1. Leishmania amazonensis downregulates macrophage iNOS expression via Histone Deacetylase 1 (HDAC1): a novel parasite evasion mechanism
- Author
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Nicolas Fasel, Ulisses Gazos Lopes, Gabrielle B L Silva, Áislan de Carvalho Vivarini, Carolina Torturella Rath, José Vitorino dos Santos, Renata M. Pereira, Teresa Cristina Calegari-Silva, Alessandra Mattos Saliba, Carlos Eduardo Pereira Corbett, Karina Luiza Dias-Teixeira, Amanda S S Pacheco, Charlene A S Pinto, and Claudia Maria de Castro Gomes
- Subjects
0301 basic medicine ,Adult ,Male ,animal structures ,Adolescent ,Sp1 Transcription Factor ,030106 microbiology ,Immunology ,Cells, Cultured ,Child ,Extinction, Biological ,Female ,Histone Deacetylase 1/genetics ,Histone Deacetylase 1/metabolism ,Host-Parasite Interactions ,Humans ,Immune Evasion ,Leishmania braziliensis/physiology ,Leishmaniasis, Cutaneous/genetics ,Leishmaniasis, Cutaneous/immunology ,Macrophages/immunology ,Middle Aged ,Nitric Oxide/metabolism ,Nitric Oxide Synthase Type II/genetics ,Nitric Oxide Synthase Type II/metabolism ,Parasite Load ,Promoter Regions, Genetic/genetics ,Protein Binding ,RNA, Small Interfering/genetics ,Skin/pathology ,Sp1 Transcription Factor/metabolism ,Young Adult ,HDAC1 ,Leishmaniasis ,Macrophage ,Parasitse ,Leishmaniasis, Cutaneous ,Nitric Oxide Synthase Type II ,Histone Deacetylase 1 ,Biology ,Nitric Oxide ,Leishmania braziliensis ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,Downregulation and upregulation ,Gene expression ,Immunology and Allergy ,Gene silencing ,RNA, Small Interfering ,Promoter Regions, Genetic ,Skin ,Macrophages ,Leishmania ,biology.organism_classification ,Molecular biology ,Nitric oxide synthase ,030104 developmental biology ,chemistry ,biology.protein ,CROMATINA ,Intracellular - Abstract
The induced expression of nitric oxide synthase (iNOS) controls the intracellular growth of Leishmania in infected macrophages. Histones deacetylases (HDACs) negatively regulate gene expression through the formation of complexes containing transcription factors such as NF-κB p50/50. Herein, we demonstrated the occupancy of p50/p50_HDAC1 to iNOS promoter associated with reduced levels of H3K9Ac. Remarkably, we found increased levels of HDAC1 in L. amazonensis-infected macrophages. HDAC1 upregulation was not found in L. major-infected macrophages. The parasite intracellular load was reduced in HDAC1 knocked-down macrophages, which presented increased nitric oxide levels. HDAC1 silencing led to the occupancy of CBP/p300 to iNOS promoter and the rise of H3K9Ac modification. Importantly, the immunostaining of skin samples from hiporeactive cutaneous leishmaniasis patients infected with L. amazonensis, revealed high levels of HDAC1. In brief, L. amazonensis induces HDAC1 in infected macrophages, which contribute to parasite survival and is associated to hiporeactive stage found in L. amazonensis infected patients.
- Published
- 2018