Genetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to Invasive Pulmonary Aspergillosis
| Autor(a) principal: | |
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| Data de Publicação: | 2021 |
| Outros Autores: | , , , , , , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10451/48989 |
Resumo: | Copyright © 2021 Gonçalves et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. |
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Genetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to Invasive Pulmonary AspergillosisAspergillusPFKFB3Antifungal immunityImmunometabolismInvasive pulmonary aspergillosisMacrophageSingle nucleotide polymorphismStem cell transplantationCopyright © 2021 Gonçalves et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.Activation of immune cells in response to fungal infection involves the reprogramming of their cellular metabolism to support antimicrobial effector functions. Although metabolic pathways such as glycolysis are known to represent critical regulatory nodes in antifungal immunity, it remains undetermined whether these are differentially regulated at the interindividual level. In this study, we identify a key role for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the immunometabolic responses to Aspergillus fumigatus. A genetic association study performed in 439 recipients of allogeneic hematopoietic stem cell transplantation (HSCT) and corresponding donors revealed that the donor, but not recipient, rs646564 variant in the PFKFB3 gene increased the risk of invasive pulmonary aspergillosis (IPA) after transplantation. The risk genotype impaired the expression of PFKFB3 by human macrophages in response to fungal infection, which was correlated with a defective activation of glycolysis and the ensuing antifungal effector functions. In patients with IPA, the risk genotype was associated with lower concentrations of cytokines in the bronchoalveolar lavage fluid samples. Collectively, these findings demonstrate the important contribution of genetic variation in PFKFB3 to the risk of IPA in patients undergoing HSCT and support its inclusion in prognostic tools to predict the risk of fungal infection in this clinical setting. IMPORTANCE The fungal pathogen Aspergillus fumigatus can cause severe and life-threatening forms of infection in immunocompromised patients. Activation of glycolysis is essential for innate immune cells to mount effective antifungal responses. In this study, we report the contribution of genetic variation in the key glycolytic activator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) to the risk of invasive pulmonary aspergillosis (IPA) after allogeneic hematopoietic stem cell transplantation. The PFKFB3 genotype associated with increased risk of infection was correlated with an impairment of the antifungal effector functions of macrophages in vitro and in patients with IPA. This work highlights the clinical relevance of genetic variation in PFKFB3 to the risk of IPA and supports its integration in risk stratification and preemptive measures for patients at high risk of IPA.This work was supported by the Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-SER/29635/2017, PTDC/MED-GEN/28778/2017, UIDB/50026/2020, and UIDP/50026/2020), the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000039), the Institut Mérieux (Mérieux Research Grant 2017), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID Research Grant 2017), the European Union’s Horizon 2020 research and innovation program under grant agreement no. 847507, and the “la Caixa” Foundation (ID 100010434) and FCT under the agreement LCF/PR/HR17/52190003. Individual support was provided by FCT (SFRH/BD/136814/2018 to S.M.G., PD/BD/137680/2018 to D.A., CEECIND/04058/2018 to C.C., and CEECIND/03628/2017 to A.C.). M.G.N. was supported by an ERC Advanced Grant and a Spinoza Grant of the Netherlands Organization for Scientific Research.ASM JournalsRepositório da Universidade de LisboaGonçalves, Samuel M.Antunes, DanielaLeite, LuisMercier, ToineHorst, Rob TerVieira, JoanaEspada, EduardoPinho Vaz, CarlosBranca, RosaCampilho, FernandoFreitas, FátimaLigeiro, DárioMarques, Antóniovan de Veerdonk, Frank L.Joosten, Leo A. B.Lagrou, KatrienMaertens, JohanNetea, Mihai G.Lacerda, JoãoCampos, AntónioCunha, CristinaCarvalho, Agostinho2021-07-19T12:03:49Z2021-05-282021-05-28T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/48989engmBio. 2021 May 28:e0036921.2161-212910.1128/mBio.00369-212150-7511info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-11-20T18:07:43Zoai:repositorio.ul.pt:10451/48989Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-11-20T18:07:43Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
| dc.title.none.fl_str_mv |
Genetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to Invasive Pulmonary Aspergillosis |
| title |
Genetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to Invasive Pulmonary Aspergillosis |
| spellingShingle |
Genetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to Invasive Pulmonary Aspergillosis Gonçalves, Samuel M. Aspergillus PFKFB3 Antifungal immunity Immunometabolism Invasive pulmonary aspergillosis Macrophage Single nucleotide polymorphism Stem cell transplantation |
| title_short |
Genetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to Invasive Pulmonary Aspergillosis |
| title_full |
Genetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to Invasive Pulmonary Aspergillosis |
| title_fullStr |
Genetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to Invasive Pulmonary Aspergillosis |
| title_full_unstemmed |
Genetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to Invasive Pulmonary Aspergillosis |
| title_sort |
Genetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to Invasive Pulmonary Aspergillosis |
| author |
Gonçalves, Samuel M. |
| author_facet |
Gonçalves, Samuel M. Antunes, Daniela Leite, Luis Mercier, Toine Horst, Rob Ter Vieira, Joana Espada, Eduardo Pinho Vaz, Carlos Branca, Rosa Campilho, Fernando Freitas, Fátima Ligeiro, Dário Marques, António van de Veerdonk, Frank L. Joosten, Leo A. B. Lagrou, Katrien Maertens, Johan Netea, Mihai G. Lacerda, João Campos, António Cunha, Cristina Carvalho, Agostinho |
| author_role |
author |
| author2 |
Antunes, Daniela Leite, Luis Mercier, Toine Horst, Rob Ter Vieira, Joana Espada, Eduardo Pinho Vaz, Carlos Branca, Rosa Campilho, Fernando Freitas, Fátima Ligeiro, Dário Marques, António van de Veerdonk, Frank L. Joosten, Leo A. B. Lagrou, Katrien Maertens, Johan Netea, Mihai G. Lacerda, João Campos, António Cunha, Cristina Carvalho, Agostinho |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
Gonçalves, Samuel M. Antunes, Daniela Leite, Luis Mercier, Toine Horst, Rob Ter Vieira, Joana Espada, Eduardo Pinho Vaz, Carlos Branca, Rosa Campilho, Fernando Freitas, Fátima Ligeiro, Dário Marques, António van de Veerdonk, Frank L. Joosten, Leo A. B. Lagrou, Katrien Maertens, Johan Netea, Mihai G. Lacerda, João Campos, António Cunha, Cristina Carvalho, Agostinho |
| dc.subject.por.fl_str_mv |
Aspergillus PFKFB3 Antifungal immunity Immunometabolism Invasive pulmonary aspergillosis Macrophage Single nucleotide polymorphism Stem cell transplantation |
| topic |
Aspergillus PFKFB3 Antifungal immunity Immunometabolism Invasive pulmonary aspergillosis Macrophage Single nucleotide polymorphism Stem cell transplantation |
| description |
Copyright © 2021 Gonçalves et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021-07-19T12:03:49Z 2021-05-28 2021-05-28T00:00:00Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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http://hdl.handle.net/10451/48989 |
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http://hdl.handle.net/10451/48989 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
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mBio. 2021 May 28:e0036921. 2161-2129 10.1128/mBio.00369-21 2150-7511 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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ASM Journals |
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ASM Journals |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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