{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:17:24Z","timestamp":1785421044913,"version":"3.56.0"},"reference-count":26,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2026,3,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The asexual replicating intracellular stages of\n                      <jats:italic toggle=\"yes\">Plasmodium<\/jats:italic>\n                      reside within the parasitophorous vacuole (PV) and become extracellular through an active, protease-mediated process known as egress. While egress is critical for parasite viability and dissemination, the number of effector proteases involved in this process remains unknown. The genome of\n                      <jats:italic toggle=\"yes\">P. berghei<\/jats:italic>\n                      , a rodent malaria parasite, encodes five serine repeat antigens (SERAs) that bear a central papain protease domain and a serine or cysteine residue in their active site. Of these, only\n                      <jats:italic toggle=\"yes\">Pbsera3<\/jats:italic>\n                      is indispensable for blood-stage development, thus limiting its functional investigation. Using a yeast-based Flp\/\n                      <jats:italic toggle=\"yes\">FRT<\/jats:italic>\n                      conditional mutagenesis system, we successfully obtained\n                      <jats:italic toggle=\"yes\">Pbsera3<\/jats:italic>\n                      -edited sporozoites that invaded hepatocytes and developed normally in late liver stages but failed to initiate a blood-stage infection. Interestingly, we observed PbSERA3 localization on the surface of ookinetes and sporozoites under non-permeabilized conditions, likely indicating its extracellular nature. Further, PbSERA3 is processed in ookinete and sporozoite stages, yielding two bona fide products as reported in the blood stages. Given that PbSERA3 and its ortholog in\n                      <jats:italic toggle=\"yes\">P. falciparum<\/jats:italic>\n                      (PfSERA6) are substrates for subtilisin-like protease (SUB1), proteolytic maturation of PfSERA6 may also be a conserved and critical event for hepatic egress. Developing inhibitors that prevent maturation of PbSERA3\/PfSERA6 may have important therapeutic implications for preventing clinical malaria.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      The intracellular stages of\n                      <jats:italic toggle=\"yes\">Plasmodium<\/jats:italic>\n                      that replicate asexually reside within a vacuole delimited by a parasitophorous vacuolar membrane (PVM). A family of serine-rich antigens (SERAs), with a cysteine residue in its catalytic site, is implicated in liberating these parasites from PVM. In\n                      <jats:italic toggle=\"yes\">P. berghei<\/jats:italic>\n                      , a rodent malaria parasite, PbSERA3, an ortholog of PfSERA6, is indispensable for the parasite. However, its maturation by another parasite protease called subtilisin 1 (SUB1) is critical for its effector functions. During EEF development, the processed PbSERA3 is translocated across the PVM and possibly implicated in hepatic takeover. A direct role of PbSERA3 in liver stages is lacking to date. Our study generated conditional mutants of PbSERA3 and demonstrated normal development of the mutant in hepatocytes, but an inability to cause blood-stage infection. These observations point to the role of PbSERA3 in hepatic egress. We further demonstrated the extracellular nature of PbSERA3 in the ookinete, midgut, and salivary gland sporozoite stages, with a bona fide processing pattern similar to that of blood stages. Our studies demonstrated the essentiality of PbSERA3 in liver stages, making it an attractive target for antimalarial therapy. As PbSERA3 mutants manifest a late developmental arrest in the liver, they have implications in eliciting cross-stage immunity, owing to a shared repertoire of antigens with blood stages.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.03818-25","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T21:02:12Z","timestamp":1769806932000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["<i>Plasmodium berghei<\/i>\n                    serine repeat antigen 3 (PbSERA3) is required for hepatic merozoite egress"],"prefix":"10.1128","volume":"17","author":[{"given":"Dipti","family":"Singh","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04a7rxb17","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Animal Biology, School of Life Sciences, University of Hyderabad","place":["Hyderabad, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smita","family":"Patri","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04a7rxb17","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Animal Biology, School of Life Sciences, University of Hyderabad","place":["Hyderabad, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narahari","family":"Veeda","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04a7rxb17","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Animal Biology, School of Life Sciences, University of Hyderabad","place":["Hyderabad, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandan Kumar","family":"Verma","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04a7rxb17","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Animal Biology, School of Life Sciences, University of 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