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. Attached Files Name Description MIMEType Size Downloads matthews-hostporphobilinogen-2020.pdf Published version application/pdf 1.42MB 3 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, 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 Persistent URL http://hdl.handle.net/10536/DRO/DU:30132206 Document type: Journal Article Collections: Faculty of Health School of Medicine Open Access Collection Related Links Link Description Link to full-text (open access)     Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved. 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. 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