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

Schnider, CB, Yang, H, Starrs, L, Ehmann, A, Rahimi, F, Di Pierro, E, Graziadei, G, Matthews, K, De Koning-Ward, T, Bauer, DC, Foote, SJ, McMorran, BJ and Burgio, G 2020, Host Porphobilinogen Deaminase Deficiency Confers Malaria Resistance in Plasmodium chabaudi but Not in Plasmodium berghei or Plasmodium falciparum During Intraerythrocytic Growth, Frontiers in Cellular and Infection Microbiology, vol. 10, pp. 1-12, doi: 10.1101/589242.

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Title Host Porphobilinogen Deaminase Deficiency Confers Malaria Resistance in Plasmodium chabaudi but Not in Plasmodium berghei or Plasmodium falciparum During Intraerythrocytic Growth
Formatted title Host Porphobilinogen Deaminase Deficiency Confers Malaria Resistance in Plasmodium chabaudi but Not in Plasmodium berghei or Plasmodium falciparum During Intraerythrocytic Growth
Author(s) Schnider, CB
Yang, H
Starrs, L
Ehmann, A
Rahimi, F
Di Pierro, E
Graziadei, G
Matthews, K
De Koning-Ward, TORCID iD for De Koning-Ward, T orcid.org/0000-0001-5810-8063
Bauer, DC
Foote, SJ
McMorran, BJ
Burgio, G
Journal name Frontiers in Cellular and Infection Microbiology
Volume number 10
Article ID 464
Start page 1
End page 12
Total pages 12
Publisher Frontiers Media
Place of publication Lausanne, Switzerland
Publication date 2020-09-02
ISSN 2235-2988
Keyword(s) Plasmodium
porphobilinogen deaminase
porphyria
erythrocytes
N-ethyl-N-nitrosourea
malaria
host resistance
intraerythrocytic growth
Science & Technology
Life Sciences & Biomedicine
Immunology
Microbiology
porphobilinogen [deaminase]
HIGH-EFFICIENCY TRANSFECTION
RED-BLOOD-CELL
HEME-BIOSYNTHESIS
READ ALIGNMENT
PARASITE
FERROCHELATASE
SELECTION
DEHYDRATASE
MEMBRANE
PROTEOME
Summary Background: The selective pressure imparted by intraerythrocytic infection with Plasmodium parasites, the causative agents of malaria has led to many mutations in erythrocytic genes that confer host resistance. Identification and characterization of mutations affecting host resistance to Plasmodium infection enables a deeper understanding of host–pathogen interactions and potentially new ways by which to prevent infection.Methods: Using ENU-induced mutagenesis, and screening for erythrocyte abnormalities and resistance to Plasmodium chabaudi infection, we identified a novel nonsense mutation in the gene encoding porphobilinogen deaminase (PBGD) in mice.Results: Heterozygote Pbgd mice exhibited microcytosis and 25% reduction in cellular PBGD activity, but were healthy otherwise. When challenged with blood-stage P. chabaudi, the heterozygotes were significantly protected against infection, showed reduced parasite growth, and had a survival advantage. The mutation did not affect erythrocyte susceptibility to parasite invasion. Instead, the mechanism of underlying resistance to infection involved intraerythrocytic parasite death and reduced propagation of viable parasites. This was not observed when P. falciparum was cultured in erythrocytes from patients with acute intermittent porphyria (AIP), who have low PBGD levels or with P. berghei infection in Pbgd deficient mice. Furthermore, the growth capacity of PBGD-null P. falciparum and P. berghei parasites, which grew at the same rate as their wild-type counterparts in normal erythrocytes, was not reduced in the AIP erythrocytes or Pbgd-deficient mice.Conclusions: Our results suggest that PBGD deficiency confers resistance to infection with P. chabaudi during the blood-stage of infection and erythrocytic or parasite PBGD is likely to be dispensable for parasite maturation.
Language eng
DOI 10.1101/589242
Indigenous content off
Field of Research 110899 Medical Microbiology not elsewhere classified
0601 Biochemistry and Cell Biology
0605 Microbiology
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2020, Schnider, Yang, Starrs, Ehmann, Rahimi, Di Pierro, Graziadei, Matthews, De Koning-Ward, Bauer, Foote, Burgio and McMorran
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30132206

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.