The Bacterial Toxin CNF1 Induces Activation and Maturation of Human Monocyte-Derived Dendritic Cells

Abstract

Cytotoxic necrotizing factor 1 (CNF1) is a bacterial protein toxin primarily expressed by pathogenic Escherichia coli strains, causing extraintestinal infections. The toxin is believed to enhance the invasiveness of E. coli by modulating the activity of Rho GTPases in host cells, but it has interestingly also been shown to promote inflammation, stimulate host immunity and function as a potent immunoadjuvant. The mechanisms underlying the immunostimulatory properties of CNF1 are, however, poorly characterized, and little is known about the direct effects of the toxin on immune cells. Here, we show that CNF1 induces expression of maturation markers on human immature monocyte-derived dendritic cells (moDCs) without compromising cell viability. Consistent with the phenotypic maturation, CNF1 further triggered secretion of proinflammatory cytokines and increased the capacity of moDCs to stimulate proliferation of allogenic naïve CD4+ T cells. A catalytically inactive form of the toxin did not induce moDC maturation, indicating that the enzymatic activity of CNF1 triggers immature moDCs to undergo phenotypic and functional maturation. As the maturation of dendritic cells plays a central role in initiating inflammation and activating the adaptive immune response, the present findings shed new light on the immunostimulatory properties of CNF1 and may explain why the toxin functions as an immunoadjuvant.

RNA-Dependent Regulation of Virulence in Pathogenic Bacteria

“…One major function of bacterial toxicity is to kill surveilling immune cells such as neutrophils (do Vale et al, 2016). While this is an immune-evading mechanism employed by pathogenic bacteria, the proteins constituting these toxins and their delivery conduits are highly immunostimulatory (Miao et al, 2010; Gall-Mas et al, 2018). Additionally, toxin expression and secretion are energy intensive (Lee and Rietsch, 2015; Joo et al, 2016).…”

Fatal Necrotising Soft Tissue Infection Caused by Escherichia coli in Alcoholic Liver Cirrhosis

“…The virulence factors suspected of having an association with skin and soft tissue infection were cytotoxic necrotising factor 1 and hemolysin (4,14). These toxins were both positive in this patient, and were reported in other cases to trigger inflammation during infection (15,16) as a result of interactions with neutrophils and monocyte-derived dendritic cells. The patient in this case had a weakened immune system caused by liver cirrhosis, which may have altered the appropriate immune response to interaction with these toxins.…”

Activation of Focal Adhesion Kinase Restores Simulated Microgravity-Induced Inhibition of Osteoblast Differentiation via Wnt/Β-Catenin Pathway

“…The control cells were placed in the incubator under 1-g conditions. CNF1 has been extensively used to treat mammalian cells in cell cultures at concentrations ranging between 10 and 100 ng/mL for measurement of CNF1’s effect on molecular pathway modulations [ 54 , 55 , 56 ]. To assess conversional effect of CNF1 on SMG, we chose to add an intermediate dose of CNF1 (30 ng/mL) to the above MC3T3-E1 cells cultured under SMG, as we previously described [ 16 , 17 ].…”