Molecular Genetics Evidence for the in Vivo Roles of the Two Major NADPH-dependent Disulfide Reductases in the Malaria Parasite

Abstract

Malaria-associated pathology is caused by the continuous expansion of Plasmodium parasites inside host erythrocytes. To maintain a reducing intracellular milieu in an oxygen-rich environment, malaria parasites have evolved a complex antioxidative network based on two central electron donors, glutathione and thioredoxin. Here, we dissected the in vivo roles of both redox pathways by gene targeting of the respective NADPHdependent disulfide reductases. We show that Plasmodium berghei glutathione reductase and thioredoxin reductase are dispensable for proliferation of the pathogenic blood stages. Intriguingly, glutathione reductase is vital for extracellular parasite development inside the insect vector, whereas thioredoxin reductase is dispensable during the entire parasite life cycle. Our findings suggest that glutathione reductase is the central player of the parasite redox network, whereas thioredoxin reductase fulfils a specialized and dispensable role for P. berghei. These results also indicate redundant roles of the Plasmodium redox pathways during the pathogenic blood phase and query their suitability as promising drug targets for antimalarial intervention strategies.

Selenoproteins of African trypanosomes are dispensable for parasite survival in a mammalian host

“…On the other hand, although the lack of selenoproteins was not detrimental for the in vitro proliferation of procyclic T. brucei [6], it is still possible that they fulfill a relevant role in the insect stage as shown for a subset of major surface glycoproteins [43]. Similarly, Plasmodium berghei glutathione reductase is dispensable in the murine host but necessary for proliferation in the mosquito [44]. If this were the case for trypanosomal selenoproteins, it might explain the strict conservation of the costly selenocysteine biosynthetic machinery in trypanosomatids.…”

Global Phenotypic Screening for Antimalarials

“…These results led to the conclusion that LDH is not druggable. TrxR met a similar fate (Buchholz, et al, 2010). …”

Degrees of chloroquine resistance in Plasmodium – Is the redox system involved?

“…GR can also be disrupted in P. berghei (Buchholz et al, 2010; Pastrana-Mena et al, 2010), demonstrating that this protein is also dispensable for asexual blood stage development. As was found for γ-GCS, GR was shown to be essential for oocyst development in the mosquito.…”