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Structural And Functional Changes Of The Duodenum In Human Norovirus Infection
  1. Hanno Troeger (hanno.troeger{at}charite.de)
  1. Charite - Medical University Berlin, Germany
    1. Christoph Loddenkemper (christoph.loddenkemper{at}charite.de)
    1. Charite - Medical University Berlin, Germany
      1. Thomas Schneider (thomas.schneider{at}charite.de)
      1. Charite - Medical University Berlin, Germany
        1. Eckart Schreier (schreiere{at}rki.de)
        1. Robert Koch-Institut, Berlin, Germany
          1. Hans-Joerg Epple (hans-joerg.epple{at}charite.de)
          1. Charite - Medical University Berlin, Germany
            1. Martin Zeitz (martin.zeitz{at}charite.de)
            1. Charite - Medical University Berlin, Germany
              1. Michael Fromm (michael.fromm{at}charite.de)
              1. Charite - Medical University Berlin, Germany
                1. Joerg D Schulzke (joerg.schulzke{at}charite.de)
                1. Charite - Medical University Berlin, Germany

                  Abstract

                  Background: Norovirus infection is the most frequent cause of infectious diarrhea in the western world. This study aimed to functionally and structurally characterize the diseased duodenum in human biopsies.

                  Methods: Norovirus infection was diagnosed by the Kaplan-criteria and confirmed by PCR of stool samples. Duodenal biopsies were obtained endoscopically. In miniaturized Ussing chambers short circuit current, flux measurements and impedance spectroscopy was performed. Histological analysis including apoptosis staining and characterization of intraepithelial lymphocytes was performed. Tight junction proteins were quantified by immunoblotting.

                  Results: In norovirus infection epithelial resistance decreased from 24±2 Ω·cm2 in controls to 10±1 Ω·cm2. Mannitol flux increased from 113±24 in controls to 242±29 nmol·h-1·cm-2. Microdissection revealed a reduced villous surface area by 47±6.6%. Intraepithelial lymphocytes were increased to 63±7 per 100 enterocytes with an increased rate of perforin-positive cells. Expression of tight junctional proteins occludin, claudin-4 and claudin-5 was reduced. Epithelial apoptotic ratio was doubled in norovirus infection. Furthermore, basal short circuit current was increased in norovirus infection and could be reduced by bumetanide and NPPB.

                  Conclusions: Norovirus infection leads to epithelial barrier dysfunction paralleled by a reduction of sealing tight junctional proteins and an increase in epithelial apoptosis, which may partly be mediated by increased cytotoxic intraepithelial lymphocytes. Furthermore, active anion secretion is markedly stimulated. Thus, the diarrhea in norovirus infection is driven by both, a leak flux and a secretory component.

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