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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

journal contribution
posted on 2020-09-02, 00:00 authored by Cilly Bernardette Schnider, Hao Yang, Lora Starrs, Anna Ehmann, Farid Rahimi, Elena Di Pierro, Giovanna Graziadei, Kat MatthewsKat Matthews, Tania De Koning-WardTania De Koning-Ward, Denis C Bauer, Simon J Foote, Brendan J McMorran, Gaetan Burgio
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.



Frontiers in Cellular and Infection Microbiology



Article number



1 - 12


Frontiers Media


Lausanne, Switzerland





Publication classification

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