alexagid

• Mediaas, Sindre Dahl; Haug, Markus; Louet, Claire; Wahl, Sissel Gyrid Freim; Gidon, Alexandre & Flo, Trude Helen (2024). Metformin improves Mycobacterium avium infection by strengthening macrophage antimicrobial functions. Frontiers in Immunology. 15. doi: 10.3389/fimmu.2024.1463224. Full text in Research Archive
• Pacheco, Jonathan; Peña, Karina A.; Savransky, Sofya; Gidon, Alexandre; Hammond, Gerald R. V. & Janetzko, John [Show all 7 contributors for this article] (2024). Fast-diffusing receptor collisions with slow-diffusing peptide ligand assemble the ternary parathyroid hormone–GPCR–arrestin complex. Nature Communications. 15(1). doi: 10.1038/s41467-024-54772-3. Full text in Research Archive
• Nore, Kristin Grotle; Louet, Claire; Bugge, Marit; Gidon, Alexandre; Jørgensen, Marthe Jøntvedt & Jenum, Synne [Show all 9 contributors for this article] (2023). The Cyclooxygenase 2 Inhibitor Etoricoxib as Adjunctive Therapy in Tuberculosis Impairs Macrophage Control of Mycobacterial Growth. Journal of Infectious Diseases. ISSN 0022-1899. 229(3), p. 888–897. doi: 10.1093/infdis/jiad390. Full text in Research Archive Show summary

  Background Current tuberculosis treatment regimens could be improved by adjunct host-directed therapies (HDT) targeting host responses. We investigated the antimycobacterial capacity of macrophages from patients with tuberculosis in a phase 1/2 randomized clinical trial (TBCOX2) of the cyclooxygenase-2 inhibitor etoricoxib. Methods Peripheral blood mononuclear cells from 15 patients with tuberculosis treated with adjunctive COX-2i and 18 controls (standard therapy) were collected on day 56 after treatment initiation. The ex vivo capacity of macrophages to control mycobacterial infection was assessed by challenge with Mycobacterium avium, using an in vitro culture model. Macrophage inflammatory responses were analyzed by gene expression signatures, and concentrations of cytokines were analyzed in supernatants by multiplex. Results Macrophages from patients receiving adjunctive COX-2i treatment had higher M. avium loads than controls after 6 days, suggesting an impaired capacity to control mycobacterial infection compared to macrophages from the control group. Macrophages from the COX-2i group had lower gene expression of TNF, IL-1B, CCL4, CXCL9, and CXCL10 and lowered production of cytokines IFN-β and S100A8/A9 than controls. Conclusions Our data suggest potential unfavorable effects with impaired macrophage capacity to control mycobacterial growth in patients with tuberculosis receiving COX-2i treatment. Larger clinical trials are required to analyze the safety of COX-2i as HDT in patients with tuberculosis. Clinical Trials Registration NCT02503839.

• Basson, Adelle; Olaisen, Camilla; Selvik, Linn-Karina M.; Lyng, Randi Valsø; Lysvand, Hilde & Gidon, Alexandre [Show all 9 contributors for this article] (2022). The Streptococcus agalactiae R3 surface protein is encoded by sar5. PLOS ONE. 17(7). doi: 10.1371/journal.pone.0263199. Full text in Research Archive Show summary

  Streptococcus agalactiae (group B streptococcus; GBS) is an important human pathogen causing pneumonia, sepsis and meningitis in neonates, as well as infections in pregnant women, immunocompromised individuals, and the elderly. For the future control of GBS-inflicted disease, GBS surface exposed proteins are particularly relevant as they may act as antigens for vaccine development and/or as serosubtype markers in epidemiological settings. Even so, the genes encoding some of the surface proteins established as serosubtype markers by antibody-based methods, like the R3 surface protein, are still unknown. Here, by examining a Norwegian GBS collection consisting of 140 strains, we find that R3 protein expression correlates with the presence of the gene sar5. By inducible expression of sar5 in an R3-negative bacterial strain we show that the sar5 gene product is specifically recognized by an R3 monoclonal antibody. With this we identify sar5 as the gene encoding the R3 surface protein, a serosubtype marker of hitherto unknown genetic origin.

• Røst, Lisa M.; Louet, Claire; Bruheim, Per; Flo, Trude Helen & Gidon, Alexandre (2022). Pyruvate Supports RET-Dependent Mitochondrial ROS Production to Control Mycobacterium avium Infection in Human Primary Macrophages. Frontiers in Immunology. 13. doi: 10.3389/fimmu.2022.891475. Full text in Research Archive Show summary

  Macrophages deploy a variety of antimicrobial programs to contain mycobacterial infection. Upon activation, they undergo extensive metabolic reprogramming to meet an increase in energy demand, but also to support immune effector functions such as secretion of cytokines and antimicrobial activities. Here, we report that mitochondrial import of pyruvate is linked to production of mitochondrial ROS and control of Mycobacterium avium (M. avium) infection in human primary macrophages. Using chemical inhibition, targeted mass spectrometry and single cell image analysis, we showed that macrophages infected with M. avium switch to aerobic glycolysis without any major imbalances in the tricarboxylic acid cycle volume or changes in the energy charge. Instead, we found that pyruvate import contributes to hyperpolarization of mitochondria in infected cells and increases production of mitochondrial reactive oxygen species by the complex I via reverse electron transport, which reduces the macrophage burden of M. avium. While mycobacterial infections are extremely difficult to treat and notoriously resistant to antibiotics, this work stresses out that compounds specifically inducing mitochondrial reactive oxygen species could present themself as valuable adjunct treatments.

• Gidon, Alexandre; Louet, Claire; Røst, Lisa M.; Bruheim, Per & Flo, Trude Helen (2021). The Tumor Necrosis Factor Alpha and Interleukin 6 Auto-paracrine Signaling Loop Controls Mycobacterium avium Infection via Induction of IRF1/IRG1 in Human Primary Macrophages. mBio. ISSN 2161-2129. 12(5). doi: 10.1128/mBio.02121-21. Full text in Research Archive Show summary

  Macrophages sense and respond to pathogens by induction of antimicrobial and inflammatory programs to alert other immune cells and eliminate the infectious threat. We have previously identified the transcription factor IRF1 to be consistently activated in macrophages during Mycobacterium avium infection, but its precise role during infection is not clear. Here, we show that tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) autocrine/paracrine signaling contributes to controlling the intracellular growth of M. avium in human primary macrophages through activation of IRF1 nuclear translocation and expression of IRG1, a mitochondrial enzyme that produces the antimicrobial metabolite itaconate. Small interfering RNA (siRNA)-mediated knockdown of IRF1 or IRG1 increased the mycobacterial load, whereas exogenously provided itaconate was bacteriostatic at high concentrations. While the overall level of endogenous itaconate was low in M. avium-infected macrophages, the repositioning of mitochondria to M. avium phagosomes suggests a mechanism by which itaconate can be delivered directly to M. avium phagosomes in sufficient quantities to inhibit growth. Using mRNA hybridization, we further show that uninfected bystander cells actively contribute to the resolution of infection by producing IL-6 and TNF-α, which, via paracrine signaling, activate IRF1/IRG1 and strengthen the antimicrobial activity of infected macrophages. This mechanism contributes to the understanding of why patients on anti-inflammatory treatment, e.g., with tocilizumab or infliximab, can be more susceptible to mycobacterial disease.

• Niyonzima, Nathalie; Rahman, Jubayer; Kunz, Natalie; West, Erin; Freiwald, Tilo & Desai, Jigar V. [Show all 37 contributors for this article] (2021). Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation. Science immunology. 6(66), p. eabf2489–eabf2489. doi: 10.1126/sciimmunol.abf2489. Full text in Research Archive Show summary

  While serum-circulating complement destroys invading pathogens, intracellularly active complement, termed the “complosome,” functions as a vital orchestrator of cell-metabolic events underlying T cell effector responses. Whether intracellular complement is also nonredundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and generate autocrine C5a via formation of an intracellular C5 convertase. Cholesterol crystal sensing by macrophages induced C5aR1 signaling on mitochondrial membranes, which shifted ATP production via reverse electron chain flux toward reactive oxygen species generation and anaerobic glycolysis to favor IL-1β production, both at the transcriptional level and processing of pro–IL-1β. Consequently, atherosclerosis-prone mice lacking macrophage-specific C5ar1 had ameliorated cardiovascular disease on a high-cholesterol diet. Conversely, inflammatory gene signatures and IL-1β produced by cells in unstable atherosclerotic plaques of patients were normalized by a specific cell-permeable C5aR1 antagonist. Deficiency of the macrophage cell-autonomous C5 system also protected mice from crystal nephropathy mediated by folic acid. These data demonstrate the unexpected intracellular formation of a C5 convertase and identify C5aR1 as a direct modulator of mitochondrial function and inflammatory output from myeloid cells. Together, these findings suggest that the complosome is a contributor to the biologic processes underlying sterile inflammation and indicate that targeting this system could be beneficial in macrophage-dependent diseases, such as atherosclerosis.

• Åsberg, Signe Elisabeth; Mediaas, Sindre Dahl; Marstad, Anne; Ryan, Liv; Louet, Claire & Sporsheim, Bjørnar [Show all 10 contributors for this article] (2020). Antibiotic treatment routes Mycobacterium avium to phagolysosomes without triggering proinflammatory cytokine production in human Mϕs. Journal of Leukocyte Biology. ISSN 0741-5400. doi: 10.1002/JLB.4HI0420-306R. Full text in Research Archive Show summary

  Mycobacterium avium (Mav) causes chronic infections in immunocompromised patients that require long‐term antibiotic treatment. We have previously shown that Mav takes residence in host Mϕs and establishes a compartment (MavC) in which it is hidden from host defenses. Failure to establish the MavC traps Mav in Lamp1+ phagolysosomes where growth is prevented, and inflammatory signaling activated through TLRs 7/8. To elucidate how antibiotic treatment affects mycobacterial trafficking and host defenses, we infected human primary Mϕs with Mav for 4 days prior to treatment with a macrolide, aminoglycoside, and ethambutol. We show that Mav is killed and the MavC fuses with Lamp1+ lysosomes following antibiotic treatment. However, this does not result in nuclear translocation of NF‐κB or production of inflammatory cytokines, suggesting different Lamp1+ lysosomal compartments can form that differ in their innate signaling capabilities. Thus, we show that upon antibiotic treatment of a chronic infection, Mav is quietly disposed of by Mϕs.

• Gidon, Alexandre; Åsberg, Signe; Louet, Claire; Ryan, Liv; Haug, Markus & Flo, Trude Helen (2017). Persistent mycobacteria evade an antibacterial program mediated by phagolysosomal TLR7/8/MyD88 in human primary macrophages. PLoS Pathogens. ISSN 1553-7366. 13(8). doi: 10.1371/journal.ppat.1006551. Full text in Research Archive Show summary

  Pathogenic mycobacteria reside in macrophages where they avoid lysosomal targeting and degradation through poorly understood mechanisms proposed to involve arrest of phagosomal maturation at an early endosomal stage. A clear understanding of how this relates to host defenses elicited from various intracellular compartments is also missing and can only be studied using techniques allowing single cell and subcellular analyses. Using confocal imaging of human primary macrophages infected with Mycobacterium avium (Mav) we show evidence that Mav phagosomes are not arrested at an early endosomal stage, but mature to a (LAMP1+/LAMP2+/CD63+) late endosomal/phagolysosomal stage where inflammatory signaling and Mav growth restriction is initiated through a mechanism involving Toll-like receptors (TLR) 7 and 8, the adaptor MyD88 and transcription factors NF-κB and IRF-1. Furthermore, a fraction of the mycobacteria re-establish in a less hostile compartment (LAMP1-/LAMP2-/CD63-) where they not only evade destruction, but also recognition by TLRs, growth restriction and inflammatory host responses that could be detrimental for intracellular survival and establishment of chronic infections.

• Gidon, Alexandre; Feinstein, Timothy N.; Xiao, Kunhong & Vilardaga, Jean-Pierre (2015). Studying the regulation of endosomal cAMP production in GPCR signaling. Methods in Cell Biology. ISSN 0091-679X. doi: 10.1016/bs.mcb.2015.10.007. Full text in Research Archive

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• Flo, Trude Helen; Gidon, Alexandre; Mediaas, Sindre Dahl & Bugge, Marit (2023). Spatiotemporal studies of host responses to mycobacteria in macrophages. Full text in Research Archive
• Flo, Trude Helen; Beckwith, Kai Sandvold; Beckwith, Marianne Sandvold; Gidon, Alexandre; Mediaas, Sindre Dahl & Sætra, Ragnhild Sofie Ragnhildstveit [Show all 9 contributors for this article] (2022). Spatiotemporal Relations of Mycobacteria and Human Macrophages. Full text in Research Archive
• Basson, Adelle; Olaisen, Camilla; Selvik, Linn-Karina M.; Lyng, Randi Valsø; Lysvand, Hilde & Gidon, Alexandre [Show all 9 contributors for this article] (2022). The Streptococcus agalactiae R3 surface protein is encoded by sar5. Full text in Research Archive
• Flo, Trude Helen; Beckwith, Kai Sandvold; Beckwith, Marianne Sandvold; Gidon, Alexandre; Ullmann, Sindre & Sætra, Ragnhild Sofie Ragnhildstveit [Show all 7 contributors for this article] (2021). Mycobacterium tuberculosis infection in human macrophages. Full text in Research Archive
• Flo, Trude Helen; Gidon, Alexandre; Mediaas, Sindre Dahl & Dragset, Marte Singsås (2020). AMR in mycobacterial infections and the search for new treatments. Full text in Research Archive
• Mediaas, Sindre Dahl; Gidon, Alexandre; Haug, Markus & Flo, Trude Helen (2020). THE EFFECT OF HOST-DIRECTED THERAPY ON INTRANASAL MYCOBACTERIUM AVIUM INFECTION. Full text in Research Archive
• Flo, Trude Helen; Beckwith, Kai Sandvold; Beckwith, Marianne Sandvold; Gidon, Alexandre; Ullmann, Sindre & Sætra, Ragnhild Sofie Ragnhildstveit (2019). Plasma membrane damage by Mycobacterium tuberculosis induce inflammasome activation and pyroptosis in host macrophages. Full text in Research Archive
• Gidon, Alexandre; Louet, Claire & Flo, Trude Helen (2018). Single cell analysis reveals an IRF1/ACOD1 auto-paracrine loop controlled by IL-6/TNF-a to restrict persistent mycobacteria in human primary macrophage. Full text in Research Archive
• Flo, Trude Helen; Gidon, Alexandre & Lerm, Maria (2018). Discovering new therapeutic targets and drugs to combat AMR tuberculosis: proteomics characterization and drug screening of mycobacterium-infected macrophages. Full text in Research Archive
• Ostrop, Jenny; Kerntke, Christina; Sørbø, Håvard Gullik; Spanjers, Roos; Louet, Claire & Gidon, Alexandre [Show all 9 contributors for this article] (2017). FcRγ is a central adaptor subunit for immune receptors on human macrophages. Full text in Research Archive
• Ostrop, Jenny; Kerntke, Christina; Sørbø, Håvard Gullik; Jozefowski, Katrin; Hupfer, Thomas & Louet, Claire [Show all 11 contributors for this article] (2017). FcRγ is a central adaptor subunit for immune receptors on myeloid cells. Full text in Research Archive
• Gidon, Alexandre; Åsberg, Signe; Louet, Claire; Ryan, Liv; Haug, Markus & Flo, Trude Helen (2017). Persistent mycobacteria evade an antibacterial program mediated by phagolysosomal TLR7/8/MyD88 in human primary macrophages. Full text in Research Archive
• Gidon, Alexandre (2017). Persistent mycobacteria evade an antibacterial program mediated by phagolysosomal TLR7/8/MyD88 in human primary macrophages. Full text in Research Archive
• Gidon, Alexandre; Åsberg, Signe Elisabeth; Louet, Claire; Ryan, Liv & Flo, Trude Helen (2016). Mycobacterium avium interfering with phagosome maturation evades an antibacterial program activated by phagolysosomal TLR7/8/MyD88 in human primary macrophages. Full text in Research Archive
• Gidon, Alexandre; Åsberg, Signe Elisabeth; Louet, Claire; Ryan, Liv & Flo, Trude Helen (2016). Inflammatory Encounters of Mycobacteria in Space and Time. Full text in Research Archive
• Gidon, Alexandre; Åsberg, Signe Elisabeth; Louet, Claire; Ryan, Liv & Flo, Trude Helen (2016). Mycobacterium avium evades an antibacterial program mediated by phagolysosomal TLR7/8/MyD88. Full text in Research Archive
• Gidon, Alexandre; Åsberg, Signe Elisabeth; Louet, Claire; Ryan, Liv & Flo, Trude Helen (2016). Mycobacterium avium evades an antibacterial program mediated by phagolysosomal TLR7/8/MyD88. Full text in Research Archive
• Gidon, Alexandre (2015). Traffic and Signaling: a close relationship in M. Avium infected Primary Human Macrophages. Full text in Research Archive
• Gidon, Alexandre (2015). M.Avium induces Inflammatory Signaling from Lysosomal Compartments in Human Primary Macrophages. Full text in Research Archive
• Åsberg, Signe; Flo, Trude Helen; Underhill, David & Gidon, Alexandre (2018). The Drug, the Bug and the Macrophage: Interactions between antibiotics, mycobacteria and macrophages at the single cell and subcellular level. Norges teknisk-naturvitenskapelige universitet. ISSN 9788232634477. Full text in Research Archive

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