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Genetic determinants of fungi-induced ROS production are associated with the risk of invasive pulmonary aspergillosis

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dc.contributor.authorMatzaraki, Vasiliki
dc.contributor.authorBeno, Alexandra
dc.contributor.authorJaeger, Martin
dc.contributor.authorGresnigt, Mark S.
dc.contributor.authorKeur, Nick
dc.contributor.authorBoahen, Collins
dc.contributor.authorCunha, Cristina
dc.contributor.authorGonçalves, Samuel M.
dc.contributor.authorLeite, Luis
dc.contributor.authorLacerda, João
dc.contributor.authorCampos, António
dc.contributor.authorvan de Veerdonk, Frank L.
dc.contributor.authorJoosten, Leo
dc.contributor.authorNetea, Mihai G.
dc.contributor.authorCarvalho, Agostinho
dc.contributor.authorKumar, Vinod
dc.date.accessioned2022-11-25T15:31:40Z
dc.date.available2022-11-25T15:31:40Z
dc.date.issued2022
dc.description© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).pt_PT
dc.description.abstractReactive oxygen species (ROS) are an essential component of the host defense against fungal infections. However, little is known about how common genetic variation affects ROS-mediated antifungal host defense. In the present study, we investigated the genetic factors that regulate ROS production capacity in response to the two human fungal pathogens: Candida albicans and Aspergillus fumigatus. We investigated fungal-stimulated ROS production by immune cells isolated from a population-based cohort of approximately 200 healthy individuals (200FG cohort), and mapped ROS-quantitative trait loci (QTLs). We identified several genetic loci that regulate ROS levels (P < 9.99 × 10-6), with some of these loci being pathogen-specific, and others shared between the two fungi. These ROS-QTLs were investigated for their influence on the risk of invasive pulmonary aspergillosis (IPA) in a disease relevant context. We stratified hematopoietic stem-cell transplant (HSCT) recipients based on the donor's SNP genotype and tested their impact on the risk of IPA. We identified rs4685368 as a ROS-QTL locus that was significantly associated with an increased risk of IPA after controlling for patient age and sex, hematological malignancy, type of transplantation, conditioning regimen, acute graft-versus-host-disease grades III-IV, and antifungal prophylaxis. Collectively, this data provides evidence that common genetic variation can influence ROS production capacity, and, importantly, the risk of developing IPA among HSCT recipients. This evidence warrants further research for patient stratification based on the genetic profiling that would allow the identifications of patients at high-risk for an invasive fungal infection, and who would benefit the most from a preventive strategy.pt_PT
dc.description.sponsorshipThis study was supported by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 847507 (HDM-FUN). MGN was supported by an ERC Advanced grant (833247) and a Spinoza grant of the Netherlands Association for Scientific Research. VK was supported by a Research Grant [2017] of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Hypatia tenure track grant. AC was supported by the Fundação para a Ciência e a Tecnologia (FCT) (UIDB/50026/2020 and UIDP/50026/2020), the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000039), and the “la Caixa” Foundation (ID 100010434) and FCT under the agreement LCF/PR/HR17/52190003. CC was supported by FCT (CEECIND/04058/2018 and PTDC/SAU-SER/29,635/2017) and the Gilead Research Scholars Program – Antifungals. SMG was the recipient of a PhD fellowship funded by FCT (SFRH/BD/136,814/2018). MSG was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft - DFG) Emmy Noether Program (project no. 434385622/GR 5617/1-1).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationRedox Biol. 2022 Jul 4;55:102391pt_PT
dc.identifier.doi10.1016/j.redox.2022.102391pt_PT
dc.identifier.eissn2213-2317
dc.identifier.urihttp://hdl.handle.net/10451/55248
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationNORTE-01-0145-FEDER-000039pt_PT
dc.relationLA - ICVS/3B's - Associate Laboratory
dc.relationLA - ICVS/3B's - Associate Laboratory
dc.relationNot Available
dc.relationMetabolic Regulation of Antifungal Immunity through the Mevalonate Pathway
dc.relation.publisherversionhttps://www.sciencedirect.com/journal/redox-biologypt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectA. fumigatuspt_PT
dc.subjectC. albicanspt_PT
dc.subjectInvasive aspergillosispt_PT
dc.subjectQTLspt_PT
dc.subjectReactive oxygen speciespt_PT
dc.subjectStem-cell transplant recipientspt_PT
dc.titleGenetic determinants of fungi-induced ROS production are associated with the risk of 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.awardTitleNot Available
oaire.awardTitleMetabolic Regulation of Antifungal Immunity through the Mevalonate Pathway
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F50026%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F50026%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/CEEC IND 2018/CEECIND%2F04058%2F2018%2FCP1581%2FCT0015/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC%2FSAU-SER%2F29635%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/POR_NORTE/SFRH%2FBD%2F136814%2F2018/PT
oaire.citation.titleRedox Biologypt_PT
oaire.citation.volume55pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamCEEC IND 2018
oaire.fundingStream9471 - RIDTI
oaire.fundingStreamPOR_NORTE
person.familyNameLacerda
person.givenNameJoão
person.identifier559297
person.identifier.ciencia-id6412-2B63-2364
person.identifier.orcid0000-0003-1351-2809
person.identifier.scopus-author-id6603819609
project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
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project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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