Protein methyltransferase 7 deficiency in Leishmania major increases neutrophil associated pathology in murine model

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Diniz, Juliana Alcoforado ^[1] ; Chaves, Mariana M. ^{[2, 3]} ; Vaselek, Slavica ^[4] ; Miserani Magalhaes, Rubens D. ^[1] ; Ricci-Azevedo, Rafael ^[1] ; de Carvalho, Renan V. H. ^[1] ; Lorenzon, Lucas B. ^[1] ; Ferreira, Tiago R. ^[2] ; Zamboni, Dario ^[1] ; Walrad, Pegine B. ^[5] ; Volf, Petr ^[4] ; Sacks, David L. ^[2] ; Cruz, Angela K. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Cell & Mol Biol, Ribeirao Preto, SP - Brazil

^[2] NIAID, Lab Parasit Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 - USA

^[3] Univ Sao Paulo, Dept Cell & Mol Biol, Ribeirao Preto, SP - Brazil

^[4] Charles Univ Prague, Dept Parasitol, Prague - Czech Republic

^[5] Univ York, Dept Biol, York, N Yorkshire - England

• Tipo de documento: Artigo Científico
• Fonte: PLoS Neglected Tropical Diseases; v. 15, n. 3 MAR 2021.
• Citações Web of Science: 0

Resumo

Author summary Understanding the genetics of Leishmania, a protozoan parasite causing leishmaniasis, is relevant for understanding fundamental questions on the pathogen's biology and its interaction with hosts. We explore mechanisms used by Leishmania to promptly adapt to different hosts investigating the control of gene expression occurring at the post-transcriptional level in the parasite. Methylation of arginine performed by Protein Arginine Methyltransferase (PRMTs), among other post-translational modifications, may alter the function and interactions of target proteins, some of them are RNA binding proteins, known regulators of gene expression. In this study, we unveil the impact of PRMT7 on parasite development and pathogenicity. In addition to a negative correlation between the levels of LmjPRMT7 and parasite pathogenicity, we observed an impairment of the parasite development in the sand fly vector. Remarkably, despite a severe lesion development in mice, we observed no differences in parasite burden between infections with the pathogenic LmjPRMT7 knockout parasite or the attenuated parental line. Instead, the severe pathology observed is associated with an exacerbated inflammatory response correlated with excessive neutrophil recruitment. Leishmania major is the main causative agent of cutaneous leishmaniasis in the Old World. In Leishmania parasites, the lack of transcriptional control is mostly compensated by post-transcriptional mechanisms. Methylation of arginine is a conserved post-translational modification executed by Protein Arginine Methyltransferase (PRMTs). The genome from L. major encodes five PRMT homologs, including the cytosolic protein associated with several RNA-binding proteins, LmjPRMT7. It has been previously reported that LmjPRMT7 could impact parasite infectivity. In addition, a more recent work has clearly shown the importance of LmjPRMT7 in RNA-binding capacity and protein stability of methylation targets, demonstrating the role of this enzyme as an important epigenetic regulator of mRNA metabolism. In this study, we unveil the impact of PRMT7-mediated methylation on parasite development and virulence. Our data reveals that higher levels of LmjPRMT7 can impair parasite pathogenicity, and that deletion of this enzyme rescues the pathogenic phenotype of an attenuated strain of L. major. Interestingly, lesion formation caused by LmjPRMT7 knockout parasites is associated with an exacerbated inflammatory reaction in the tissue correlated with an excessive neutrophil recruitment. Moreover, the absence of LmjPRMT7 also impairs parasite development within the sand fly vector Phlebotomus duboscqi. Finally, a transcriptome analysis shed light onto possible genes affected by depletion of this enzyme. Taken together, this study highlights how post-transcriptional regulation can affect different aspects of the parasite biology. (AU)

• Processo FAPESP: 19/18607-5 - Identificação computacional e caracterização estrutural de RNA não codificadores em Leishmania braziliensis
• Beneficiário: Rubens Daniel Miserani Magalhães
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/14657-0 - O impacto da metilação mediada por PRMT7 no processo de diferenciação de promastigotas em amastigotas e virulência do parasito Leishmania major
• Beneficiário: Juliana Alcoforado Diniz
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 18/02761-2 - Papel da proteina arginina metil transferase 7 na infectividade e diferenciacao de Leishmania major
• Beneficiário: Juliana Alcoforado Diniz
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 17/02998-0 - Efeitos de Toxoplasma gondii e Paracoccidioides brasiliensis, exercidos através de suas respectivas lectinas sobre vias intracelulares ativadas pelo reconhecimento de glicanos N-ligados a receptores do tipo Toll em neutrófilos
• Beneficiário: Rafael Ricci de Azevedo
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 15/13618-8 - Regulando trans-reguladores: investigação da via molecular de PRMT7 como regulador epigenético da virulência em Leishmania
• Beneficiário: Angela Kaysel Cruz
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 16/00969-0 - Estudo do papel de arginina metiltransferases em Leishmania braziliensis
• Beneficiário: Lucas Bigolin Lorenzon
• Modalidade de apoio: Bolsas no Brasil - Doutorado