{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T12:52:52Z","timestamp":1789908772984,"version":"4.0.1"},"reference-count":75,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI117017, R01AI130171"],"award-info":[{"award-number":["R01AI117017, R01AI130171"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mSphere"],"published-print":{"date-parts":[[2026,7,28]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      How\n                      <jats:italic toggle=\"yes\">Plasmodium falciparum<\/jats:italic>\n                      responds to stresses such as antimalarial drug pressure and uses them to trigger developmental decisions such as the production of sexual gametocytes remains poorly understood. Here, we investigated the function of the leucine-rich repeat protein LRR5 (PF3D7_1432400). Previous genome-wide\n                      <jats:italic toggle=\"yes\">piggyBac<\/jats:italic>\n                      mutagenesis established that disruptions of LRR5 increase sensitivity to artemisinin and heat-shock and enhance gametocyte production. Using an optimized single-cell RNA sequencing approach applied to unsynchronized parasite cultures, we profiled transcriptional heterogeneity across the intraerythrocytic developmental cycle in wild-type NF54 parasites and an isogenic LRR5\n                      <jats:italic toggle=\"yes\">piggyBac<\/jats:italic>\n                      mutant (LRR5pB). Disruption of LRR5 reshaped the parasite transcriptome across multiple stages, with marked downregulation of pathways involved in protein folding, protein export, and host-cell remodeling, including Maurer\u2019s cleft components, the PTEX export machinery, and the exported chaperone HSP70-x. In contrast, cytoplasmic heat-shock proteins and translation-associated genes were upregulated, suggesting a compensatory stress response. Notably, LRR5pB parasites displayed premature activation of gametocyte-associated transcriptional programs, including elevated expression of the early gametocyte marker Pfs16, which was confirmed at the protein level. Pseudotime analysis further revealed accelerated transcriptional progression with mistimed expression of trophozoite-, merozoite-, and gametocyte-associated gene clusters. Together, these findings suggest LRR5 as a link between proteostasis, host-cell remodeling, and developmental timing in\n                      <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                      .\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Malaria parasites must survive environmental stress while deciding whether to continue asexual replication in the blood stream or instead commit to sexual gametocytes for transmission. Understanding how these processes are coordinated is critical for developing new strategies to block both disease and transmission. In this study, we used single-cell transcriptomics to examine how disruption of the\n                        <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                        protein LRR5 alters parasite development. By analyzing individual parasites from unsynchronized cultures, we uncovered hidden changes in stress-response pathways, host-cell remodeling, and early activation of genes linked to sexual development. Our findings show that loss of LRR5 weakens the parasite\u2019s ability to manage stress while prematurely priming parasites for gametocyte formation. These results suggest LRR5 as a link to stress adaptation to transmission potential.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/msphere.00186-26","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T12:02:01Z","timestamp":1781524921000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["<i>Plasmodium falciparum<\/i>\n                    leucine-rich repeat 5 disruption alters the transcription progression during asexual and sexual stage development"],"prefix":"10.1128","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5470-1342","authenticated-orcid":true,"given":"Camilla V.","family":"Pires","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/032db5x82","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Global Health and Interdisciplinary Research, Department of Global, Environmental, and Genomic Health Sciences, College of Public Health, University of South Florida","place":["Tampa, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7582-3824","authenticated-orcid":false,"given":"Chengqi C. Q.","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/032db5x82","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Global Health and Interdisciplinary Research, Department of Global, Environmental, and Genomic Health Sciences, College of Public Health, University of South Florida","place":["Tampa, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5443-0992","authenticated-orcid":false,"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/032db5x82","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Global Health and Interdisciplinary Research, Department of Global, Environmental, and Genomic Health Sciences, College of Public Health, University of South Florida","place":["Tampa, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4474-8912","authenticated-orcid":false,"given":"Chiara","family":"Micchelli","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/032db5x82","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Global Health and Interdisciplinary Research, Department of Global, Environmental, and Genomic Health Sciences, College of Public Health, University of South Florida","place":["Tampa, USA"]},{"id":[{"id":"https:\/\/ror.org\/032db5x82","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Medicine, Morsani College of Medicine, University of South Florida","place":["Tampa, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prem","family":"Prakash","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/032db5x82","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Global Health and Interdisciplinary Research, Department of Global, Environmental, and Genomic Health Sciences, College of Public Health, University of South Florida","place":["Tampa, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3033-2212","authenticated-orcid":false,"given":"Jenna","family":"Oberstabler","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/032db5x82","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Global Health and Interdisciplinary Research, Department of Global, Environmental, and Genomic Health Sciences, College of Public Health, University of South Florida","place":["Tampa, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9835-1014","authenticated-orcid":true,"given":"Julian C.","family":"Rayner","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Cambridge Institute for Medical Research, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1246-7404","authenticated-orcid":false,"given":"Thomas D.","family":"Otto","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00vtgdb53","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Infection, Immunity, and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow","place":["Glasgow, United Kingdom"]},{"id":[{"id":"https:\/\/ror.org\/01evwfd48","id-type":"ROR","asserted-by":"publisher"}],"name":"Bernhard Nocht Institute for Tropical Medicine","place":["Hamburg, Germany"]},{"id":[{"id":"https:\/\/ror.org\/00g30e956","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Hamburg","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3707-7979","authenticated-orcid":true,"given":"John H.","family":"Adams","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/032db5x82","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Global Health and Interdisciplinary Research, Department of Global, Environmental, and Genomic Health Sciences, College of Public Health, University of South Florida","place":["Tampa, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","unstructured":"WHO. 2021 World malaria report"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30552-3"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01924-13"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01868-12"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1086\/656476"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-10-56"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)00487-9"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1003203"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-017-1680-8"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn814"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.12688\/wellcomeopenres.15194.2"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aap7847"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2180-9-83"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.05099-11"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013282"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.04164-22"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24814-1"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00273-16"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.05014-22"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2006.05119.x"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0959-440x(01)00266-4"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.220015"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S153095"},{"key":"e_1_3_6_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2007.07.001"},{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008506"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.00008-21"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.33105"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2018.08.003"},{"key":"e_1_3_7_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw2619"},{"key":"e_1_3_7_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adj4088"},{"key":"e_1_3_7_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abm7348"},{"key":"e_1_3_7_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0181656"},{"key":"e_1_3_7_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.12596"},{"key":"e_1_3_7_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2012.01840.x"},{"key":"e_1_3_7_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep42188"},{"key":"e_1_3_7_8_2","doi-asserted-by":"publisher","DOI":"10.1017\/s0031182000068219"},{"key":"e_1_3_7_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-6851(94)90111-2"},{"key":"e_1_3_7_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exppara.2007.01.021"},{"key":"e_1_3_7_11_2","doi-asserted-by":"publisher","unstructured":"Yahiya S Saunders CN Straschil U Fischer OJ Rueda-Zubiaurre A Haase S Vizcay-Barrena G Jordan S Hassan S Delves MJ et al.. 2021. Plasmodium falciparum protein Pfs16 is a target for transmission-blocking antimalarial drug development. bioRxiv. doi:10.1101\/2021.06.14.448287:2021.06.14.448287","DOI":"10.1101\/2021.06.14.448287:2021.06.14.448287"},{"key":"e_1_3_7_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.001540"},{"key":"e_1_3_7_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00053-1"},{"key":"e_1_3_7_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msad220"},{"key":"e_1_3_7_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.rsci.2024.12.003"},{"key":"e_1_3_7_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2008.01260.x"},{"key":"e_1_3_7_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.03.071"},{"key":"e_1_3_7_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1000093107"},{"key":"e_1_3_7_19_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1012008"},{"key":"e_1_3_7_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1171400"},{"key":"e_1_3_7_21_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.77447"},{"key":"e_1_3_7_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M803129200"},{"key":"e_1_3_7_23_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20130124"},{"key":"e_1_3_7_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.328591"},{"key":"e_1_3_7_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13574"},{"key":"e_1_3_7_26_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011006"},{"key":"e_1_3_7_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13555"},{"key":"e_1_3_7_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2025.113427"},{"key":"e_1_3_7_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/EC.00008-11"},{"key":"e_1_3_7_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2003.10.014"},{"key":"e_1_3_7_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0166-6851(97)00123-0"},{"key":"e_1_3_7_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/mss081"},{"key":"e_1_3_7_33_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006659"},{"key":"e_1_3_7_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501858102"},{"key":"e_1_3_7_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro3519"},{"key":"e_1_3_7_36_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.200279.115"},{"key":"e_1_3_7_37_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2006.00776.x"},{"key":"e_1_3_7_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504679102"},{"key":"e_1_3_7_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14049"},{"key":"e_1_3_7_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2018.11.005"},{"key":"e_1_3_7_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4096"},{"key":"e_1_3_7_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"e_1_3_7_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0969-x"},{"key":"e_1_3_7_44_2","unstructured":"Oberstaller J. 2021. pfGO: P. falciparum functional enrichment analysis tools. https:\/\/doi.org\/10.5281\/zenodo.5931520"},{"key":"e_1_3_7_45_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab929"},{"key":"e_1_3_7_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2007.04.008"},{"key":"e_1_3_7_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-62703-026-7_2"}],"updated-by":[{"DOI":"10.1128\/msphere.00592-26","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000}}],"container-title":["mSphere"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/msphere.00186-26","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/msphere.00186-26","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T13:01:31Z","timestamp":1785243691000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/msphere.00186-26"}},"subtitle":[],"editor":[{"given":"Gustavo","family":"Arrizabalaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":75,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7,28]]}},"alternative-id":["10.1128\/msphere.00186-26"],"URL":"https:\/\/doi.org\/10.1128\/msphere.00186-26","relation":{},"ISSN":["2379-5042"],"issn-type":[{"value":"2379-5042","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]},"assertion":[{"value":"2026-03-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00186-26"}}