A new approach to generate a safe double-attenuated Plasmodium liver stage vaccine

Nagel, Andreas; Prado, M. J. B. A.; Heitmann, Anna; Tartz, Susanne; Jacobs, Thomas; Deschermeier, Christina; Helm, Susanne; Stanway, Rebecca R.; Heussler, Volker

doi:10.1016/j.ijpara.2013.01.010

Cited by 18 publications

(45 citation statements)

References 53 publications

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“…Furthermore, as subunits of the complex have been deleted in P. falciparum, P. berghei and P. yoelii, it is just one of two FASII enzymes to be the subject of genetic studies in all three species (Table 1). In each case, loss of PDH function had no effect on the growth of bloodstage parasites [99][100][101], consistent with the dispensability of FASII at this stage [97,98,[102][103][104]. Beyond the blood stage, loss of the PDH complex resulted in similar outcomes for P. berghei and P. yoelii, with knockouts displaying defects only in late liver stage development [99,100].…”

Section: Pyruvate Dehydrogenase Complex (Pdh)mentioning

confidence: 53%

“…Although FASII was indeed essential for T. gondii tachyzoites [45], the pathway was found to be completely dispensable in bloodstage Plasmodium, and only required for liver stage development in the rodent models [97,98]. These findings were further supported by additional genetic [99][100][101][102][103][104] and biochemical experiments [30], and the DOXP pathway emerged as the only essential metabolic function of the apicoplast in bloodstage parasites in vitro. These studies discredited FASII as therapeutic anti-malarial drug target, and confirmed that each of its supposed inhibitors likely also interfered with other processes.…”

Section: Introductionmentioning

confidence: 90%

“…In each case, loss of PDH function had no effect on the growth of bloodstage parasites [99][100][101], consistent with the dispensability of FASII at this stage [97,98,[102][103][104]. Beyond the blood stage, loss of the PDH complex resulted in similar outcomes for P. berghei and P. yoelii, with knockouts displaying defects only in late liver stage development [99,100]. The P. berghei PDH knockout was evaluated as a GAP vaccine, and although the line was less attenuated than its P. yoelii counterpart [99], promising results were achieved by combining it with a second genetic modification [100].…”

Section: Pyruvate Dehydrogenase Complex (Pdh)mentioning

confidence: 99%

“…In P. berghei, loss of the inner membrane pPT appeared lethal for bloodstage parasites, whereas loss of the outer membrane pPT resulted in defects in both mosquito and liver stage development [114]. For the inner membrane pPT, the phenotype of the knockout cannot be attributed to loss of FASII given the pathway is dispensable in bloodstage parasites [97][98][99][100][101][102][103][104]. Instead, it likely reflects the role of the transporter in supporting the DOXP pathway, which is essential in bloodstage P. falciparum [30] and presumably also P. berghei.…”

Section: Plastidic Phosphate Transporters (Ppts)mentioning

confidence: 99%

“…FASII knockouts were similarly identified as possible candidates for genetically attenuated parasite (GAP) vaccines, and selected lines were evaluated for their safety and ability to provoke protective immune responses in mice. Although attenuation was incomplete in some FASII knockouts [100,103], others could provide safe and long-lasting protection [110], and hopes were high that similar strategies might be used to generate a human GAP vaccine. However, when enzymes of FASII were recently targeted for deletion in P. falciparum, it revealed a previously unknown difference between the human and rodent parasites, with loss of the pathway instead resulting in a block in sporozoite development [101,104] (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts

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The malaria parasite Plasmodium possesses a relict, non-photosynthetic plastid known as the apicoplast. The apicoplast is essential for parasite survival, and harbors several plant-like metabolic pathways including a type II fatty acid synthesis (FASII) pathway. The FASII pathway was discovered in 1998, and much of the early research in the field pursued it as a therapeutic drug target. These studies identified a range of compounds with activity against bloodstage parasites and led to the localization and characterization of most enzymes in the pathway. However, when genetic studies revealed FASII was dispensable in bloodstage parasites, it effectively discounted the pathway as a therapeutic drug target, and suggested these compounds instead interfered with other processes. Interest in FASII then shifted toward its disruption for malaria prophylaxis and vaccine development, with experiments in rodent malaria models identifying a crucial role for the pathway in the parasite's transition from the liver to the blood. Unexpectedly however, the human malaria parasite P. falciparum was recently found to differ from rodent models and require FASII for mosquito stage development. This requirement blocked the production of the FASII-deficient forms that might be used as a genetically attenuated parasite vaccine, suggesting the pathway was also unsuitable as a vaccine target. This review discusses how perception of FASII has changed over time, and presents key findings about each enzyme in the pathway to identify remaining questions and opportunities for malaria control.

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