Nitric Oxide Resistance in <i>Leishmania</i> (<i>Viannia</i>) <i>braziliensis</i> Involves Regulation of Glucose Consumption, Glutathione Metabolism and Abundance of Pentose Phosphate Pathway Enzymes
In American Tegumentary Leishmaniasis production of cytokines, reactive oxygen species and nitric oxide (NO) by host macrophages normally lead to parasite death. However, some <i>Leishmania braziliensis</i> strains exhibit natural NO resistance. NO-resistant strains cause more lesions an...
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| Format: | Article |
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MDPI AG
2022-01-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/2/277 |
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| author | Nathalia Pinho Ana Cristina Bombaça Jacek R. Wiśniewski Geovane Dias-Lopes Leonardo Saboia-Vahia Elisa Cupolillo José Batista de Jesus Roque P. de Almeida Gabriel Padrón Rubem Menna-Barreto Patricia Cuervo |
| author_facet | Nathalia Pinho Ana Cristina Bombaça Jacek R. Wiśniewski Geovane Dias-Lopes Leonardo Saboia-Vahia Elisa Cupolillo José Batista de Jesus Roque P. de Almeida Gabriel Padrón Rubem Menna-Barreto Patricia Cuervo |
| author_sort | Nathalia Pinho |
| collection | DOAJ |
| description | In American Tegumentary Leishmaniasis production of cytokines, reactive oxygen species and nitric oxide (NO) by host macrophages normally lead to parasite death. However, some <i>Leishmania braziliensis</i> strains exhibit natural NO resistance. NO-resistant strains cause more lesions and are frequently more resistant to antimonial treatment than NO-susceptible ones, suggesting that NO-resistant parasites are endowed with specific mechanisms of survival and persistence. To tests this, we analyzed the effect of pro- and antioxidant molecules on the infectivity in vitro of <i>L. braziliensis</i> strains exhibiting polar phenotypes of resistance or susceptibility to NO. In addition, we conducted a comprehensive quantitative mass spectrometry-based proteomics analysis of those parasites. NO-resistant parasites were more infective to peritoneal macrophages, even in the presence of high levels of reactive species. Principal component analysis of protein concentration values clearly differentiated NO-resistant from NO-susceptible parasites, suggesting that there are natural intrinsic differences at molecular level among those strains. Upon NO exposure, NO-resistant parasites rapidly modulated their proteome, increasing their total protein content and glutathione (GSH) metabolism. Furthermore, NO-resistant parasites showed increased glucose analogue uptake, and increased abundance of phosphotransferase and G6PDH after nitrosative challenge, which can contribute to NADPH pool maintenance and fuel the reducing conditions for the recovery of GSH upon NO exposure. Thus, increased glucose consumption and GSH-mediated redox capability may explain the natural resistance of <i>L. braziliensis</i> against NO. |
| first_indexed | 2024-03-09T22:44:27Z |
| format | Article |
| id | doaj.art-52278bc05eba45ac9dabf9df71915365 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T22:44:27Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-52278bc05eba45ac9dabf9df719153652023-11-23T18:31:14ZengMDPI AGAntioxidants2076-39212022-01-0111227710.3390/antiox11020277Nitric Oxide Resistance in <i>Leishmania</i> (<i>Viannia</i>) <i>braziliensis</i> Involves Regulation of Glucose Consumption, Glutathione Metabolism and Abundance of Pentose Phosphate Pathway EnzymesNathalia Pinho0Ana Cristina Bombaça1Jacek R. Wiśniewski2Geovane Dias-Lopes3Leonardo Saboia-Vahia4Elisa Cupolillo5José Batista de Jesus6Roque P. de Almeida7Gabriel Padrón8Rubem Menna-Barreto9Patricia Cuervo10Laboratório de Pesquisa em Leishmanioses, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, BrazilLaboratório de Biologia Celular, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, BrazilBiochemical Proteomics Group, Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, 82152 Planegg, GermanyLaboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, BrazilLaboratório de Pesquisa em Leishmanioses, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, BrazilLaboratório de Pesquisa em Leishmanioses, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, BrazilDepartamento de Medicina, Universidade Federal de São João Del Rei, São João del Rei 35501-296, MG, BrazilDepartment of Medicine, Hospital Universitário, EBSERH, Universidade Federal de Sergipe, Aracaju 49100-000, SE, BrazilLaboratório de Pesquisa em Leishmanioses, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, BrazilLaboratório de Biologia Celular, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, BrazilLaboratório de Pesquisa em Leishmanioses, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, BrazilIn American Tegumentary Leishmaniasis production of cytokines, reactive oxygen species and nitric oxide (NO) by host macrophages normally lead to parasite death. However, some <i>Leishmania braziliensis</i> strains exhibit natural NO resistance. NO-resistant strains cause more lesions and are frequently more resistant to antimonial treatment than NO-susceptible ones, suggesting that NO-resistant parasites are endowed with specific mechanisms of survival and persistence. To tests this, we analyzed the effect of pro- and antioxidant molecules on the infectivity in vitro of <i>L. braziliensis</i> strains exhibiting polar phenotypes of resistance or susceptibility to NO. In addition, we conducted a comprehensive quantitative mass spectrometry-based proteomics analysis of those parasites. NO-resistant parasites were more infective to peritoneal macrophages, even in the presence of high levels of reactive species. Principal component analysis of protein concentration values clearly differentiated NO-resistant from NO-susceptible parasites, suggesting that there are natural intrinsic differences at molecular level among those strains. Upon NO exposure, NO-resistant parasites rapidly modulated their proteome, increasing their total protein content and glutathione (GSH) metabolism. Furthermore, NO-resistant parasites showed increased glucose analogue uptake, and increased abundance of phosphotransferase and G6PDH after nitrosative challenge, which can contribute to NADPH pool maintenance and fuel the reducing conditions for the recovery of GSH upon NO exposure. Thus, increased glucose consumption and GSH-mediated redox capability may explain the natural resistance of <i>L. braziliensis</i> against NO.https://www.mdpi.com/2076-3921/11/2/277<i>Leishmania braziliensis</i>nitric oxide resistanceAmerican Tegumentary Leishmaniasis (ATL)nitrosative stressreactive oxygen speciesreactive nitrogen species |
| spellingShingle | Nathalia Pinho Ana Cristina Bombaça Jacek R. Wiśniewski Geovane Dias-Lopes Leonardo Saboia-Vahia Elisa Cupolillo José Batista de Jesus Roque P. de Almeida Gabriel Padrón Rubem Menna-Barreto Patricia Cuervo Nitric Oxide Resistance in <i>Leishmania</i> (<i>Viannia</i>) <i>braziliensis</i> Involves Regulation of Glucose Consumption, Glutathione Metabolism and Abundance of Pentose Phosphate Pathway Enzymes Antioxidants <i>Leishmania braziliensis</i> nitric oxide resistance American Tegumentary Leishmaniasis (ATL) nitrosative stress reactive oxygen species reactive nitrogen species |
| title | Nitric Oxide Resistance in <i>Leishmania</i> (<i>Viannia</i>) <i>braziliensis</i> Involves Regulation of Glucose Consumption, Glutathione Metabolism and Abundance of Pentose Phosphate Pathway Enzymes |
| title_full | Nitric Oxide Resistance in <i>Leishmania</i> (<i>Viannia</i>) <i>braziliensis</i> Involves Regulation of Glucose Consumption, Glutathione Metabolism and Abundance of Pentose Phosphate Pathway Enzymes |
| title_fullStr | Nitric Oxide Resistance in <i>Leishmania</i> (<i>Viannia</i>) <i>braziliensis</i> Involves Regulation of Glucose Consumption, Glutathione Metabolism and Abundance of Pentose Phosphate Pathway Enzymes |
| title_full_unstemmed | Nitric Oxide Resistance in <i>Leishmania</i> (<i>Viannia</i>) <i>braziliensis</i> Involves Regulation of Glucose Consumption, Glutathione Metabolism and Abundance of Pentose Phosphate Pathway Enzymes |
| title_short | Nitric Oxide Resistance in <i>Leishmania</i> (<i>Viannia</i>) <i>braziliensis</i> Involves Regulation of Glucose Consumption, Glutathione Metabolism and Abundance of Pentose Phosphate Pathway Enzymes |
| title_sort | nitric oxide resistance in i leishmania i i viannia i i braziliensis i involves regulation of glucose consumption glutathione metabolism and abundance of pentose phosphate pathway enzymes |
| topic | <i>Leishmania braziliensis</i> nitric oxide resistance American Tegumentary Leishmaniasis (ATL) nitrosative stress reactive oxygen species reactive nitrogen species |
| url | https://www.mdpi.com/2076-3921/11/2/277 |
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