Flp/FRT-mediated disruption of ptex150 and exp2 in Plasmodium falciparum sporozoites inhibits liver-stage development
- Author(s)
- McConville, R; Krol, JMM; Steel, RWJ; O'Neill, MT; Davey, BK; Hodder, AN; Nebl, T; Cowman, AF; Kneteman, N; Boddey, JA;
- Details
- Publication Year 2024-07-09,Volume 121,Issue #28,Page e2403442121
- Journal Title
- Proceedings of the National Academy of Sciences of the United States of America
- Abstract
- 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.
- Publisher
- NAS
- Keywords
- *Plasmodium falciparum/growth & development/genetics/metabolism; Animals; *Protozoan Proteins/metabolism/genetics; *Sporozoites/metabolism/growth & development; Mice; *Liver/parasitology/metabolism; Humans; *Hepatocytes/parasitology/metabolism; *Malaria, Falciparum/parasitology; hepatocyte; humanized mice; malaria; protein export; translocon
- Research Division(s)
- Infectious Diseases And Immune Defence
- PubMed ID
- 38968107
- Publisher's Version
- https://doi.org/10.1073/pnas.2403442121
- Open Access at Publisher's Site
https://doi.org/10.1073/pnas.2403442121- Terms of Use/Rights Notice
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Creation Date: 2024-07-10 09:21:05
Last Modified: 2024-07-10 09:35:04