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Genetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to Invasive Pulmonary Aspergillosis

2021-05-28Journal article Open access
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dc.contributor.authorGonçalves, Samuel M.
dc.contributor.authorAntunes, Daniela
dc.contributor.authorLeite, Luis
dc.contributor.authorMercier, Toine
dc.contributor.authorHorst, Rob Ter
dc.contributor.authorVieira, Joana
dc.contributor.authorEspada, Eduardo
dc.contributor.authorPinho Vaz, Carlos
dc.contributor.authorBranca, Rosa
dc.contributor.authorCampilho, Fernando
dc.contributor.authorFreitas, Fátima
dc.contributor.authorLigeiro, Dário
dc.contributor.authorMarques, António
dc.contributor.authorvan de Veerdonk, Frank L.
dc.contributor.authorJoosten, Leo A. B.
dc.contributor.authorLagrou, Katrien
dc.contributor.authorMaertens, Johan
dc.contributor.authorNetea, Mihai G.
dc.contributor.authorLacerda, João
dc.contributor.authorCampos, António
dc.contributor.authorCunha, Cristina
dc.contributor.authorCarvalho, Agostinho
dc.date.accessioned2021-07-19T12:03:49Z
dc.date.available2021-07-19T12:03:49Z
dc.date.issued2021-05-28
dc.descriptionCopyright © 2021 Gonçalves et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.pt_PT
dc.description.abstractActivation 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.pt_PT
dc.description.sponsorshipThis 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationmBio. 2021 May 28:e0036921.pt_PT
dc.identifier.doi10.1128/mBio.00369-21pt_PT
dc.identifier.eissn2150-7511
dc.identifier.issn2161-2129
dc.identifier.urihttp://hdl.handle.net/10451/48989
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherASM Journalspt_PT
dc.relationNORTE-01-0145-FEDER-000039pt_PT
dc.relationLCF/PR/HR17/52190003pt_PT
dc.relationLA - ICVS/3B's - Associate Laboratory
dc.relationLA - ICVS/3B's - Associate Laboratory
dc.relationMetabolic Regulation of Antifungal Immunity through the Mevalonate Pathway
dc.relationThe role of Pentraxin-3 in the immunometabolic regulation of antifungal immunity
dc.relationNot Available
dc.relationNot Available
dc.relation.publisherversionhttps://journals.asm.org/journal/mbiopt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAspergilluspt_PT
dc.subjectPFKFB3pt_PT
dc.subjectAntifungal immunitypt_PT
dc.subjectImmunometabolismpt_PT
dc.subjectInvasive pulmonary aspergillosispt_PT
dc.subjectMacrophagept_PT
dc.subjectSingle nucleotide polymorphismpt_PT
dc.subjectStem cell transplantationpt_PT
dc.titleGenetic variation in PFKFB3 impairs antifungal immunometabolic responses and predisposes to Invasive Pulmonary Aspergillosispt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleLA - ICVS/3B's - Associate Laboratory
oaire.awardTitleLA - ICVS/3B's - Associate Laboratory
oaire.awardTitleMetabolic Regulation of Antifungal Immunity through the Mevalonate Pathway
oaire.awardTitleThe role of Pentraxin-3 in the immunometabolic regulation of antifungal immunity
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oaire.awardURIinfo:eu-repo/grantAgreement/FCT/CEEC IND 2017/CEECIND%2F03628%2F2017%2FCP1458%2FCT0026/PT
oaire.citation.titlemBiopt_PT
oaire.fundingStream9471 - RIDTI
oaire.fundingStream9471 - RIDTI
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamPOR_NORTE
oaire.fundingStreamPOR_NORTE
oaire.fundingStreamCEEC IND 2018
oaire.fundingStreamCEEC IND 2017
person.familyNameEspada
person.familyNameLacerda
person.givenNameEduardo
person.givenNameJoão
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person.identifier.ciencia-id6412-2B63-2364
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