Host porphobilinogen deaminase deficiency confers malaria resistance in Plasmodium chabaudi but not in Plasmodium berghei or Plasmodium falciparum during intraerythrocytic growth

Author:

Schnider Cilly Bernardette,Yang Hao,Starrs Lora,Ehmann Anna,Rahimi FaridORCID,Di Pierro Elena,Graziadei Giovanna,Matthews Kathryn,De Koning-Ward TaniaORCID,Bauer Denis C.ORCID,Foote Simon J.ORCID,Burgio GaetanORCID,McMorran Brendan J.ORCID

Abstract

ABSTRACTAn 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 as PbgdMRI58155. Heterozygote PbgdMRI58155 mice 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-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.IMPORTANCEThe 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 by Plasmodium for the host versus parasite-encoded forms of PBGD in both in vivo and in vitro settings. The findings demonstrated that parasite PBGD was dispensable, but that the host enzyme was important specifically during in vivo infection by P. chabaudi, and collectively suggest that Plasmodium requires a certain threshold of the enzyme to sustain its intraerythrocytic growth. Plasmodium may therefore be vulnerable to other interventions that limit host PBGD activity.

Publisher

Cold Spring Harbor Laboratory

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3