Research Article: Vibrio cholerae Evades Neutrophil Extracellular Traps by the Activity of Two Extracellular Nucleases

Date Published: September 5, 2013

Publisher: Public Library of Science

Author(s): Andrea Seper, Ava Hosseinzadeh, Gregor Gorkiewicz, Sabine Lichtenegger, Sandro Roier, Deborah R. Leitner, Marc Röhm, Andreas Grutsch, Joachim Reidl, Constantin F. Urban, Stefan Schild, Arturo Zychlinsky.


The Gram negative bacterium Vibrio cholerae is the causative agent of the secretory diarrheal disease cholera, which has traditionally been classified as a noninflammatory disease. However, several recent reports suggest that a V. cholerae infection induces an inflammatory response in the gastrointestinal tract indicated by recruitment of innate immune cells and increase of inflammatory cytokines. In this study, we describe a colonization defect of a double extracellular nuclease V. cholerae mutant in immunocompetent mice, which is not evident in neutropenic mice. Intrigued by this observation, we investigated the impact of neutrophils, as a central part of the innate immune system, on the pathogen V. cholerae in more detail. Our results demonstrate that V. cholerae induces formation of neutrophil extracellular traps (NETs) upon contact with neutrophils, while V. cholerae in return induces the two extracellular nucleases upon presence of NETs. We show that the V. cholerae wild type rapidly degrades the DNA component of the NETs by the combined activity of the two extracellular nucleases Dns and Xds. In contrast, NETs exhibit prolonged stability in presence of the double nuclease mutant. Finally, we demonstrate that Dns and Xds mediate evasion of V. cholerae from NETs and lower the susceptibility for extracellular killing in the presence of NETs. This report provides a first comprehensive characterization of the interplay between neutrophils and V. cholerae along with new evidence that the innate immune response impacts the colonization of V. cholerae in vivo. A limitation of this study is an inability for technical and physiological reasons to visualize intact NETs in the intestinal lumen of infected mice, but we can hypothesize that extracellular nuclease production by V. cholerae may enhance survival fitness of the pathogen through NET degradation.

Partial Text

The Gram negative facultative human pathogen Vibrio cholerae is the causative agent of cholera, which is defined as an acute, secretory diarrheal disease. Today, the global burden of cholera is estimated to reach several million cases per year, with the majority located in the endemic areas of Africa and Asia [1]. However, explosive outbreaks facilitated by natural disasters, high population density and poor sanitation can occur worldwide as recently demonstrated by the cholera epidemic in Haiti, where cholera cases have not been reported before 2010 [2].

Until now, only little attention has been drawn to the innate immune response during a V. cholerae infection. Naturally, the overall inflammatory response to V. cholerae colonization is moderate compared to that seen during infections with enteroinvasive bacterial pathogens, e.g. Yersinia enterocolitica or Salmonella enterica, which are capable of penetrating the gut epithelium of the host and cause systemic infection [50], [51]. However, emerging evidence by the recent literature indicates a substantial inflammatory response during cholera infection, which is marked by an induction of inflammatory cytokines as well as by recruitment of innate immune cells to the site of infection [10]–[12]. In agreement with these reports, we also observed a significant upregulation of inflammatory markers as well as infiltration of neutrophils into the murine gastrointestinal tract upon colonization with V. cholerae.




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