Host porphobilinogen deaminase deficiency confers malaria resistance inPlasmodium chabaudibut not inPlasmodium bergheiorPlasmodium falciparumduring intraerythrocytic growth
Authors: Schnider Cilly Bernardette , Yang Hao , Starrs Lora , Ehmann Anna , Rahimi Farid , Di Pierro Elena , Graziadei Giovanna , Matthews Kathryn , De Koning-Ward Tania , Bauer Denis C. , Foote Simon J. , Burgio Gaetan , McMorran Brendan J. 
Published: March 2019

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 nonsense mutation in the gene encoding porphobilinogen deaminase (PBGD) in mice, denoted here asPbgdMRI58155. HeterozygotePbgdMRI58155mice exhibited approximately 50% reduction in cellular PBGD activity in both mature erythrocytes and reticulocytes, although enzyme activity was approximately 10 times higher in reticulocytes than erythrocytes. When challenged with blood-stageP. 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 byP. chabaudiwas normal, but that following intraerythrocytic establishment a significantly greater proportions of parasites died and therefore affected their ability to propagate. ThePlasmodiumresistance phenotype was not recapitulated inPbgd-deficient mice infected withP. berghei, which prefers reticulocytes, or whenP. falciparumwas cultured in erythrocytes from patients with acute intermittent porphyria (AIP), which had modest (20-50%) reduced levels of PBGD. Furthermore, the growth ofPbgd-nullP. falciparumandPbgd-nullP. bergheiparasites, 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 orPbgd-deficient mice. Our results confirm the dispensability of parasite PBGD forP. bergheiinfection and intraerythrocytic growth ofP. falciparum, but for the first time identify a requirement for host erythrocyte PBGD byP. chabaudiduringin vivoblood stage infection.

IMPORTANCE

The causative agent of malaria,Plasmodium, adopts a parasitic lifestyle during erythrocyte infection, and as such relies on host cell factors for its survival and growth. Host-encoded mutations that alter the availability of these factors confer disease resistance, including several well-known genetic erythrocyte abnormalities that have arisen due to the historical evolutionary pressure of malaria. This study identified in mice a novel malaria resistance-conferring host mutation in the heme biosynthesis enzyme, porphobilinogen deaminase (PBGD), and compared the relative requirements byPlasmodiumfor the host versus parasite-encoded forms of PBGD in bothin vivoandin vitrosettings. The findings demonstrated that parasite PBGD was dispensable, but that the host enzyme was important specifically duringin vivoinfection byP. chabaudi, and collectively suggest thatPlasmodiumrequires a certain threshold of the enzyme to sustain its intraerythrocytic growth.Plasmodiummay therefore be vulnerable to other interventions that limit host PBGD activity.