{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T07:19:39Z","timestamp":1792653579853,"version":"4.5.0"},"reference-count":59,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2014,6,3]],"date-time":"2014-06-03T00:00:00Z","timestamp":1401753600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T00:00:00Z","timestamp":1404172800000},"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":[[2014,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Cryptococcus<\/jats:italic>\n                    spp. cause life-threatening fungal infection of the central nervous system (CNS), predominantly in patients with a compromised immune system. Why\n                    <jats:named-content content-type=\"genus-species\">Cryptococcus neoformans<\/jats:named-content>\n                    has this remarkable tropism for the CNS is not clear. Recent research on cerebral pathogenesis of\n                    <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n                    revealed a predominantly transcellular migration of cryptococci across the brain endothelium; however, the identities of key fungal virulence factors that function specifically to invade the CNS remain unresolved. Here we found that a novel, secreted metalloprotease (Mpr1) that we identified in the extracellular proteome of\n                    <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n                    (CnMpr1) is required for establishing fungal disease in the CNS. Mpr1 belongs to a poorly characterized M36 class of fungalysins that are expressed in only some fungal species. A strain of\n                    <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n                    lacking the gene encoding Mpr1 (\n                    <jats:italic>mpr1\u0394<\/jats:italic>\n                    ) failed to breach the endothelium in an\n                    <jats:italic>in vitro<\/jats:italic>\n                    model of the human blood-brain barrier (BBB). A mammalian host infected with the\n                    <jats:italic>mpr1\u0394<\/jats:italic>\n                    null strain demonstrated significant improvement in survival due to a reduced brain fungal burden and lacked the brain pathology commonly associated with cryptococcal disease. The\n                    <jats:italic>in vivo<\/jats:italic>\n                    studies further indicate that Mpr1 is not required for fungal dissemination and Mpr1 likely targets the brain endothelium specifically. Remarkably, the sole expression of Cn\n                    <jats:italic>MPR1<\/jats:italic>\n                    in\n                    <jats:named-content content-type=\"genus-species\">Saccharomyces cerevisiae<\/jats:named-content>\n                    resulted in a robust migration of yeast cells across the brain endothelium, demonstrating Mpr1\u2019s specific activity in breaching the BBB and suggesting that Mpr1 may function independently of the hyaluronic acid-CD44 pathway. This distinct role for Mpr1 may develop into innovative treatment options and facilitate a brain-specific drug delivery platform.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    <jats:named-content content-type=\"genus-species\">Cryptococcus neoformans<\/jats:named-content>\n                    is a medically relevant fungal pathogen causing significant morbidity and mortality, particularly in immunocompromised individuals. An intriguing feature is its strong neurotropism, and consequently the hallmark of cryptococcal disease is a brain infection, cryptococcal meningoencephalitis. For\n                    <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n                    to penetrate the central nervous system (CNS), it first breaches the blood-brain barrier via a transcellular pathway; however, the identities of fungal factors required for this transmigration remain largely unknown. In an effort to identify extracellular fungal proteins that could mediate interactions with the brain endothelium, we undertook a proteomic analysis of the extracellular proteome and identified a secreted metalloprotease (Mpr1) belonging to the M36 class of fungalysins. Here we found that Mpr1 promotes migration of\n                    <jats:named-content content-type=\"genus-species\">C. neoformans<\/jats:named-content>\n                    across the brain endothelium and into the CNS by facilitating attachment of cryptococci to the endothelium surface, thus underscoring the critical role of M36 proteases in fungal pathogenesis.\n                  <\/jats:p>","DOI":"10.1128\/mbio.01101-14","type":"journal-article","created":{"date-parts":[[2014,6,4]],"date-time":"2014-06-04T01:44:45Z","timestamp":1401846285000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":135,"title":["Invasion of the Central Nervous System by Cryptococcus neoformans Requires a Secreted Fungal Metalloprotease"],"prefix":"10.1128","volume":"5","author":[{"given":"Kiem","family":"Vu","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of California, Genome and Biomedical Sciences Facility, Davis, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick","family":"Tham","sequence":"additional","affiliation":[{"name":"Department of Biology, Cell and Molecular Biology Program, San Diego State University, San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Uhrig","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, University of California, Genome and Biomedical Sciences Facility, Davis, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"George R.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, School of Medicine, Genome and Biomedical Sciences Facility, University of California, Davis, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarisa","family":"Na 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