Host Porphobilinogen Deaminase Deficiency Confers Malaria Resistance in Plasmodium chabaudi but Not in Plasmodium berghei or Plasmodium falciparum During Intraerythrocytic Growth
dc.contributor.author | Schnider, Cilly | |
dc.contributor.author | Yang, Hao | |
dc.contributor.author | Starrs, Lora | |
dc.contributor.author | Ehmann, Anna | |
dc.contributor.author | Rahimi, Farid | |
dc.contributor.author | Di Pierro, Elena | |
dc.contributor.author | Graziadei, Giovanna | |
dc.contributor.author | Matthews, Kathryn | |
dc.contributor.author | de Koning-Ward, Tania F. | |
dc.contributor.author | Bauer, Denis C | |
dc.contributor.author | Foote, Simon | |
dc.contributor.author | Burgio, Gaetan | |
dc.contributor.author | McMorran, Brendan | |
dc.date.accessioned | 2022-07-26T02:16:55Z | |
dc.date.available | 2022-07-26T02:16:55Z | |
dc.date.issued | 2020 | |
dc.date.updated | 2023-10-22T07:16:09Z | |
dc.description.abstract | An 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.sponsorship | The 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.mimetype | application/pdf | en_AU |
dc.identifier.issn | 2235-2988 | en_AU |
dc.identifier.uri | http://hdl.handle.net/1885/269931 | |
dc.language.iso | en_AU | en_AU |
dc.provenance | This 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.publisher | Frontiers Research Foundation | |
dc.relation | http://purl.org/au-research/grants/nhmrc/490037 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/605524 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1047090 | |
dc.relation | http://purl.org/au-research/grants/nhmrc/1066502 | |
dc.relation | http://purl.org/au-research/grants/arc/DP120100061 | |
dc.rights | Copyright © 2020 Schnider, Yang, Starrs, Ehmann, Rahimi, Di Pierro, Graziadei, Matthews, De Koning-Ward, Bauer, Foote, Burgio and McMorran. | |
dc.rights.license | Creative Commons Attribution License (CC BY) | en_AU |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_AU |
dc.source | Frontiers in Cellular and Infection Microbiology | |
dc.subject | malaria, Plasmodium | |
dc.subject | host resistance | |
dc.subject | intraerythrocytic growth | |
dc.subject | porphobilinogen [deaminase] | |
dc.title | Host Porphobilinogen Deaminase Deficiency Confers Malaria Resistance in Plasmodium chabaudi but Not in Plasmodium berghei or Plasmodium falciparum During Intraerythrocytic Growth | |
dc.type | Journal article | |
dcterms.accessRights | Open Access | en_AU |
local.bibliographicCitation.issue | 464 | en_AU |
local.bibliographicCitation.lastpage | 12 | en_AU |
local.bibliographicCitation.startpage | 1 | en_AU |
local.contributor.affiliation | Schnider, Cilly, College of Health and Medicine, ANU | en_AU |
local.contributor.affiliation | Yang, Hao, College of Health and Medicine, ANU | en_AU |
local.contributor.affiliation | Starrs, Lora, College of Health and Medicine, ANU | en_AU |
local.contributor.affiliation | Ehmann, Anna, College of Health and Medicine, ANU | en_AU |
local.contributor.affiliation | Rahimi, Farid, College of Science, ANU | en_AU |
local.contributor.affiliation | Di Pierro, Elena, Rare Diseases Center | en_AU |
local.contributor.affiliation | Graziadei, Giovanna, Rare Diseases Center | en_AU |
local.contributor.affiliation | Matthews, Kathryn, Deakin University | en_AU |
local.contributor.affiliation | de Koning-Ward, Tania F., Deakin University | en_AU |
local.contributor.affiliation | Bauer, Denis C, CSIRO Sydney | en_AU |
local.contributor.affiliation | Foote, Simon, College of Science, ANU | en_AU |
local.contributor.affiliation | Burgio, Gaetan, College of Health and Medicine, ANU | en_AU |
local.contributor.affiliation | McMorran, Brendan, College of Health and Medicine, ANU | en_AU |
local.contributor.authoremail | u5402096@anu.edu.au | en_AU |
local.contributor.authoruid | Schnider, Cilly, t1927 | en_AU |
local.contributor.authoruid | Yang, Hao, u5402096 | en_AU |
local.contributor.authoruid | Starrs, Lora, u4301798 | en_AU |
local.contributor.authoruid | Ehmann, Anna, u1022514 | en_AU |
local.contributor.authoruid | Rahimi, Farid, u4885897 | en_AU |
local.contributor.authoruid | Foote, Simon, u5697711 | en_AU |
local.contributor.authoruid | Burgio, Gaetan, u5727247 | en_AU |
local.contributor.authoruid | McMorran, Brendan, u5267721 | en_AU |
local.description.notes | Imported from ARIES | en_AU |
local.identifier.absfor | 310702 - Infectious agents | en_AU |
local.identifier.absfor | 310100 - Biochemistry and cell biology | en_AU |
local.identifier.absfor | 320704 - Medical parasitology | en_AU |
local.identifier.ariespublication | a383154xPUB14728 | en_AU |
local.identifier.citationvolume | 10 | en_AU |
local.identifier.doi | 10.3389/fcimb.2020.00464 | en_AU |
local.identifier.scopusID | 2-s2.0-85091027977 | |
local.identifier.thomsonID | WOS:000570512800001 | |
local.identifier.uidSubmittedBy | a383154 | en_AU |
local.publisher.url | https://www.frontiersin.org/journals/cellular-and-infection-microbiology | en_AU |
local.type.status | Published Version | en_AU |
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