A replication-competent late liver stage–attenuated human malaria parasite

Goswami, Debashree; Betz, William J.; Locham, Navin K.; Parthiban, Chaitra; Brager, Carolyn; Schäfer, Carola; Camargo, Nelly; Nguyen, Trang; Kennedy, Spencer Y.; Murphy, Sean C.; Vaughan, Ashley M.; Kappe, Stefan H. I.

doi:10.1172/jci.insight.135589

Cited by 54 publications

(64 citation statements)

References 67 publications

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“…The use of such parasites would bypass the need for P. vivax sporozoite production and measures for hypnozoite removal (Payne et al, 2017). In addition, such chimeric sporozoites might also be used in whole, attenuated sporozoite vaccination approaches (Bijker et al, 2015;Goswami et al, 2020). Vaccination with chimeric, attenuated sporozoites might induce cross-protective immune responses against both P. falciparum and P. vivax.…”

Section: Discussionmentioning

confidence: 99%

Generation of a Genetically Modified Chimeric Plasmodium falciparum Parasite Expressing Plasmodium vivax Circumsporozoite Protein for Malaria Vaccine Development

Miyazaki

Marin-Mogollon

Imai

et al. 2020

Front. Cell. Infect. Microbiol.

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Chimeric rodent malaria parasites with the endogenous circumsporozoite protein (csp) gene replaced with csp from the human parasites Plasmodium falciparum (Pf) and P. vivax (Pv) are used in preclinical evaluation of CSP vaccines. Chimeric rodent parasites expressing PfCSP have also been assessed as whole sporozoite (WSP) vaccines. Comparable chimeric P. falciparum parasites expressing CSP of P. vivax could be used both for clinical evaluation of vaccines targeting PvCSP in controlled human P. falciparum infections and in WSP vaccines targeting P. vivax and P. falciparum. We generated chimeric P. falciparum parasites expressing both PfCSP and PvCSP. These Pf-PvCSP parasites produced sporozoite comparable to wild type P. falciparum parasites and expressed PfCSP and PvCSP on the sporozoite surface. Pf-PvCSP sporozoites infected human hepatocytes and induced antibodies to the repeats of both PfCSP and PvCSP after immunization of mice. These results support the use of Pf-PvCSP sporozoites in studies optimizing vaccines targeting PvCSP.

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Section: Discussionmentioning

confidence: 99%

Generation of a Genetically Modified Chimeric Plasmodium falciparum Parasite Expressing Plasmodium vivax Circumsporozoite Protein for Malaria Vaccine Development

Miyazaki

Marin-Mogollon

Imai

et al. 2020

Front. Cell. Infect. Microbiol.

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“…Oligonucleotide primers used for the creation and analysis of Pfcdpk4¯ parasites are detailed in Supplementary Data S5. Deletion of PfCDPK4 (PlasmoDB identifier Gene -PF3D7_0717500) was achieved based on the previously reported CRISPR/Cas9 strategy using the pFC plasmid (39). The PfCDPK4 locus was deleted using double crossover homologous recombination.…”

Section: Methodsmentioning

confidence: 99%

Plasmodium falciparum Calcium Dependent Protein Kinase 4 is critical for male gametogenesis and transmission to the mosquito vector

Kumar

Haile

Hoopmann

et al. 2021

Preprint

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Gametocytes of the malaria parasite Plasmodium are taken up by the mosquito vector with an infectious blood meal, representing a critical stage for parasite transmission. Calcium dependent protein kinases play key roles in calcium mediated signaling across the complex life cycle of the parasite. We sought to understand their role in human parasite transmission from the host to the mosquito vector and thus investigated the role of the human infective parasite Plasmodium falciparum CDPK4 in the parasite life cycle. P. falciparum cdpk4 parasites created by targeted gene deletion showed no effect in blood stage development or gametocyte development. However, cdpk4 parasites showed a severe defect in male gametogenesis and the emergence of flagellated male gametes. To understand the molecular underpinnings of this defect, we performed mass spectrometry based phosphoproteomic analyses of wild type and Plasmodium falciparum cdpk4 late gametocyte stages, to identify key CDPK4 mediated phosphorylation events that may be important for the regulation of male gametogenesis. We further employed in vitro assays to identify these putative substrates of Plasmodium falciparum CDPK4. This indicated that CDPK4 regulates male gametogenesis by directly or indirectly controlling key essential events such as DNA replication, mRNA translation and cell motility. Taken together, our work demonstrates that PfCDPK4 is a central kinase that regulates exflagellation, and thereby is critical for parasite transmission to the mosquito vector.

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“…Afterward, a reverse vaccinology approach based on Plasmodium genomes 11 , bioinformatics tools predicting antigens and/or essential proteins, and improvements in transfection methods for Plasmodium genetic manipulation [12][13][14] has led to the generation of several parasite stage-specific knock-outs exploitable as genetically attenuated parasite (GAP) vaccines 7,15,16 . GAP was designed to overcome the uncertainty associated with random DNA breaks in RAS and minimize the risks associated with radiation, including the production of free radicals.…”

Section: Introductionmentioning

confidence: 99%

Chemoprophylaxis vaccination with a Plasmodium liver stage autophagy mutant affords enhanced and long-lasting protection

et al. 2021

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Genetically attenuated sporozoite vaccines can elicit long-lasting protection against malaria but pose risks of breakthrough infection. Chemoprophylaxis vaccination (CVac) has proven to be the most effective vaccine strategy against malaria. Here, we demonstrate that a liver stage-specific autophagy mutant of Plasmodium berghei (ATG8 overexpressor), when used as a live vaccine under a CVac regimen, provides superior long-lasting protection, in both inbred and outbred mice, as compared to WT-CVac. Uniquely, the protection elicited by this mutant is predominantly dependent on a CD8+ T-cell response through an IFN-γ-independent mechanism and is associated with a stable population of antigen-experienced CD8+ T cells. Jointly, our findings support the exploitation of liver-stage mutants as vaccines under a CVac protocol. This vaccination strategy is also a powerful model to study the mechanisms of protective immunity and discover new protective antigens.

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A replication-competent late liver stage–attenuated human malaria parasite

Cited by 54 publications

References 67 publications

Generation of a Genetically Modified Chimeric Plasmodium falciparum Parasite Expressing Plasmodium vivax Circumsporozoite Protein for Malaria Vaccine Development

Generation of a Genetically Modified Chimeric Plasmodium falciparum Parasite Expressing Plasmodium vivax Circumsporozoite Protein for Malaria Vaccine Development

Plasmodium falciparum Calcium Dependent Protein Kinase 4 is critical for male gametogenesis and transmission to the mosquito vector

Chemoprophylaxis vaccination with a Plasmodium liver stage autophagy mutant affords enhanced and long-lasting protection

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