{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T11:42:00Z","timestamp":1768563720313,"version":"3.49.0"},"reference-count":64,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T00:00:00Z","timestamp":1735603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"crossref","award":["310030_182465"],"award-info":[{"award-number":["310030_182465"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Multidisciplinary Center for Infectious Diseases","award":["MA-09"],"award-info":[{"award-number":["MA-09"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Malaria caused by <jats:italic>Plasmodium<\/jats:italic> parasites remains a large health burden. One approach to combat this disease involves vaccinating individuals with whole sporozoites that have been genetically modified to arrest their development at a specific stage in the liver by targeted gene deletion, resulting in a genetically attenuated parasite (GAP). Through a comprehensive phenotyping screen, we identified the <jats:italic>hscb<\/jats:italic> gene, encoding a putative iron-sulfur protein assembly chaperone, as crucial for liver stage development, making it a suitable candidate gene for GAP generation. Parasites lacking <jats:italic>Plasmodium berghei<\/jats:italic> HscB (<jats:italic>Pb<\/jats:italic>HscB) exhibited normal sporozoite production in mosquitoes, but their liver stage development was severely impaired, characterized by slow growth and delayed expression of merozoite surface protein 1 (MSP1). <jats:italic>In vivo<\/jats:italic> experiments demonstrated that <jats:italic>Pb<\/jats:italic>HscB-deficient parasites exhibited a delay in prepatency of 2\u20134 days, emphasizing the significance of <jats:italic>Pb<\/jats:italic>HscB for exo-erythrocytic development. Although knockout of <jats:italic>Pb<\/jats:italic>HscB alone allowed breakthrough infections, it is a potent candidate for a dual gene deletion strategy. PlasMei2, an RNA-binding protein, was previously found to be crucial for the completion of liver stage development. We generated a <jats:italic>Pb<\/jats:italic>HscB-<jats:italic>Pb<\/jats:italic>Mei2-double attenuated parasite line, serving as a late liver stage-arresting replication-competent (LARC) GAP, providing a solid block of liver-to-blood stage transition.<\/jats:p>","DOI":"10.1371\/journal.pone.0316164","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T18:42:56Z","timestamp":1735670576000},"page":"e0316164","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Generation of a genetically double-attenuated Plasmodium berghei parasite that fully arrests growth during late liver stage development"],"prefix":"10.1371","volume":"19","author":[{"given":"Melanie","family":"Schmid","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raphael","family":"Beyeler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reto","family":"Caldelari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth","family":"Rehmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8028-9825","authenticated-orcid":true,"given":"Volker","family":"Heussler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4646-6925","authenticated-orcid":true,"given":"Magali","family":"Roques","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,12,31]]},"reference":[{"key":"pone.0316164.ref001","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/0035-9203(90)90258-G","article-title":"An estimation of the number of malaria sporozoites ejected by a feeding mosquito","volume":"84","author":"R Rosenberg","year":"1990","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"pone.0316164.ref002","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-024-44962-4","article-title":"Revisiting the Plasmodium sporozoite inoculum and elucidating the efficiency with which malaria parasites progress through the mosquito","volume":"15","author":"S Kanatani","year":"2024","journal-title":"Nat Commun"},{"key":"pone.0316164.ref003","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.chom.2007.12.007","article-title":"Host cell traversal is important for progression of the malaria parasite through the dermis to the liver","volume":"3","author":"R Amino","year":"2008","journal-title":"Cell Host Microbe"},{"key":"pone.0316164.ref004","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1084\/jem.20121130","article-title":"Role of host cell traversal by the malaria sporozoite during liver infection","volume":"210","author":"J Tavares","year":"2013","journal-title":"J Exp Med"},{"key":"pone.0316164.ref005","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1126\/science.291.5501.141","article-title":"Migration of Plasmodium sporozoites through cells before infection","volume":"291","author":"MM Mota","year":"2001","journal-title":"Science"},{"key":"pone.0316164.ref006","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1126\/science.1129720","article-title":"Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids","volume":"313","author":"A Sturm","year":"2006","journal-title":"Science"},{"key":"pone.0316164.ref007","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1056\/NEJM199701093360202","article-title":"A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. 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