Browsing by keyword "AE"
Now showing items 1-2 of 2
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Attaching-and-Effacing Pathogens Exploit Junction Regulatory Activities of N-WASP and SNX9 to Disrupt the Intestinal BarrierBackground and Aims: Neural Wiskott-Aldrich Syndrome protein (N-WASP) is a key regulator of the actin cytoskeleton in epithelial tissues and is poised to mediate cytoskeletal-dependent aspects of apical junction complex (AJC) homeostasis. Attaching-and-effacing (AE) pathogens disrupt this homeostasis through translocation of the effector molecule early secreted antigenic target-6 (ESX)-1 secretion-associated protein F (EspF). Although the mechanisms underlying AJC disruption by EspF are unknown, EspF contains putative binding sites for N-WASP and the endocytic regulator sorting nexin 9 (SNX9). We hypothesized that N-WASP regulates AJC integrity and AE pathogens use EspF to induce junction disassembly through an N-WASP- and SNX9-dependent pathway. Methods: We analyzed mice with intestine-specific N-WASP deletion and generated cell lines with N-WASP and SNX9 depletion for dynamic functional assays. We generated EPEC and Citrobacter rodentium strains complemented with EspF bearing point mutations abolishing N-WASP and SNX9 binding to investigate the requirement for these interactions. Results: Mice lacking N-WASP in the intestinal epithelium showed spontaneously increased permeability, abnormal AJC morphology, and mislocalization of occludin. N-WASP depletion in epithelial cell lines led to impaired assembly and disassembly of tight junctions in response to changes in extracellular calcium. Cells lacking N-WASP or SNX9 supported actin pedestals and type III secretion, but were resistant to EPEC-induced AJC disassembly and loss of transepithelial resistance. We found that during in vivo infection with AE pathogens, EspF must bind both N-WASP and SNX9 to disrupt AJCs and induce intestinal barrier dysfunction. Conclusions: Overall, these studies show that N-WASP critically regulates AJC homeostasis, and the AE pathogen effector EspF specifically exploits both N-WASP and SNX9 to disrupt intestinal barrier integrity during infection.
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National Institutes of Health Pathways to Prevention Workshop: Physical Activity and Health for Wheelchair UsersHealth benefits of physical activity are well recognized in the general population for reducing the risk of chronic health conditions. Less is known about the effects of physical activity on people currently using or who may use wheeled mobility devices in the future, specifically individuals with multiple sclerosis, cerebral palsy, and spinal cord injury who are at increased likelihood for use of a wheeled mobility device. On December 1-3, 2020, the National Institutes of Health convened the Pathways to Prevention workshop: "Can Physical Activity Improve the Health of Wheelchair Users?" to consider the available scientific evidence on the clinical benefits and harms of physical activity for people currently using or who may use wheeled mobility devices in the future, with the aim of developing recommendations to fill gaps in the evidence base. A multidisciplinary team of content area experts developed the agenda and an evidence-based practice center prepared the evidence report. An independent panel, selected by the National Institutes of Health, attended the workshop; convened to develop recommendations on the basis of the systematic review, presentations, and public comments received during the workshop; and revised recommendations based on public comments received. This final report summarizes the panel's findings and identifies current gaps in knowledge. The panel made recommendations for new research efforts, including novel methods and new research infrastructure to improve the evidence base about the effects of physical activity on people currently using or who may use wheeled mobility devices in the future.
