ORCID Profile
0000-0001-8625-050X
Current Organisations
Hudson Institute of Medical Research
,
Université du Québec à Trois-Rivières
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Publisher: Wiley
Date: 27-09-2006
Publisher: Springer New York
Date: 07-12-2017
DOI: 10.1007/978-1-4939-6563-2_9
Abstract: MicroRNAs (miRNAs) are involved in most cellular processes and are deregulated in several diseases. Antisense miRNA oligonucleotides (AMOs) therefore present novel therapeutic opportunities. Currently, in vivo delivery of AMOs often relies on high doses of nucleic acids, with nonspecific uptake by most tissues. Critically, AMOs accumulate in phagocytic cells where they can interfere with immune functions, such as the activation of Toll-Like Receptors (TLRs). In this chapter, we describe a method to assess the possible off-target effects of AMOs on TLR7, 8, and 9 sensing.
Publisher: Elsevier BV
Date: 07-2020
Publisher: American Society for Microbiology
Date: 25-02-2020
Abstract: Recent studies suggest that extracellular cGAMP can be taken up by macrophages to engage STING through several mechanisms. Our work demonstrates that connexin-dependent communication between epithelial cells and macrophages plays a significant role in the lification of antiviral responses mediated by cGAMP and suggests that pharmacological strategies aimed at modulating connexins may have therapeutic applications to control antiviral responses in humans.
Publisher: Oxford University Press (OUP)
Date: 10-05-2016
DOI: 10.1093/NAR/GKW405
Publisher: Oxford University Press (OUP)
Date: 29-09-2017
DOI: 10.1093/NAR/GKW878
Publisher: Elsevier BV
Date: 10-2020
Publisher: American Society for Microbiology
Date: 08-11-2017
Abstract: Inflammatory responses, while essential for pathogen clearance, can also be deleterious to the host. Chemical inhibition of topoisomerase 1 (Top1) by low-dose c tothecin (CPT) can suppress transcriptional induction of antiviral and inflammatory genes and protect animals from excessive and damaging inflammatory responses. We describe the unexpected finding that minor DNA damage from topoisomerase 1 inhibition with low-dose CPT can trigger a strong antiviral immune response through cyclic GMP-AMP synthase (cGAS) detection of cytoplasmic DNA. This argues against CPT having only anti-inflammatory activity. Furthermore, expression of the simian virus 40 (SV40) large T antigen was paramount to the proinflammatory antiviral activity of CPT, as it potentiated cytoplasmic DNA leakage and subsequent cGAS recruitment in human and mouse cell lines. This work suggests that the capacity of Top1 inhibitors to blunt inflammatory responses can be counteracted by viral oncogenes and that this should be taken into account for their therapeutic development. IMPORTANCE Recent studies suggest that low-dose DNA-damaging compounds traditionally used in cancer therapy can have opposite effects on antiviral responses, either suppressing (with the ex le of CPT) or potentiating (with the ex le of doxorubicin) them. Our work demonstrates that the minor DNA damage promoted by low-dose CPT can also trigger strong antiviral responses, dependent on the presence of viral oncogenes. Taken together, these results call for caution in the therapeutic use of low-dose chemotherapy agents to modulate antiviral responses in humans.
Publisher: Frontiers Media SA
Date: 19-03-2018
Publisher: Elsevier BV
Date: 2020
Publisher: MDPI AG
Date: 25-10-2016
DOI: 10.3390/NCRNA2040012
Publisher: Frontiers Media SA
Date: 24-01-2018
Publisher: Springer Singapore
Date: 2017
DOI: 10.1007/978-981-10-5987-2_8
Abstract: Stimulator of interferon (IFN) genes (STING) is a key mediator in the immune response to cytoplasmic DNA sensed by cyclic GMP-AMP (cGAMP) synthase (cGAS). After synthesis by cGAS, cGAMP acts as a second messenger activating STING in the cell harboring cytoplasmic DNA but also in adjacent cells through gap junction transfer. While the role of the cGAS-STING pathway in pathogen detection is now well established, its importance in cancer immunity has only recently started to emerge. Nonetheless, STING appears to be an essential component in the recruitment of immune cells to the tumor microenvironment, which is paramount to immune clearance of the tumor. This review presents an overview of the growing literature around the role of the cGAS-STING pathway in the tumor microenvironment, with a specific focus on the role that cancer cells may play in the direct activation of this pathway, and its lification through cell-cell transfer of cGAMP.
Publisher: Cold Spring Harbor Laboratory
Date: 20-12-2018
Abstract: Endogenous microRNAs (miRNAs) often exist as multiple isoforms (known as “isomiRs”) with predominant variation around their 3′-end. Increasing evidence suggests that different isomiRs of the same family can have erse functional roles, as recently demonstrated with the ex le of miR-222-3p 3′-end variants. While isomiR levels from a same miRNA family can vary between tissues and cell types, change of templated isomiR stoichiometry to stimulation has not been reported to date. Relying on small RNA-sequencing analyses, we demonstrate here that miR-222-3p 3′-end variants nt are specifically decreased upon interferon (IFN) β stimulation of human fibroblasts, while shorter isoforms are spared. This length-dependent dynamic regulation of long miR-222-3p 3′-isoforms and other miRNA families was confirmed in human monocyte-derived dendritic cells following infection with Salmonella Typhimurium, underlining the breadth of 3′-length regulation by infection, beyond the ex le of miR-222-3p. We further show that stem–loop miRNA Taqman RT-qPCR exhibits selectivity between 3′-isoforms, according to their length, and that this can lead to misinterpretation of results when these isoforms are differentially regulated. Collectively, and to our knowledge, this work constitutes the first demonstration that the stoichiometry of highly abundant templated 3′-isoforms of a same miRNA family can be dynamically regulated by a stimulus. Given that such 3′-isomiRs can have different functions, our study underlines the need to consider isomiRs when investigating miRNA-based regulation.
Publisher: Cold Spring Harbor Laboratory
Date: 11-03-2023
DOI: 10.1101/2023.03.10.532157
Abstract: There is a growing appreciation that the direct interaction between bacteriophages and the mammalian host can facilitate erse and unexplored symbioses. Yet the impact these bacteriophages may have on mammalian cellular and immunological processes is poorly understood. Here we applied highly purified phage T4, free from bacterial by-products and endotoxins to mammalian cells and analyzed the cellular responses using luciferase reporter and antibody microarray assays. Phage preparations were applied in vitro to either A549 lung epithelial cells, MDCK-I kidney cells, or primary mouse bone marrow derived macrophages with the phage-free supernatant serving as a comparative control. Highly purified T4 phages were rapidly internalized by mammalian cells and accumulated within macropinosomes but did not activate the inflammatory DNA response TLR9 or cGAS-STING pathways. Following eight hours of incubation with T4 phage, whole cell lysates were analyzed via antibody microarray that detected expression and phosphorylation levels of human signaling proteins. T4 phage internalization led to the activation of AKT-dependent pathways, resulting in an increase in cell metabolism, survival, and actin reorganization, the last being critical for macropinocytosis and potentially regulating a positive feedback loop to drive further phage internalization. T4 phages additionally down-regulated CDK1 and its downstream effectors, leading to an inhibition of cell cycle progression and an increase in cellular growth through a prolonged G1 phase. These interactions demonstrate that highly purified T4 phages do not activate DNA-mediated inflammatory pathways but do trigger protein phosphorylation cascades that promote cellular growth and survival. We conclude that mammalian cells are internalizing bacteriophages as a food source to promote cellular growth and metabolism.
Publisher: Oxford University Press (OUP)
Date: 09-10-2012
DOI: 10.1093/NAR/GKS903
Publisher: Springer Singapore
Date: 2018
Publisher: Springer New York
Date: 2018
DOI: 10.1007/978-1-4939-7568-6_20
Abstract: DNA sensing by the STING pathway is emerging to be a crucial component of the antitumor immune response. Although it plays a key role in the activation of tumor immune cells, exactly how STING is activated by tumor cells is not fully understood. Recent evidence suggests that cGAS can be directly engaged and produces 2'3'-cyclic-GMP-AMP (cGAMP) within certain tumor cells upon stimulation with DNA damaging agents. Because cGAMP can transfer between adjacent cells, the capacity of tumor cells to produce cGAMP may activate tumor immune cells, even in the absence of functional STING signaling within the tumor. Here we describe a simple coculture protocol allowing for the functional characterization of cGAS/STING activity in tumor cells, together with cGAMP transfer to adjacent cells. This approach will help define how different tumors engage the STING pathway, and whether synthetic STING agonists should be used to potentiate the antitumor effects of chemotherapies.
Publisher: Oxford University Press (OUP)
Date: 16-06-2020
DOI: 10.1093/NAR/GKAA523
Abstract: Oligonucleotide-based therapeutics have become a reality, and are set to transform management of many diseases. Nevertheless, the modulatory activities of these molecules on immune responses remain incompletely defined. Here, we show that gene targeting 2′-O-methyl (2′OMe) gapmer antisense oligonucleotides (ASOs) can have opposing activities on Toll-Like Receptors 7 and 8 (TLR7/8), leading to ergent suppression of TLR7 and activation of TLR8, in a sequence-dependent manner. Surprisingly, TLR8 potentiation by the gapmer ASOs was blunted by locked nucleic acid (LNA) and 2′-methoxyethyl (2′MOE) modifications. Through a screen of 192 2′OMe ASOs and sequence mutants, we characterized the structural and sequence determinants of these activities. Importantly, we identified core motifs preventing the immunosuppressive activities of 2′OMe ASOs on TLR7. Based on these observations, we designed oligonucleotides strongly potentiating TLR8 sensing of Resiquimod, which preserve TLR7 function, and promote strong activation of phagocytes and immune cells. We also provide proof-of-principle data that gene-targeting ASOs can be selected to synergize with TLR8 agonists currently under investigation as immunotherapies, and show that rational ASO selection can be used to prevent unintended immune suppression of TLR7. Taken together, our work characterizes the immumodulatory effects of ASOs to advance their therapeutic development.
Publisher: Elsevier BV
Date: 02-2009
No related grants have been discovered for Genevieve Pepin.