/BOkra was predominantly absorbed through enterocytes, whereas L-PTC/A62A targeted intestinal microfold cells. Furthermore, we demonstrated that 1,2-fucosylation of intestinal mucin determined the oral toxicity of L-PTCs as well as their entry routes; more specifically, these routes were governed by the carbohydrate-binding spectrum of hemagglutinin (HA) complex, which is one of the L-PTC components. Disruption of fucosylation in fucosyltrasferase-2 (Fut2)-null mice hindered the intestinal mucin penetration of L-PTC/BOkra via HA and reduced the susceptibility to its oral intoxication. Our data establish the molecular mechanism by which the oral toxicity of BoNTs is increased after they cross intestinal mucus layers.

microbiology↗

bioRxiv2024

Identification of a Highly Functional Effector CD8+ T Cell Program After Transplantation in Mice and Humans

T cell mediated allograft rejection leads to early graft loss for kidney transplant patients. To better understand the mechanism by which T cells mediate rejection, we investigated the fate and function of graft-specific CD8+ T cells expressing the activated isoform of CD43 in mice and humans. Agonism of CD43 1B11 in vitro induced CD8+ T cell proliferation in the presence of sub-threshold antigen stimulation, and CD43 1B11 mAb treatment in vivo overcame costimulation-blockade induced tolerance to skin grafts. Relative to CD43 1B11- populations, CD43 1B11+ CD8+ T cells maintained high T-bet expression along with stem-like molecules IL-7R and TCF-1 at both effector and memory timepoints, and were more persistent following adoptive transfer. In kidney transplant patients, graft-infiltrating CD8+ T cells that expressed CD43 and the glycosyltransferase GCNT1 had an effector phenotype that includes high expression of IFNG, ICOS, and perforins/granzymes. In healthy human donors and transplant candidates, the CD43 1D4 mAb clone defined antigen-experienced cytokine-producing CD8+ T cells. In sum, these data support a progressive differentiation model by which highly proliferative effector CD43 1B11+ CD8+ T cells infiltrate allografts also efficiently persist into memory after antigen clearance.

immunology↗