Biology subjects

Mazeres, S.

Publications and source records attributed to Mazeres, S..

3 recordsLinked to original sources

bioRxiv2021

Pseudomonas aeruginosa infection reveals a Caspase-1-dependent neutrophil pyroptosis pathway that restrains damaging Histone release

Multiple neutrophil death programs contribute to host defense against infections. Although expressing all necessary components, neutrophils specifically fail to undergo pyroptosis, a lytic form of cell death triggered by the activation of the pro-inflammatory complex inflammasome. In the light of the arm race, we hypothesized that intrinsic neutrophil pyroptosis resistance might be bypassed in response to specific microbial species. We show that Pseudomonas aeruginosa (P. aeruginosa) stimulates Caspase-1-dependent pyroptosis in human and murine neutrophils. Mechanistically, activated NLRC4 inflammasome supports Caspase-1-driven Gasdermin-D (GSDMD) activation, IL-1{beta} cytokine release and neutrophil pyroptosis. Furthermore, GSDMD activates Peptidyl Arginine Deaminase-4 which drives an "incomplete NETosis" where neutrophil DNA fills the cell cytosol but fails crossing plasma membrane. Finally, we show that neutrophil Caspase-1 account for IL-1{beta} production and contributes to various P. aeruginosa strains spread in mice. Overall, we demonstrate that neutrophils are fully competent for Caspase-1-dependent pyroptosis, which drives an unsuspected "incomplete NETosis". SummaryNeutrophils play an essential roles against infections. Although multiple neutrophil death programs contribute to host defense against infections, they fail to undergo pyroptosis, a pro-inflammatory form of cell death. Upon Infections, pyroptosis can be induced in macrophages or epithelial cells upon activation of pro-inflammatory complexes, inflammasomes that trigger Caspase-1-driven Gasdermin dependent plasma membrane lysis. In the light of host-microbe interactions, we hypothesized that yet to find microbial species might hold the capacity to overcome neutrophil resistance to inflammasome-driven pyroptosis. Among several bacterial species, we describe that the bacterium Pseudomonas aeruginosa specifically engages the NLRC4 inflammasome, which promotes Caspase-1-dependent Gasdermin-D activation and subsequent neutrophil pyroptosis. Furthermore, inflammasome-driven pyroptosis leads to DNA decondensation and expansion into the host cell cytosol but not to the so called Neutrophil Extracellular Trap (NET) release as DNA fails breaching the plasma membrane. Finally, in vivo P. aeruginosa infections highlight that Caspase-1-driven neutrophil pyroptosis is functional and is detrimental upon P. aeruginosa infection. Altogether, our results unexpectedly underline neutrophil competence for Caspase-1-dependent pyroptosis, a process that contributes to host susceptibility to P. aeruginosa infection.

immunology↗

bioRxiv2020

Mycobacteria-host interactions in human bronchiolar airway organoids

Tuberculosis, one of the oldest human pathogens remains a major global health threat. Recent advances in organoid technology offer a unique opportunity to grow different human "organs" in vitro, including the human airway, that faithfully recapitulate tissue architecture and function. We have explored the potential of human airway organoids (AOs) as a novel system in which to model tuberculosis infection. To this end, we adapted biosafety containment level 3-approved procedures to allow successful microinjection of Mycobacterium tuberculosis, the causative agent of tuberculosis, into AOs. We reveal that mycobacteria infected epithelial cells with low efficiency, and that the organoid microenvironment was able to control, but not eliminate the pathogen. We demonstrate that AOs responded to infection by inducing cytokine and antimicrobial peptide production, and inhibiting mucins. Given the importance of myeloid cells in tuberculosis infection, we co-cultured mycobacteria-infected organoids with human monocyte-derived macrophages, and found that these cells were recruited to the organoid epithelium. We conclude that adult stem cell-derived airway organoids can be used to model early events of tuberculosis infection and offer new avenues for fundamental and therapeutic research.

systems biology↗

bioRxiv2020

Phthiocerol dimycocerosates from Mycobacterium tuberculosis increase the membrane activity of bacterial effectors and host receptors

Mycobacterium tuberculosis (Mtb) synthesizes a variety of atypical lipids that are exposed at the cell surface and help the bacterium infect macrophages and escape elimination by the cells immune responses. In the present study, we investigate the mechanism of action of one family of hydrophobic lipids, the phthiocerol dimycocerosates (DIM/PDIM), major lipid virulence factors. DIM are transferred from the envelope of Mtb to host membranes during infection. Using the polarity-sensitive fluorophore C-Laurdan, we visualized that DIM increase the membrane polarity of a supported lipid bilayer put in contact with mycobacteria, even beyond the site of contact. We observed that DIM activate the complement receptor 3, a predominant receptor for phagocytosis of Mtb by macrophages. DIM also increased the activity of membrane-permeabilizing effectors of Mtb, among which the virulence factor EsxA. This is consistent with previous observations that DIM help Mtb disrupt host cell membranes. Taken together, our data show that transferred DIM spread within the target membrane, remodel lipid organization and increase the activity of host cell receptors and bacterial effectors, diverting in a nonspecific manner host cell functions. We therefore bring new insight into the molecular mechanisms by which DIM increase Mtbs capability to escape the cells immune responses.

microbiology↗