Global gene expression of human malaria parasite liver stages throughout intrahepatocytic development

Zanghì, Gigliola; Patel, Hardik; Camargo, Nelly; Smith, Jenny L.; Bae, Yeji; Flannery, Erika L.; Chuenchob, Vorada; Fishbaugher, Matthew; Mikolajczak, Sebastian A.; Roobsoong, Wanlapa; Sattabongkot, Jetsumon; Hayes, Kiera; Vaughan, Ashley M.; Kappe, Stefan H. I.

doi:10.1101/2023.01.05.522945

Cited by 5 publications

(1 citation statement)

References 66 publications

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“…However, the apparent absence of HSP101 from P. berghei EEFs provides further rationale to characterize PTEX in P. falciparum liver stages. A recent study demonstrated expression of HSP101 at the periphery of P. falciparum EEFs ( 73 ) and a function during the liver stage remains plausible. The FlpL/ FRT system adapted herein provides an ideal approach to address the functional importance of HSP101 in liver stages.…”

Section: Discussionmentioning

confidence: 99%

Flp/ FRT -mediated disruption of ptex150 and exp2 in Plasmodium falciparum sporozoites inhibits liver-stage development

McConville,

Krol,

Steel

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Plasmodium falciparum causes severe malaria and assembles a protein translocon (PTEX) complex at the parasitophorous vacuole membrane (PVM) of infected erythrocytes, through which several hundred proteins are exported to facilitate growth. The preceding liver stage of infection involves growth in a hepatocyte-derived PVM; however, the importance of protein export during P. falciparum liver infection remains unexplored. Here, we use the FlpL/ FRT system to conditionally excise genes in P. falciparum sporozoites for functional liver-stage studies. Disruption of PTEX members ptex150 and exp2 did not affect sporozoite development in mosquitoes or infectivity for hepatocytes but attenuated liver-stage growth in humanized mice. While PTEX150 deficiency reduced fitness on day 6 postinfection by 40%, EXP2 deficiency caused 100% loss of liver parasites, demonstrating that PTEX components are required for growth in hepatocytes to differing degrees. To characterize PTEX loss-of-function mutations, we localized four liver-stage Plasmodium export element (PEXEL) proteins. P. falciparum liver specific protein 2 (LISP2), liver-stage antigen 3 (LSA3), circumsporozoite protein (CSP), and a Plasmodium berghei LISP2 reporter all localized to the periphery of P. falciparum liver stages but were not exported beyond the PVM. Expression of LISP2 and CSP but not LSA3 was reduced in ptex150-FRT and exp2-FRT liver stages, suggesting that expression of some PEXEL proteins is affected directly or indirectly by PTEX disruption. These results show that PTEX150 and EXP2 are important for P. falciparum development in hepatocytes and emphasize the emerging complexity of PEXEL protein trafficking.

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Section: Discussionmentioning

confidence: 99%

Flp/ FRT -mediated disruption of ptex150 and exp2 in Plasmodium falciparum sporozoites inhibits liver-stage development

McConville,

Krol,

Steel

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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The artemisinin-induced dormant stages of Plasmodium falciparum exhibit hallmarks of cellular quiescence/senescence and drug resilience

Tripathi,

Stoklasa,

Nayak

et al. 2024

Nat Commun

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A conserved Plasmodium nuclear protein is critical for late liver stage development

Goswami,

Arredondo,

Betz

et al. 2024

Commun Biol

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Malaria, caused by Plasmodium parasites, imposes a significant health burden and live-attenuated parasites are being pursued as vaccines. Here, we report on the creation of a genetically attenuated parasite by the deletion of Plasmodium LINUP, encoding a liver stage nuclear protein. In the rodent parasite Plasmodium yoelii, LINUP expression was restricted to liver stage nuclei after the onset of liver stage schizogony. Compared to wildtype P. yoelii, P. yoelii LINUP gene deletion parasites (linup -) exhibited no phenotype in blood stages and mosquito stages but suffered developmental arrest late in liver stage schizogony with a pronounced defect in exo-erythrocytic merozoite formation. This defect caused severe attenuation of the liver stage-to-blood stage transition and immunization of mice with linupparasites conferred robust protection against infectious sporozoite challenge. LINUP gene deletion in the human parasite Plasmodium falciparum also caused a severe defect in late liver stage differentiation. Importantly, P. falciparum linupliver stages completely failed to transition from the liver stage to a viable blood stage infection in a humanized mouse model. These results suggest that P. falciparum LINUP is an ideal target for late liver stage attenuation that can be incorporated into a late liver stage-arresting replication competent whole parasite vaccine.

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Global gene expression of human malaria parasite liver stages throughout intrahepatocytic development

Cited by 5 publications

References 66 publications

Flp/ FRT -mediated disruption of ptex150 and exp2 in Plasmodium falciparum sporozoites inhibits liver-stage development

Flp/ FRT -mediated disruption of ptex150 and exp2 in Plasmodium falciparum sporozoites inhibits liver-stage development

The artemisinin-induced dormant stages of Plasmodium falciparum exhibit hallmarks of cellular quiescence/senescence and drug resilience

A conserved Plasmodium nuclear protein is critical for late liver stage development

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