Biology subjects

Kanaya, T.

Publications and source records attributed to Kanaya, T..

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↗

bioRxiv2019

Attenuated Salmonella typhimurium cancer therapy has direct effects on the tumor epithelium in colorectal cancer

Bacterial cancer therapy (BCT) shows great promise for treatment of solid tumors, yet basic mechanisms of bacterial-induced tumor suppression remain undefined. The intestinal epithelium is the natural route of infection for Salmonella and thus harbors innate immune defenses which protect against infection. Attenuated strains of Salmonella enterica serovar Typhimurium (STm) have commonly been used in mouse models of BCT, largely with the use of xenograft and orthotopic transplant cancer models. We aimed to better understand the tumor epithelium-targeted mechanisms of BCT by using mouse models of intestinal tumorigenesis and tumor organoid cultures to assess the effectiveness and mechanisms of treatment with aromatase A-deficient STm (STm{Delta}aroA). STm{Delta}aroA delivered by oral gavage could significantly reduce tumor burden and tumor load in both a colitis-associated colon cancer model (CAC) and in a spontaneous intestinal cancer model, Apcmin/+ mice. STm{Delta}aroA colonization of tumors caused alterations in transcription of mRNAs associated with epithelial-mesenchymal transition as well as metabolic and cell cycle-related transcripts. Metabolomic analysis of tumors demonstrated alteration in the metabolic environment of STm{Delta}aroA-treated tumors, suggesting STm{Delta}aroA imposes metabolic competition on the tumor. Use of tumor organoid cultures in vitro demonstrated that STm{Delta}aroA can directly affect the tumor epithelium with alterations in transcripts and metabolites similar to in vivo-treated tumors. Thereby, we demonstrate that bacterial cancer therapy is efficacious in autochthonous intestinal cancer models, that BCT imposes metabolic competition, and that BCT has direct effects on the tumor epithelium, which have not previously been appreciated.\n\nOne Sentence SummaryAttenuated Salmonella enterica serovar Typhimurium can home to gastrointestinal tumors and directly affect the tumor epithelium, inducing transcriptional and metabolic changes that lead to reduced tumor burden in mice.

cancer biology↗

bioRxiv2018

Cellular polarity asymmetrically functionalizes pathogen recognition receptor-mediated intrinsic immune response in human intestinal epithelium cells

Intestinal epithelial cells (IECs) act as a physical barrier separating the commensal-containing intestinal tract from the sterile interior. These cells have found a complex balance allowing them to be prepared for pathogen attacks while still tolerating the presence of bacteria/viral stimuli present in the lumen of the gut. Using primary human IECs, we probed the mechanisms, which allow for such a tolerance. We discovered that viral infection emanating from the basolateral side of IECs elicited a stronger intrinsic immune response as compared to lumenal apical infection. We determined that this asymmetric immune response was driven by the clathrin-sorting adapter AP-1B which mediates the polarized sorting of Toll-like receptor 3 (TLR3) toward the basolateral side of IECs. Mice and human IECs lacking AP-1B showed an exacerbated immune response following apical stimulation. Together these results suggest a model where the cellular polarity program plays an integral role in the ability of IECs to partially tolerate apical commensals while remaining fully responsive against invasive basolateral pathogens.

immunology↗