Neutrophil-mediated inflammation in the pathogenesis of Clostridium difficile infections

Abstract

Clostridium difficile is the most important cause of nosocomial infectious diarrhea in the western world. C. difficile infections are a major healthcare burden with approximately 500,000 new cases every year and an estimated annual cost of nearly $1 billion in the U.S. Furthermore, the infections are no longer restricted to health care facilities, and recent studies indicate spread of C. difficile infection to the community as well. The clinical spectrum of C. difficile infection ranges from asymptomatic colonization to severe diarrhea, fulminant colitis and death. This spectrum results from a complex interplay between bacterial virulence factors, the colonic microbiome and the host inflammatory response. The overall vigor of host inflammatory response is believed to be an important determinant of C. difficile disease severity, and a more robust immune response is associated with worse outcomes. Neutrophils are the primary cells that respond to C. difficile invasion and neutrophilic inflammation is the hallmark of C. difficile-associated disease. In this review, we will focus on the role of neutrophils (infiltration to infected tissue, pathogen clearance and resolution of inflammation) in the immuno-pathogenesis of C. difficile-associated disease (CDAD).

The alternative sigma factor σB plays a crucial role in adaptive strategies of Clostridium difficile during gut infection

“…In the course of infection, C. difficile produces two toxins TcdA and TcdB that alter the enterocyte cytoskeleton, thereby inducing intestinal-cell lysis and inflammation (Abt et al, 2016;Janoir, 2016). Indeed, the death of the epithelial cells triggers secretion of multiple factors stimulating major recruitment of neutrophils, which leads to an intensive local inflammatory reaction (Abt et al, 2016;Jose and Madan, 2016). During the inflammation process, ROS including hydrogen peroxide (H 2 O 2 ) and O 2 2 as well as NO and its derivative reactive species (RNS) are produced at bactericidal concentrations by the host immune cells.…”

“…During inflammation, aside from NO and RNS, ROS are also produced by the host immune cells (Abt et al, 2016;Jose and Madan, 2016). Thus, we also wondered whether Fig.…”

“…Next, toxigenic strains of C. difficile produce two toxins, TcdA and TcdB, which are the major virulence factors. These toxins cause alteration of the actin cytoskeleton of intestinal epithelial cells and lead to major neutrophil recruitment favouring an intensive local inflammatory process (Peniche et al, 2013;Jose and Madan, 2016). Some C. difficile strains also produce an ADP-ribosylating binary toxin (Janoir, 2016).…”

“…After germination, vegetative cells encounter different stresses such as pH variations and hyperosmolarity and are exposed to bile acids, to antibiotics, or to cationic antimicrobial peptides (CAMPs) produced by the host and/or by the microbiota (Abt et al, 2016). Moreover, during infection, C. difficile produces several factors (e.g., toxins, Slayer proteins and flagellin) that trigger inflammation leading to the production of several antimicrobial compounds by the host immune system, e.g., reactive oxygen species (ROS), nitric oxide (NO) and reactive nitrogen species (RNS) (Abt et al, 2016;Jose and Madan, 2016). Thus, to adapt to and survive the exposure to these stresses within the host, C. difficile must induce protection, detoxification and repair pathways as well as regulatory networks sensing these stressful stimuli.…”

The σB signalling activation pathway in the enteropathogen Clostridioides difficile

“…The toxigenic strains of C. difficile produce two toxins, TcdA and TcdB, which are the major virulence factors required for the development of symptoms. These toxins cause the alteration of actin cytoskeleton in intestinal epithelial cells that leads to a major neutrophil recruitment favouring an intensive local inflammation process (Peniche et al, , Jose and Madan, ). Although toxins are regarded as primary virulence factors, the establishment of C. difficile in its colonic niche is also dependent on additional virulence factors such as the adhesin Cwp66, the flagellum, the fibronectin‐binding protein FbpA and the surface layer precursor protein SlpA (Janoir, ).…”