Targeting Macrophage Histone H3 Modification as a Leishmania Strategy to Dampen the NF-κB/NLRP3-Mediated Inflammatory Response
Hervé Lecoeur,
Eric Prina,
Thibault Rosazza,
Kossiwa Kokou,
Paya N’Diaye,
Nathalie Aulner,
Hugo Varet,
Giovanni Bussotti,
Yue Xing,
Geneviève Milon,
Robert Weil,
Guangxun Meng,
Gerald F. Späth
Affiliations
Hervé Lecoeur
INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, Département des Parasites et Insectes Vecteurs, Institut Pasteur, 25 Rue du Dr Roux, 75015 Paris, France; Institut Pasteur of Shanghai, The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Chinese Academy of Sciences, Shanghai 200031, China; Institut Pasteur International Mixed Unit “Inflammation and Leishmania infection,” Paris, France
Eric Prina
INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, Département des Parasites et Insectes Vecteurs, Institut Pasteur, 25 Rue du Dr Roux, 75015 Paris, France; Institut Pasteur International Mixed Unit “Inflammation and Leishmania infection,” Paris, France
Thibault Rosazza
INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, Département des Parasites et Insectes Vecteurs, Institut Pasteur, 25 Rue du Dr Roux, 75015 Paris, France; Institut Pasteur International Mixed Unit “Inflammation and Leishmania infection,” Paris, France
Kossiwa Kokou
INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, Département des Parasites et Insectes Vecteurs, Institut Pasteur, 25 Rue du Dr Roux, 75015 Paris, France; Institut Pasteur of Shanghai, The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Chinese Academy of Sciences, Shanghai 200031, China; Institut Pasteur International Mixed Unit “Inflammation and Leishmania infection,” Paris, France
Paya N’Diaye
INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, Département des Parasites et Insectes Vecteurs, Institut Pasteur, 25 Rue du Dr Roux, 75015 Paris, France
Nathalie Aulner
Unité de Technologie et de Services Photonic BioImaging, Centre de Recherche et de Ressources Technologiques, Direction de la Technologie et des Programmes Scientifiques, Institut Pasteur, 28 Rue du Dr Roux, 75015 Paris, France
Hugo Varet
Hub de Bioinformatique et Biostatistique, Département Biologie Computationnelle, Institut Pasteur, USR 3756 CNRS, Paris, France
Giovanni Bussotti
Hub de Bioinformatique et Biostatistique, Département Biologie Computationnelle, Institut Pasteur, USR 3756 CNRS, Paris, France
Yue Xing
Institut Pasteur of Shanghai, The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Chinese Academy of Sciences, Shanghai 200031, China; Institut Pasteur International Mixed Unit “Inflammation and Leishmania infection,” Paris, France
Geneviève Milon
Institut Pasteur, 25 Rue du Dr Roux, 75015 Paris, France
Robert Weil
Sorbonne Universités, Institut National de la Santé et de la Recherche Médicale (INSERM, UMR1135), Centre National de la Recherche Scientifique (CNRS, ERL8255), Centre d’Immunologie et des Maladies Infectieuses CIMI, Paris, France
Guangxun Meng
Institut Pasteur of Shanghai, The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Chinese Academy of Sciences, Shanghai 200031, China; Institut Pasteur International Mixed Unit “Inflammation and Leishmania infection,” Paris, France
Gerald F. Späth
INSERM U1201, Unité de Parasitologie Moléculaire et Signalisation, Département des Parasites et Insectes Vecteurs, Institut Pasteur, 25 Rue du Dr Roux, 75015 Paris, France; Institut Pasteur International Mixed Unit “Inflammation and Leishmania infection,” Paris, France; Corresponding author
Summary: Aberrant macrophage activation during intracellular infection generates immunopathologies that can cause severe human morbidity. A better understanding of immune subversion strategies and macrophage phenotypic and functional responses is necessary to design host-directed intervention strategies. Here, we uncover a fine-tuned transcriptional response that is induced in primary and lesional macrophages infected by the parasite Leishmania amazonensis and dampens NF-κB and NLRP3 inflammasome activation. Subversion is amastigote-specific and characterized by a decreased expression of activating and increased expression of de-activating components of these pro-inflammatory pathways, thus revealing a regulatory dichotomy that abrogates the anti-microbial response. Changes in transcript abundance correlate with histone H3K9/14 hypoacetylation and H3K4 hypo-trimethylation in infected primary and lesional macrophages at promoters of NF-κB-related, pro-inflammatory genes. Our results reveal a Leishmania immune subversion strategy targeting host cell epigenetic regulation to establish conditions beneficial for parasite survival and open avenues for host-directed, anti-microbial drug discovery. : Lecoeur et al. demonstrate that the parasite Leishmania amazonensis modifies expression of NF-kB-related genes and prevents NLRP3 inflammasome activation of host macrophages in vitro and in vivo by changing histone H3 modifications at the promotor of pro-inflammatory genes. This mechanism of immune subversion opens avenues for host-directed, anti-leishmanial therapies. Keywords: Leishmania amazonensis, amastigotes, lesional macrophage, NF-κB, NLRP3 inflammasome, H3 acetylation, H3 methylation, epigenetics, histone
