Biology subjects

Marsman, G.

Publications and source records attributed to Marsman, G..

3 recordsLinked to original sources

bioRxiv2025

The DanRI regulatory system in uropathogenic Escherichia coli subverts neutrophil responses

Uropathogenic Escherichia coli (UPEC) is the primary cause of urinary tract infections (UTI). To establish an infection, UPEC must evade infiltrating neutrophils and their antimicrobial neutrophil extracellular traps (NETs). In this study, we identify a previously uncharacterized two-gene regulatory system within the pathogenicity island PAIUTI89II, which we named DanRI (Defense against neutrophil Regulator and Inhibitor). DanRI is induced by nucleosomes present in NETs and enables UPEC to suppress neutrophil responses by attenuating reactive oxygen species production and NET formation. Mechanistically, DanI functions as an antagonist to the transcriptional regulator DanR, thereby modulating key bacterial processes, including metabolic processes, flagellar biosynthesis, and stress response pathways. DanRI is required for UPEC fitness and long-term persistence in a mouse model of UTI. Taken together, our findings reveal DanRI as a novel regulatory system that promotes UPEC pathogenesis through immune evasion. Graphical abstract and model O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/658900v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@19095e6org.highwire.dtl.DTLVardef@1613c26org.highwire.dtl.DTLVardef@b415c3org.highwire.dtl.DTLVardef@100b79e_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

Galectin-9 has non-apoptotic cytotoxic activity towards Acute Myeloid Leukemia independent of cytarabine resistance

Acute myeloid leukemia (AML) is a malignancy still associated with poor survival rates, among others due to frequent occurrence of therapy-resistant relapse after standard-of-care treatment with cytarabine (AraC). AraC triggers apoptotic cell death, a type of cell death to which AML cells often become resistant. Therefore, therapeutic options that trigger an alternate type of cell death are of particular interest. We previously identified that the glycan-binding protein Galectin-9 (Gal-9) has tumor-selective and non-apoptotic cytotoxicity towards various types of cancer, which depended on autophagy inhibition. Thus, Gal-9 could be of therapeutic interest for (AraC-resistant) AML. In the current study, treatment with Gal-9 was cytotoxic for AML cells, including for CD34+ patient-derived AML stem cells, but not for healthy cord blood-derived CD34+ stem cells. This Gal-9-mediated cytotoxicity did not rely on apoptosis but negatively associated with autophagic flux. Importantly, both AraC-sensitive and -resistant AML cell lines as well as AML patient samples were sensitive to single agent treatment with Gal-9. Additionally, Gal-9 potentiated the cytotoxic effect of DNA demethylase inhibitor Azacytidine (Aza), a drug that is clinically used for patients that are not eligible for intensive AraC treatment. Thus, Gal-9 is a potential therapeutic agent for the treatment of AML, including AraC resistant AML, by inducing caspase-independent cell death.

cancer biology↗

bioRxiv2021

Patients with recurrent PVL+-Staphylococcus aureus infections show enhanced sensitivity to PVL-mediated formation of atypical NETs

Staphylococcus aureus (S. aureus) strains that produce the toxin Panton-Valentine leukocidin (PVL; PVL-SA) frequently cause recurrent skin and soft tissue infections (SSTI). PVL binds to and kills human neutrophils, resulting in the formation of neutrophil extracellular traps, but the pathomechanism has not been extensively studied. Furthermore, it is unclear why some individuals colonized with PVL-SA suffer from recurring infections whereas others are asymptomatic. We thus aimed to (a) investigate how PVL exerts its pathogenicity on neutrophils and (b) identify factors that could help to explain the predisposition of patients with recurring infections. We provide genetic and pharmacological evidence that PVL-induced NET formation is independent of NADPH-oxidase and reactive oxygen species (ROS) production. Moreover, through NET proteome analysis we identified that the protein content of PVL-induced NETs is different from NETs induced by mitogen or the microbial toxin nigericin. The abundance of the proteins cathelicidin (CAMP), elastase (NE), and proteinase 3 (PRTN3) was lower on PVL-induced NETs, and as such they were unable to kill S. aureus. Furthermore, we found that neutrophils from affected patients express higher levels of CD45, one of the PVL receptors, and are more susceptible to be killed at a low PVL concentration than control neutrophils. Neutrophils from patients that suffer from recurring PVL-positive infections may thus be more sensitive to PVL-induced NET formation, which might impair their ability to combat the infection. ImportanceIndividuals colonized by Staphylococcus aureus strains that produce Panton-Valentine leukocidin (PVL-SA) often present with recurrent skin and soft-tissue infections, whilst other individuals remain asymptomatic. PVL is a toxin that kills neutrophils, which results in the formation of neutrophil extracellular traps. Traps induced by other stimuli are known to be toxic to S. aureus. We found however that NETs specifically induced by PVL are not toxic to S. aureus. Furthermore, we show that neutrophils from individuals that suffer from recurring PVL-SA infections are more sensitive to PVL-induced NET formation compared to healthy individuals. The significance of our work is in identifying a mechanism through which PVL-SA may actively counter the engagement of neutrophils. Moreover, we identified that patients with recuring PVL-SA infections may be more sensitive to this mechanism, which may help to explain their clinical condition and might provide avenues for future treatment development.

immunology↗