Host Porphobilinogen Deaminase Deficiency Confers Malaria Resistance in Plasmodium chabaudi but Not in Plasmodium berghei or Plasmodium falciparum During Intraerythrocytic Growth

dc.contributor.authorSchnider, Cilly
dc.contributor.authorYang, Hao
dc.contributor.authorStarrs, Lora
dc.contributor.authorEhmann, Anna
dc.contributor.authorRahimi, Farid
dc.contributor.authorDi Pierro, Elena
dc.contributor.authorGraziadei, Giovanna
dc.contributor.authorMatthews, Kathryn
dc.contributor.authorde Koning-Ward, Tania F.
dc.contributor.authorBauer, Denis C
dc.contributor.authorFoote, Simon
dc.contributor.authorBurgio, Gaetan
dc.contributor.authorMcMorran, Brendan
dc.date.accessioned2022-07-26T02:16:55Z
dc.date.available2022-07-26T02:16:55Z
dc.date.issued2020
dc.date.updated2023-10-22T07:16:09Z
dc.description.abstractAn important component in host resistance to malaria infection are inherited mutations that give rise to abnormalities and deficiencies in erythrocyte proteins and enzymes. Understanding how such mutations confer protection against the disease may be useful for developing new treatment strategies. A mouse ENU-induced mutagenesis screen for novel malaria resistance-conferring mutations identified a novel non-sense mutation in the gene encoding porphobilinogen deaminase (PBGD) in mice, denoted here as PbgdMRI58155. Heterozygote PbgdMRI58155 mice exhibited ~50% reduction in cellular PBGD activity in both mature erythrocytes and reticulocytes, although enzyme activity was ~10 times higher in reticulocytes than erythrocytes. When challenged with blood-stage P. chabaudi, which preferentially infects erythrocytes, heterozygote mice showed a modest but significant resistance to infection, including reduced parasite growth. A series of assays conducted to investigate the mechanism of resistance indicated that mutant erythrocyte invasion by P. chabaudi was normal, but that following intraerythrocytic establishment a significantly greater proportions of parasites died and therefore, affected their ability to propagate. The Plasmodium resistance phenotype was not recapitulated in Pbgd-deficient mice infected with P. berghei, which prefers reticulocytes, or when P. falciparum was cultured in erythrocytes from patients with acute intermittent porphyria (AIP), which had modest (20-50%) reduced levels of PBGD. Furthermore, the growth of Pbgd-null P. falciparum and Pbgd-null P. berghei parasites, which grew at the same rate as their wild-type counterparts in normal cells, were not affected by the PBGD-deficient background of the AIP erythrocytes or Pbgd-deficient mice. Our results confirm the dispensability of parasite PBGD for P. berghei infection and intraerythrocytic growth of P. falciparum, but for the first time identify a requirement for host erythrocyte PBGD by P. chabaudi during in vivo blood stage infection.
dc.description.sponsorshipThe authors were supported by an International Macquarie University Research Excellence Scholarship (CS), the NHMRC (490037, 605524, APP1047090, and APP1066502), the Australian Research Council (DP120100061) and the National Collaborative Research Infrastructure (NCRIS) via the Australian Phenomics Network (APN).en_AU
dc.format.mimetypeapplication/pdfen_AU
dc.identifier.issn2235-2988en_AU
dc.identifier.urihttp://hdl.handle.net/1885/269931
dc.language.isoen_AUen_AU
dc.provenanceThis is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en_AU
dc.publisherFrontiers Research Foundation
dc.relationhttp://purl.org/au-research/grants/nhmrc/490037
dc.relationhttp://purl.org/au-research/grants/nhmrc/605524
dc.relationhttp://purl.org/au-research/grants/nhmrc/1047090
dc.relationhttp://purl.org/au-research/grants/nhmrc/1066502
dc.relationhttp://purl.org/au-research/grants/arc/DP120100061
dc.rightsCopyright © 2020 Schnider, Yang, Starrs, Ehmann, Rahimi, Di Pierro, Graziadei, Matthews, De Koning-Ward, Bauer, Foote, Burgio and McMorran.
dc.rights.licenseCreative Commons Attribution License (CC BY)en_AU
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_AU
dc.sourceFrontiers in Cellular and Infection Microbiology
dc.subjectmalaria, Plasmodium
dc.subjecthost resistance
dc.subjectintraerythrocytic growth
dc.subjectporphobilinogen [deaminase]
dc.titleHost Porphobilinogen Deaminase Deficiency Confers Malaria Resistance in Plasmodium chabaudi but Not in Plasmodium berghei or Plasmodium falciparum During Intraerythrocytic Growth
dc.typeJournal article
dcterms.accessRightsOpen Accessen_AU
local.bibliographicCitation.issue464en_AU
local.bibliographicCitation.lastpage12en_AU
local.bibliographicCitation.startpage1en_AU
local.contributor.affiliationSchnider, Cilly, College of Health and Medicine, ANUen_AU
local.contributor.affiliationYang, Hao, College of Health and Medicine, ANUen_AU
local.contributor.affiliationStarrs, Lora, College of Health and Medicine, ANUen_AU
local.contributor.affiliationEhmann, Anna, College of Health and Medicine, ANUen_AU
local.contributor.affiliationRahimi, Farid, College of Science, ANUen_AU
local.contributor.affiliationDi Pierro, Elena, Rare Diseases Centeren_AU
local.contributor.affiliationGraziadei, Giovanna, Rare Diseases Centeren_AU
local.contributor.affiliationMatthews, Kathryn, Deakin Universityen_AU
local.contributor.affiliationde Koning-Ward, Tania F., Deakin Universityen_AU
local.contributor.affiliationBauer, Denis C, CSIRO Sydneyen_AU
local.contributor.affiliationFoote, Simon, College of Science, ANUen_AU
local.contributor.affiliationBurgio, Gaetan, College of Health and Medicine, ANUen_AU
local.contributor.affiliationMcMorran, Brendan, College of Health and Medicine, ANUen_AU
local.contributor.authoremailu5402096@anu.edu.auen_AU
local.contributor.authoruidSchnider, Cilly, t1927en_AU
local.contributor.authoruidYang, Hao, u5402096en_AU
local.contributor.authoruidStarrs, Lora, u4301798en_AU
local.contributor.authoruidEhmann, Anna, u1022514en_AU
local.contributor.authoruidRahimi, Farid, u4885897en_AU
local.contributor.authoruidFoote, Simon, u5697711en_AU
local.contributor.authoruidBurgio, Gaetan, u5727247en_AU
local.contributor.authoruidMcMorran, Brendan, u5267721en_AU
local.description.notesImported from ARIESen_AU
local.identifier.absfor310702 - Infectious agentsen_AU
local.identifier.absfor310100 - Biochemistry and cell biologyen_AU
local.identifier.absfor320704 - Medical parasitologyen_AU
local.identifier.ariespublicationa383154xPUB14728en_AU
local.identifier.citationvolume10en_AU
local.identifier.doi10.3389/fcimb.2020.00464en_AU
local.identifier.scopusID2-s2.0-85091027977
local.identifier.thomsonIDWOS:000570512800001
local.identifier.uidSubmittedBya383154en_AU
local.publisher.urlhttps://www.frontiersin.org/journals/cellular-and-infection-microbiologyen_AU
local.type.statusPublished Versionen_AU

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