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 Pbgd^MRI58155. Heterozygote Pbgd^MRI58155 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.

宿主抵抗疟疾感染的一个重要组成部分是遗传突变，它会导致红细胞蛋白质和酶的异常和缺乏。了解这些突变如何提供针对该疾病的保护可能有助于开发新的治疗策略。小鼠 ENU 诱导的新型疟疾抗性突变筛选在小鼠胆色素原脱氨酶 (PBGD) 编码基因中发现了一种新型无义突变，此处表示为铅^{核磁共振成像58155} 。杂合子铅^{核磁共振成像58155}只小鼠的成熟红细胞和网织红细胞中的细胞 PBGD 活性均降低约 50%，尽管网织红细胞中的酶活性比红细胞高约 10 倍。当遇到血液阶段的挑战时查鲍迪优先感染红细胞的杂合子小鼠表现出适度但显着的感染抵抗力，包括寄生虫生长减少。为研究耐药机制而进行的一系列测定表明，突变红细胞入侵查鲍迪这是正常的，但在红细胞内建立后，寄生虫死亡的比例明显更高，因此影响了它们的繁殖能力。这疟原虫耐药表型并未重现铅- 感染有缺陷的小鼠伯氏对虾，更喜欢网织红细胞，或者当恶性疟原虫在急性间歇性卟啉症 (AIP) 患者的红细胞中培养，该患者的 PBGD 水平适度降低 (20-50%)。 此外，增长铅-无效的恶性疟原虫和铅-无效的伯氏对虾寄生虫的生长速度与其在正常细胞中的野生型对应物相同，不受 AIP 红细胞或 PBGD 缺陷背景的影响铅- 缺陷小鼠。我们的结果证实了寄生虫 PBGD 对于伯氏对虾感染和红细胞内生长恶性疟原虫，但首次确定了对宿主红细胞 PBGD 的要求查鲍迪期间体内血期感染。