{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:34:33Z","timestamp":1789619673100,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010417","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T00:00:00Z","timestamp":1656979200000}}],"reference-count":73,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI136735"],"award-info":[{"award-number":["R01AI136735"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["2R37AI066224"],"award-info":[{"award-number":["2R37AI066224"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UCSF Pulmonary Division Training Grant","award":["2T32HL007185"],"award-info":[{"award-number":["2T32HL007185"]}]},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","award":["1019894"],"award-info":[{"award-number":["1019894"]}],"id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014576","name":"Office of the President, University of California","doi-asserted-by":"publisher","award":["President's Fellowship"],"award-info":[{"award-number":["President's Fellowship"]}],"id":[{"id":"10.13039\/100014576","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI128214"],"award-info":[{"award-number":["R01AI128214"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chan-Zuckerberg Biohub"},{"DOI":"10.13039\/501100007112","name":"University of Cape Town","doi-asserted-by":"publisher","award":["University Research Council fellowship"],"award-info":[{"award-number":["University Research Council fellowship"]}],"id":[{"id":"10.13039\/501100007112","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["209293"],"award-info":[{"award-number":["209293"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000308","name":"Carnegie Corporation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000308","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100005595","name":"University of California","doi-asserted-by":"publisher","award":["MR-15-328599"],"award-info":[{"award-number":["MR-15-328599"]}],"id":[{"id":"10.13039\/100005595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 GM124149"],"award-info":[{"award-number":["R01 GM124149"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P30 GM 124169"],"award-info":[{"award-number":["P30 GM 124169"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100019697","name":"Plexxikon","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019697","id-type":"DOI","asserted-by":"publisher"}]},{"name":"US Department of Energy Office of Biological and Environmental Research"},{"name":"US Department of Energy","award":["DE-AC02-05CH11231"],"award-info":[{"award-number":["DE-AC02-05CH11231"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Intracellular pathogens secrete effectors to manipulate their host cells.\n                    <jats:italic>Histoplasma capsulatum<\/jats:italic>\n                    (\n                    <jats:italic>Hc<\/jats:italic>\n                    ) is a fungal intracellular pathogen of humans that grows in a yeast form in the host.\n                    <jats:italic>Hc<\/jats:italic>\n                    yeasts are phagocytosed by macrophages, where fungal intracellular replication precedes macrophage lysis. The most abundant virulence factor secreted by\n                    <jats:italic>Hc<\/jats:italic>\n                    yeast cells is Calcium Binding Protein 1 (Cbp1), which is absolutely required for macrophage lysis. Here we take an evolutionary, structural, and cell biological approach to understand Cbp1 function. We find that Cbp1 is present only in the genomes of closely related dimorphic fungal species of the Ajellomycetaceae family that lead primarily intracellular lifestyles in their mammalian hosts (\n                    <jats:italic>Histoplasma<\/jats:italic>\n                    ,\n                    <jats:italic>Paracoccidioides<\/jats:italic>\n                    , and\n                    <jats:italic>Emergomyces<\/jats:italic>\n                    ), but not conserved in the extracellular fungal pathogen\n                    <jats:italic>Blastomyces dermatitidis<\/jats:italic>\n                    . We observe a high rate of fixation of non-synonymous substitutions in the Cbp1 coding sequences, indicating that Cbp1 is under positive selection. We determine the\n                    <jats:italic>de novo<\/jats:italic>\n                    structures of\n                    <jats:italic>H<\/jats:italic>\n                    c H88 Cbp1 and the\n                    <jats:italic>Paracoccidioides americana<\/jats:italic>\n                    (Pb03) Cbp1, revealing a novel \u201cbinocular\u201d fold consisting of a helical dimer arrangement wherein two helices from each monomer contribute to a four-helix bundle. In contrast to Pb03 Cbp1, we show that\n                    <jats:italic>Emergomyces<\/jats:italic>\n                    Cbp1 orthologs are unable to stimulate macrophage lysis when expressed in the\n                    <jats:italic>Hc cbp1<\/jats:italic>\n                    mutant. Consistent with this result, we find that wild-type\n                    <jats:italic>Emergomyces africanus<\/jats:italic>\n                    yeast are able to grow within primary macrophages but are incapable of lysing them. Finally, we use subcellular fractionation of infected macrophages and indirect immunofluorescence to show that Cbp1 localizes to the macrophage cytosol during\n                    <jats:italic>Hc<\/jats:italic>\n                    infection, making this the first instance of a phagosomal human fungal pathogen directing an effector into the cytosol of the host cell. We additionally show that Cbp1 forms a complex with Yps-3, another known\n                    <jats:italic>Hc<\/jats:italic>\n                    virulence factor that accesses the cytosol. Taken together, these data imply that Cbp1 is a fungal virulence factor under positive selection that localizes to the cytosol to trigger host cell lysis.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1010417","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T13:37:41Z","timestamp":1655905061000},"page":"e1010417","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":25,"title":["Cbp1, a fungal virulence factor under positive selection, forms an effector complex that drives macrophage lysis"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8599-6529","authenticated-orcid":true,"given":"Dinara","family":"Azimova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4157-9429","authenticated-orcid":true,"given":"Nadia","family":"Herrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8173-4644","authenticated-orcid":true,"given":"Lucian","family":"Duvenage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Voorhies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa A.","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4531-8808","authenticated-orcid":true,"given":"Bevin C.","family":"English","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer C.","family":"Hoving","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oren","family":"Rosenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3987-7534","authenticated-orcid":true,"given":"Anita","family":"Sil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,6,22]]},"reference":[{"issue":"9","key":"ppat.1010417.ref001","first-page":"a006114","article-title":"Subversion of cell signaling by 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Holm","year":"2020","journal-title":"Protein Sci"},{"key":"ppat.1010417.ref044","doi-asserted-by":"crossref","first-page":"D297","DOI":"10.1093\/nar\/gkt1208","article-title":"MMDB and VAST+: tracking structural similarities between macromolecular complexes","volume":"42","author":"T Madej","year":"2014","journal-title":"Nucleic Acids Res"},{"issue":"18","key":"ppat.1010417.ref045","doi-asserted-by":"crossref","first-page":"10037","DOI":"10.1073\/pnas.181342398","article-title":"Electrostatics of nanosystems: application to microtubules and the ribosome","volume":"98","author":"NA Baker","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ppat.1010417.ref046","doi-asserted-by":"crossref","first-page":"W665","DOI":"10.1093\/nar\/gkh381","article-title":"PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations","volume":"32","author":"TJ Dolinsky","year":"2004","journal-title":"Nucleic Acids 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