Targeting CXCR4 to suppress virus-induced activation of plasmacytoid dendritic cells
Virology
Final Report Abstract
Plasmacytoid dendritic cells (pDCs) are a type of immune cell that play a crucial role in our immune response. These cells are specialized in producing high levels of interferons in response to viral infections. Interferons activate other immune cells and prevent viral replication. We found that a key regulator of pDCs function is the chemokine receptor CXCR4 and demonstrate that natural monoamines and polyamines, such as spermine and spermidine, inhibit viral activation of pDCs through CXCR4 engagement. Computational modeling allowed to elucidate the molecular interactions of spermine with CXCR4. CXCR4 is also used by HIV-1 to infect cells and in fact, we found that spermine inhibits CXCR4- (X4) but not CCR5 (R5)-tropic viruses. Spermine is highly abundant in human semen, which may explain why only R5-using viruses are transmitted by sexual intercourse because spermine may act as gate-keeper of X4 viruses. In agreement with high concentrations of spermine in semen, we also found that seminal plasma potently inhibits virus-induced activation of innate immune cells, which may further drive transmission of R5 viruses. Thus, our research provided novel insights into the transmission of HIV-1 through sexual contact and offers new prospects for therapy of interferonopathies caused by pDCs by targeting CXCR4 with amines or related molecules.
Publications
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Control of TLR7-mediated type I IFN signaling in pDCs through CXCR4 engagement—A new target for lupus treatment. Science Advances, 5(7).
Smith, Nikaïa; Rodero, Mathieu P.; Bekaddour, Nassima; Bondet, Vincent; Ruiz-Blanco, Yasser B.; Harms, Mirja; Mayer, Benjamin; Bader-Meunier, Brigitte; Quartier, Pierre; Bodemer, Christine; Baudouin, Véronique; Dieudonné, Yannick; Kirchhoff, Frank; Sanchez, Garcia Elsa; Charbit, Bruno; Leboulanger, Nicolas; Jahrsdörfer, Bernd; Richard, Yolande; Korganow, Anne-Sophie; ... & Herbeuval, Jean-Philippe
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Isolation of Tonsillar Mononuclear Cells to Study Ex Vivo Innate Immune Responses in a Human Mucosal Lymphoid Tissue. Journal of Visualized Experiments (160).
Smith, Nikaïa; Bekaddour, Nassima; Leboulanger, Nicolas; Richard, Yolande & Herbeuval, Jean-Philippe
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An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation. Acta Pharmaceutica Sinica B, 11(9), 2694-2708.
Harms, Mirja; Habib, Monica M.W.; Nemska, Simona; Nicolò, Antonella; Gilg, Andrea; Preising, Nico; Sokkar, Pandian; Carmignani, Sara; Raasholm, Martina; Weidinger, Gilbert; Kizilsavas, Gönül; Wagner, Manfred; Ständker, Ludger; Abadi, Ashraf H.; Jumaa, Hassan; Kirchhoff, Frank; Frossard, Nelly; Sanchez-Garcia, Elsa & Münch, Jan
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Advanced EPI-X4 Derivatives Covalently Bind Human Serum Albumin Resulting in Prolonged Plasma Stability. International Journal of Molecular Sciences, 23(23), 15029.
Rodríguez-Alfonso, Armando; Heck, Astrid; Ruiz-Blanco, Yasser Bruno; Gilg, Andrea; Ständker, Ludger; Kuan, Seah Ling; Weil, Tanja; Sanchez-Garcia, Elsa; Wiese, Sebastian; Münch, Jan & Harms, Mirja
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Dimerization of the Peptide CXCR4-Antagonist on Macromolecular and Supramolecular Protraction Arms Affords Increased Potency and Enhanced Plasma Stability. Bioconjugate Chemistry, 33(4), 594-607.
Harms, Mirja; Hansson, Rikke Fabech; Carmali, Sheiliza; Almeida-Hernández, Yasser; Sanchez-Garcia, Elsa; Münch, Jan & Zelikin, Alexander N.
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Utilization of Aminoguanidine Prevents Cytotoxic Effects of Semen. International Journal of Molecular Sciences, 23(15), 8563.
Harms, Mirja; von Maltitz, Pascal; Groß, Rüdiger; Mayer, Benjamin; Deniz, Miriam; Müller, Janis & Münch, Jan
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Development of N-Terminally Modified Variants of the CXCR4-Antagonistic Peptide EPI-X4 for Enhanced Plasma Stability. Journal of Medicinal Chemistry, 66(22), 15189-15204.
Harms, Mirja; Fabech, Hansson Rikke; Gilg, Andrea; Almeida-Hernández, Yasser; Löffler, Jessica; Rodríguez-Alfonso, Armando; Habib, Monica M. W.; Albers, Dan; Ahmed, Nermin S.; Abadi, Ashraf H.; Winter, Gordon; Rasche, Volker; Beer, Ambros J.; Weidinger, Gilbert; Preising, Nico; Ständker, Ludger; Wiese, Sebastian; Sanchez-Garcia, Elsa; Zelikin, Alexander N. & Münch, Jan
