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oai:figshare.com:article/34017860 2026-09-28T17:55:01Z category_1 category_4 category_915 category_7 category_8 category_12 category_13 category_132 portal_5 item_type_1 month_year_09_2026

PfATG18-deficient ring-stage parasites are hypersensitive to dihydroartemisinin. Yasmin Schmitz (11974910) Moumita Sengupta (25132859) Carola Schneider (3743791) Tanja Ziesmann (3318936) Franziska Hellmold (25132862) Ute Distler (115774) Rudolph Reimer (190562) Joachim Michael Matz (25132865) Biophysics Biochemistry Physical Sciences not elsewhere classified Medicine Microbiology Cell Biology Genetics Infectious Diseases related protein 18 div >< p broad architectural destabilization balance cargo influx associated protein machinery antimalarial drugs unchanged 3d electron microscopy membrane sector phenocopied endocytic membrane homeostasis endocytic membrane dynamics vacuole constantly fuses specialized digestive vacuole stage parasites hypersensitive vacuolar membrane dynamics efficient hemoglobin processing degrading hemoglobin within asexual parasite proliferation plasmodium falciparum </ atpase assembly factor atg18 links v vacuolar membrane vacuole ’ malaria parasites atpase assembly parasite ’ parasite survival parasite death incoming hemoglobin pf </ vesicle trafficking rendered ring regulatory influence quantitative live proton pump point mutation multifaceted role key regulator interactions indicates interact directly findings establish filled vesicles direct interference decrease sensitivity (A) Delayed inactivation of PfATG18 allows completion of one intraerythrocytic cycle. Parasitemia was measured after invasion and again at 68 hours post-invasion (hpi), and fold-change was calculated. DMSO or RAP was added at the indicated time points. Dashed line: no change. Individual and mean values; paired t-test; n = 4 experiments with 3 technical replicates each. **, p < 0.01; ***, p < 0.001. (B,C) Live fluorescence microscopy shows that RAP induction at 16 hpi efficiently depletes PfATG18 (B) and causes DV fragmentation in schizonts (C). Individual and mean values; paired t-test; n = 132 parasites, 4 experiments. (D-G) PfATG18 loss increases ring-stage sensitivity to dihydroartemisinin (DHA). (D) Experimental timeline for assessing ring-stage drug sensitivity. PfATG18 deletion was induced at 16 hpi, after which parasites completed the first intraerythrocytic cycle. Mature schizonts were then used to initiate a tightly synchronized (Sync) second cycle. The resulting ring stage parasites were exposed to DHA for 6 hours, and survival was assessed by Giemsa staining 16 hours later. (E) Representative morphologies, showing surviving and dead parasites at 24 hpi in the second cycle. (F) Ring-stage survival following a 6-hour DHA pulse at the indicated concentrations. (G) Relative ring-stage survival after a 12 nM DHA pulse, normalized to baseline survival in untreated controls. (H-K) PfATG18 loss does not alter ring-stage sensitivity to chloroquine (H,I) or proguanil (J,K), using the same experimental time line as shown in (D). Displayed are ring-stage survival across the indicated drug concentrations (H,J) and relative ring-stage survival following a 100 nM chloroquine pulse (I) or a 100 µM proguanil pulse, normalized to baseline survival in untreated controls. Individual and mean values; paired t-test; n = 3 experiments with 3 technical replicates each. n.s., p > 0.05; *, p < 0.05. Scale bars: 5 µm. Source data are provided as a <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1014608#ppat.1014608.s015" target="_blank">S3 File</a>. 2026-09-28T18:08:16Z Image Figure 10.1371/journal.ppat.1014608.g005 https://figshare.com/articles/figure/_p_i_Pf_i_ATG18-deficient_ring-stage_parasites_are_hypersensitive_to_dihydroartemisinin_p_/34017860 CC BY 4.0