15 research outputs found
Ătude des intĂ©ractions entre le virus de l'HĂ©patite C et les cellules dendritiques circulantes
L'infection par le virus de l'HĂ©patite C (VHC) se caractĂ©rise par une forte Ă©volution vers la chronicitĂ© qui semble associĂ©e Ă un dĂ©faut de la rĂ©ponse immunitaire spĂ©cifique. Nous avons voulu tester si ce dĂ©faut pourrait ĂȘtre dĂŒ Ă un dysfonctionnement des cellules dendritiques (DC). Pour cela, nous avons Ă©valuĂ© 1) la prĂ©sence de sĂ©quences virales du VHC au sein des deux sous-populations majoritaires de DC circulantes, les DC myĂ©loĂŻdes (MDC) et plasmacytoĂŻdes (PDC), 2) la capacitĂ© des PDC de patients chroniquement infectĂ©s Ă produire de l'IFNa en rĂ©ponse Ă une stimulation par HSV-1 et 3) la fonction allostimulatrice et de polarisation des PDC et MDC de porteurs chroniques non traitĂ©s. Nous avons montrĂ© que 1) le VHC est capable d'infecter les MDC et PDC circulantes, 2) l'infection par le VHC ne modifie ni la capacitĂ© des PDC Ă produire des IFN I, 3) ni l'aptitude des PDC et MDC Ă induire la rĂ©ponse immunitaire adaptative (allostimulation et polarisation)LYON1-BU.Sciences (692662101) / SudocSudocFranceF
Evidence of Viral Replication in Circulating Dendritic Cells during Hepatitis C Virus Infection
Quantification and Functional Analysis of Plasmacytoid Dendritic Cells in Patients with Chronic Hepatitis C Virus Infection
Inflammasome Deletion Promotes Anti-tumor NK Cell Function in an IL-1/IL-18 Independent Way in Murine Invasive Breast Cancer
International audienc
Repurposing rotavirus vaccines for intratumoral immunotherapy can overcome resistance to immune checkpoint blockade
International audienceAlthough immune checkpoint-targeted therapies are currently revolutionizing cancer care, only a minority of patients develop durable objective responses to anti-PD-1, PD-L1, and CTLA-4 therapy. Therefore, new therapeutic interventions are needed to increase the immunogenicity of tumors and overcome the resistance to these immuno-therapies. Oncolytic properties of common viruses can be exploited for the priming of antitumor immunity, and such oncolytic viruses are currently in active clinical development in combination with immune checkpoint-targeted therapies. However, the routine implementation of these therapies is limited by their manufacturing constraints, the risk of exposure of clinical staff, and the ongoing regulations on genetically modified organisms. We sought to determine whether anti-infectious disease vaccines could be used as a commercially available source of immunostimulatory agents for cancer immunotherapy. We found that rotavirus vaccines have both immunostimulatory and oncolytic properties. In vitro, they can directly kill cancer cells with features of immunogenic cell death. In vivo, intratumoral rotavirus therapy has antitumor effects that are dependent on the immune system. In several immunocompetent murine tumor models, intratumoral rotavirus overcomes resistance to and synergizes with immune checkpoint-targeted therapy. Heat-and UV-inactivated rotavirus lost their oncolytic activity but kept their synergy with immune checkpoint-targeted antibodies through the up-regulation of the double-stranded RNA receptor retinoic acid-induced gene 1 (RIG-I). Rotavirus vaccines are clinical-grade products used in pediatric and adult populations. Therefore, in situ immunization strategies with intratumoral-attenuated rotavirus could be implemented quickly in the clinic
Cross-talk between Staphylococcus aureus leukocidins-intoxicated macrophages and lung epithelial cells triggers chemokine secretion in an inflammasome-dependent manner.
International audienceStaphylococcus aureus is a major pathogen responsible for both nosocomial and community-acquired infections. Central to its virulence is its ability to secrete haemolysins, pore-forming toxins and cytolytic peptides. The large number of membrane-damaging toxins and peptides produced during S. aureus infections has hindered a precise understanding of their specific roles in diseases. Here, we used comprehensive libraries of recombinant toxins and synthetic cytolytic peptides, of S. aureus mutants and clinical strains to investigate the role of these virulence factors in targeting human macrophages and triggering IL-1ÎČ release. We found that the Panton Valentine leukocidin (PVL) is the major trigger of IL-1ÎČ release and inflammasome activation in primary human macrophages. The cytolytic peptides, ÎŽ-haemolysin and PSMα3; the pore-forming toxins, Îł-haemolysin and LukDE; and ÎČ-haemolysin synergize with PVL to amplify IL-1ÎČ release, indicating that these factors cooperate with PVL to trigger inflammation. PVL(+) S. aureus causes necrotizing pneumonia in children and young adults. The severity of this disease is due to the massive recruitment of neutrophils that cause lung damage. Importantly, we demonstrate that PVL triggers IL-1ÎČ release in human alveolar macrophages. Furthermore, IL-1ÎČ released by PVL-intoxicated macrophages stimulates the secretion of the neutrophil attracting chemokines, IL-8 and monocyte chemotactic protein-1, by lung epithelial cells. Finally, we show that PVL-induced IL-8/monocyte chemotactic protein-1 release is abolished by the inclusion of IL-1 receptor antagonist (IL-1Ra) in a mixed culture of lung epithelial cells and macrophages. Together, our results identify PVL as the predominant S. aureus secreted factor for triggering inflammasome activation in human macrophages and demonstrate how PVL-intoxicated macrophages orchestrate inflammation in the lung. Finally, our work suggests that anakinra, a synthetic IL-1Ra, may be an effective therapeutic agent to reduce the massive neutrophils infiltration observed during necrotizing pneumonia and decrease the resulting host-mediated lung injury
The Human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter
Human papillomavirus type 16 (HPV16) and other oncogenic viruses have been reported to deregulate immunity by suppressing the function of the double-stranded DNA innate sensor TLR9. However, the mechanisms leading to these events remain to be elucidated. We show that infection of human epithelial cells with HPV16 promotes the formation of an inhibitory transcriptional complex containing NF-ÎșBp50-p65 and ERα induced by the E7 oncoprotein. The E7-mediated transcriptional complex also recruited the histone demethylase JARID1B and histone deacetylase HDAC1. The entire complex bound to a specific region on the TLR9 promoter, which resulted in decreased methylation and acetylation of histones upstream of the TLR9 transcriptional start site. The involvement of NF-ÎșB and ERα in the TLR9 down-regulation by HPV16 E7 was fully confirmed in cervical tissues from human patients. Importantly, we present evidence that the HPV16-induced TLR9 down-regulation affects the interferon response which negatively regulates viral infection. Our studies highlight a novel HPV16-mediated mechanism that combines epigenetic and transcriptional events to suppress a key innate immune sensor
Breast cancer-derived transforming growth factor-ÎČ and tumor necrosis factor-α compromise interferon-α production by tumor-associated plasmacytoid dendritic cells
International audienceWe previously reported that plasmacytoid dendritic cells (pDCs) infiltrating breast tumors are impaired for their interferonâα (IFNâα) production, resulting in local regulatory T cells amplification. We designed our study to decipher molecular mechanisms of such functional defect of tumorâassociated pDC (TApDC) in breast cancer. We demonstrate that besides IFNâα, the production by Tollâlike receptor (TLR)âactivated healthy pDC of IFNâÎČ and TNFâα but not IPâ10/CXCL10 nor MIP1âα/CCL3 is impaired by the breast tumor environment. Importantly, we identified TGFâÎČ and TNFâα as major soluble factors involved in TApDC functional alteration. Indeed, recombinant TGFâÎČ1 and TNFâα synergistically blocked IFNâα production of TLRâactivated pDC, and neutralization of TGFâÎČ and TNFâα in tumorâderived supernatants restored pDCs' IFNâα production. The involvment of tumorâderived TGFâÎČ was further confirmed in situ by the detection of phosphorylated Smad2 in the nuclei of TApDC in breast tumor tissues. Mechanisms of type I IFN inhibition did not involve TLR downregulation but the inhibition of IRFâ7 expression and nuclear translocation in pDC after their exposure to tumorâderived supernatants or recombinant TGFâÎČ1 and TNFâα. Our findings indicate that targeting TApDC to restore their IFNâα production might be an achievable strategy to induce antitumor immunity in breast cancer by combining TLR7/9âbased immunotherapy with TGFâÎČ and TNFâα antagonists