Genetically attenuated malaria parasites as vaccines

Vaughan, Ashley M.; Kappe, Stefan H. I.

doi:10.1080/14760584.2017.1341835

Cited by 25 publications

(20 citation statements)

References 19 publications

(23 reference statements)

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“…RAS, which infect hepatocytes but cannot complete differentiation to merozoites, are capable of eliciting responses in both humans and mice that prevent the parasite from completing liver-stage differentiation and CD8 T cells are major mediators of RAS-induced immunity in mouse models (Holz et al, 2016;Seder et al, 2013). Genetically attenuated Plasmodium parasites (GAP), tailored to arrest late during hepatocyte infection, induce better protective immunity, and evoke larger Plasmodium-specific CD8 T cell responses than RAS or early arresting GAP without modulating CD8 T cell responses directed at the sporozoite stage (Butler et al, 2011;Vaughan and Kappe, 2017). These data strongly suggest that protective CD8 T cells can be primed not only against sporozoite antigens but also against antigens expressed only after hepatocyte infection.…”

Section: Introductionmentioning

confidence: 99%

Monocyte-Derived CD11c+ Cells Acquire Plasmodium from Hepatocytes to Prime CD8 T Cell Immunity to Liver-Stage Malaria

Kurup

Anthony

Hancox

et al. 2019

Cell Host & Microbe

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Section: Introductionmentioning

confidence: 99%

Monocyte-Derived CD11c+ Cells Acquire Plasmodium from Hepatocytes to Prime CD8 T Cell Immunity to Liver-Stage Malaria

Kurup

Anthony

Hancox

et al. 2019

Cell Host & Microbe

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“…The candidate genes for these strategies would be essential either to the liver stage of the parasite (for the development of genetically‐attenuated vaccines or prophylactic drugs) or to the sexual blood and/or early mosquito stage (for targets of transmission‐blocking drugs). Gene‐knockout lines that arrest during the late maturation of the liver‐stage parasite are possible candidates for a malaria vaccine as they can elicit a potent neutralising immune response in animal malaria models without establishing a blood‐stage infection (Vaughan & Kappe, ; Goswami, Minkah & Kappe, ). There is, therefore, much interest in generating genetically‐attenuated P. falciparum lines that arrest in the late liver stage (Vaughan et al ., ) and a transporter gene which produced this phenotype when disrupted is the multidrug‐resistance‐associated protein 2 ( mrp2 ; Table S2).…”

Section: New Insights Into Plasmodium Biologymentioning

confidence: 99%

The transportome of the malaria parasite

Martin

2019

Biological Reviews

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Membrane transport proteins, also known as transporters, control the movement of ions, nutrients, metabolites, and waste products across the membranes of a cell and are central to its biology. Proteins of this type also serve as drug targets and are key players in the phenomenon of drug resistance. The malaria parasite has a relatively reduced transportome, with only approximately 2.5% of its genes encoding transporters. Even so, assigning functions and physiological roles to these proteins, and ascertaining their contributions to drug action and drug resistance, has been very challenging. This review presents a detailed critique and synthesis of the disruption phenotypes, protein subcellular localisations, protein functions (observed or predicted), and links to antimalarial drug resistance for each of the parasite's transporter genes. The breadth and depth of the gene disruption data are particularly impressive, with at least one phenotype determined in the parasite's asexual blood stage for each transporter gene, and multiple phenotypes available for 76% of the genes. Analysis of the curated data set revealed there to be relatively little redundancy in the Plasmodium transportome; almost two‐thirds of the parasite's transporter genes are essential or required for normal growth in the asexual blood stage of the parasite, and this proportion increased to 78% when the disruption phenotypes available for the other parasite life stages were included in the analysis. These observations, together with the finding that 22% of the transportome is implicated in the parasite's resistance to existing antimalarials and/or drugs within the development pipeline, indicate that transporters are likely to serve, or are already serving, as drug targets. Integration of the different biological and bioinformatic data sets also enabled the selection of candidates for transport processes known to be essential for parasite survival, but for which the underlying proteins have thus far remained undiscovered. These include potential transporters of pantothenate, isoleucine, or isopentenyl diphosphate, as well as putative anion‐selective channels that may serve as the pore component of the parasite's ‘new permeation pathways’. Other novel insights into the parasite's biology included the identification of transporters for the potential development of antimalarial treatments, transmission‐blocking drugs, prophylactics, and genetically attenuated vaccines. The syntheses presented herein set a foundation for elucidating the functions and physiological roles of key members of the Plasmodium transportome and, ultimately, to explore and realise their potential as therapeutic targets.

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“…So far, the clinical experience with PfSPZ immunization suggests that although it affords superior protection compared with current subunit vaccines, it does not confer complete protection in areas of endemic malaria transmission (21) and therefore requires improvement. This might be achieved by creating a whole-parasite immunogen that actively replicates in the liver, thereby generating considerably increased antigen breadth and biomass, which when presented to the host's immune system, engenders superior immune protection (26,27). Indeed, proof-of-concept CHMI clinical trials with chemoprophylaxis with sporozoites (CPS) showed that allowing full liver stage development of the immunogen generates durable sterilizing protection at a dose one-twentieth of that used with the PfSPZ vaccine (28,29).…”

Section: Introductionmentioning

confidence: 99%