The NDV-3A vaccine protects mice from multidrug resistant Candida auris infection
Candida auris is an emerging, multi-drug resistant, health care-associated fungal pathogen. Its predominant prevalence in hospitals and nursing homes indicates its ability to adhere to and colonize the skin, or persist in an environment outside the host-a trait unique from other Candida species. Bes...
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| creator | Singh, Shakti Uppuluri, Priya Mamouei, Zeinab Alqarihi, Abdullah Elhassan, Hana French, Samuel Lockhart, Shawn R Chiller, Tom Edwards, Jr, John E Ibrahim, Ashraf S |
| description | Candida auris is an emerging, multi-drug resistant, health care-associated fungal pathogen. Its predominant prevalence in hospitals and nursing homes indicates its ability to adhere to and colonize the skin, or persist in an environment outside the host-a trait unique from other Candida species. Besides being associated globally with life-threatening disseminated infections, C. auris also poses significant clinical challenges due to its ability to adhere to polymeric surfaces and form highly drug-resistant biofilms. Here, we performed bioinformatic studies to identify the presence of adhesin proteins in C. auris, with sequence as well as 3-D structural homologies to the major adhesin/invasin of C. albicans, Als3. Anti-Als3p antibodies generated by vaccinating mice with NDV-3A (a vaccine based on the N-terminus of Als3 protein formulated with alum) recognized C. auris in vitro, blocked its ability to form biofilms and enhanced macrophage-mediated killing of the fungus. Furthermore, NDV-3A vaccination induced significant levels of C. auris cross-reactive humoral and cellular immune responses, and protected immunosuppressed mice from lethal C. auris disseminated infection, compared to the control alum-vaccinated mice. The mechanism of protection is attributed to anti-Als3p antibodies and CD4+ T helper cells activating tissue macrophages. Finally, NDV-3A potentiated the protective efficacy of the antifungal drug micafungin, against C. auris candidemia. Identification of Als3-like adhesins in C. auris makes it a target for immunotherapeutic strategies using NDV-3A, a vaccine with known efficacy against other Candida species and safety as well as efficacy in clinical trials. Considering that C. auris can be resistant to almost all classes of antifungal drugs, such an approach has profound clinical relevance. |
| doi_str_mv | 10.1371/journal.ppat.1007460 |
| format | Article |
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Its predominant prevalence in hospitals and nursing homes indicates its ability to adhere to and colonize the skin, or persist in an environment outside the host-a trait unique from other Candida species. Besides being associated globally with life-threatening disseminated infections, C. auris also poses significant clinical challenges due to its ability to adhere to polymeric surfaces and form highly drug-resistant biofilms. Here, we performed bioinformatic studies to identify the presence of adhesin proteins in C. auris, with sequence as well as 3-D structural homologies to the major adhesin/invasin of C. albicans, Als3. Anti-Als3p antibodies generated by vaccinating mice with NDV-3A (a vaccine based on the N-terminus of Als3 protein formulated with alum) recognized C. auris in vitro, blocked its ability to form biofilms and enhanced macrophage-mediated killing of the fungus. Furthermore, NDV-3A vaccination induced significant levels of C. auris cross-reactive humoral and cellular immune responses, and protected immunosuppressed mice from lethal C. auris disseminated infection, compared to the control alum-vaccinated mice. The mechanism of protection is attributed to anti-Als3p antibodies and CD4+ T helper cells activating tissue macrophages. Finally, NDV-3A potentiated the protective efficacy of the antifungal drug micafungin, against C. auris candidemia. Identification of Als3-like adhesins in C. auris makes it a target for immunotherapeutic strategies using NDV-3A, a vaccine with known efficacy against other Candida species and safety as well as efficacy in clinical trials. Considering that C. auris can be resistant to almost all classes of antifungal drugs, such an approach has profound clinical relevance.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1007460</identifier><identifier>PMID: 31381597</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adhesins ; Alum Compounds - chemistry ; Animals ; Antibodies ; Biofilms ; Biofilms - growth & development ; Biology and Life Sciences ; Biomedical research ; Candida ; Candida - immunology ; Candida auris ; Candidemia ; Candidiasis ; Candidiasis - immunology ; Candidiasis - microbiology ; Candidiasis - prevention & control ; CD4 antigen ; CD4-Positive T-Lymphocytes - immunology ; Clinical trials ; Disease control ; Disseminated infection ; Drug resistance ; Drug Resistance, Multiple - immunology ; Effectiveness ; Fungal infections ; Fungal Proteins - immunology ; Fungal Vaccines - administration & dosage ; Fungi ; Fungicides ; Geffen, David ; Helper cells ; Homology ; Hospitals ; Immune response ; Immune response (cell-mediated) ; Immune response (humoral) ; Immunosuppressive agents ; Immunotherapy ; Infection ; Infections ; Infectious diseases ; Macrophages ; Medicine ; Medicine and Health Sciences ; Micafungin ; Mice ; Mice, Inbred ICR ; Microbial drug resistance ; Multidrug resistance ; Multidrug resistant organisms ; N-Terminus ; Nursing homes ; People and Places ; Prevention ; Proteins ; Research and Analysis Methods ; Skin ; Testing ; Vaccination ; Vaccines ; Viral vaccines ; Yeast</subject><ispartof>PLoS pathogens, 2019-08, Vol.15 (8), p.e1007460-e1007460</ispartof><rights>COPYRIGHT 2019 Public Library of Science</rights><rights>This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”). 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Its predominant prevalence in hospitals and nursing homes indicates its ability to adhere to and colonize the skin, or persist in an environment outside the host-a trait unique from other Candida species. Besides being associated globally with life-threatening disseminated infections, C. auris also poses significant clinical challenges due to its ability to adhere to polymeric surfaces and form highly drug-resistant biofilms. Here, we performed bioinformatic studies to identify the presence of adhesin proteins in C. auris, with sequence as well as 3-D structural homologies to the major adhesin/invasin of C. albicans, Als3. Anti-Als3p antibodies generated by vaccinating mice with NDV-3A (a vaccine based on the N-terminus of Als3 protein formulated with alum) recognized C. auris in vitro, blocked its ability to form biofilms and enhanced macrophage-mediated killing of the fungus. Furthermore, NDV-3A vaccination induced significant levels of C. auris cross-reactive humoral and cellular immune responses, and protected immunosuppressed mice from lethal C. auris disseminated infection, compared to the control alum-vaccinated mice. The mechanism of protection is attributed to anti-Als3p antibodies and CD4+ T helper cells activating tissue macrophages. Finally, NDV-3A potentiated the protective efficacy of the antifungal drug micafungin, against C. auris candidemia. Identification of Als3-like adhesins in C. auris makes it a target for immunotherapeutic strategies using NDV-3A, a vaccine with known efficacy against other Candida species and safety as well as efficacy in clinical trials. Considering that C. auris can be resistant to almost all classes of antifungal drugs, such an approach has profound clinical relevance.</description><subject>Adhesins</subject><subject>Alum Compounds - chemistry</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Biofilms</subject><subject>Biofilms - growth & development</subject><subject>Biology and Life Sciences</subject><subject>Biomedical research</subject><subject>Candida</subject><subject>Candida - immunology</subject><subject>Candida auris</subject><subject>Candidemia</subject><subject>Candidiasis</subject><subject>Candidiasis - immunology</subject><subject>Candidiasis - microbiology</subject><subject>Candidiasis - prevention & control</subject><subject>CD4 antigen</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>Clinical trials</subject><subject>Disease control</subject><subject>Disseminated infection</subject><subject>Drug resistance</subject><subject>Drug Resistance, Multiple - immunology</subject><subject>Effectiveness</subject><subject>Fungal infections</subject><subject>Fungal Proteins - immunology</subject><subject>Fungal Vaccines - administration & dosage</subject><subject>Fungi</subject><subject>Fungicides</subject><subject>Geffen, David</subject><subject>Helper cells</subject><subject>Homology</subject><subject>Hospitals</subject><subject>Immune response</subject><subject>Immune response (cell-mediated)</subject><subject>Immune response (humoral)</subject><subject>Immunosuppressive agents</subject><subject>Immunotherapy</subject><subject>Infection</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Macrophages</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Micafungin</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>Microbial drug resistance</subject><subject>Multidrug resistance</subject><subject>Multidrug resistant organisms</subject><subject>N-Terminus</subject><subject>Nursing homes</subject><subject>People and Places</subject><subject>Prevention</subject><subject>Proteins</subject><subject>Research and Analysis Methods</subject><subject>Skin</subject><subject>Testing</subject><subject>Vaccination</subject><subject>Vaccines</subject><subject>Viral vaccines</subject><subject>Yeast</subject><issn>1553-7374</issn><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqVkk1vEzEQhlcIREvgHyBYiQscEuy1115fKkXhK1JVBBSultcep45218H2VvDvcci2alAvyAdb4-d9xzOeoniO0QITjt9u_RgG1S12O5UWGCFOGXpQnOK6JnNOOH1453xSPIlxixDFBLPHxQnBpMG14KfFl8srKC_e_ZiTZXmttHYDlLvgE-gUy95pKG3wfdmPXXImjJsyQHQxqSGVKzUYZ1SpxuBi6QabNc4PT4tHVnURnk37rPj-4f3l6tP8_PPH9Wp5PteM4TRvUFXll9WkYci21AqjKdStxkQ0olYtU1wzwnANwghOSNUqgQlYYzhFWlkyK14efHedj3LqRpRVJTDlHAuSifWBMF5t5S64XoXf0isn_wZ82EgVktMdyFpgznNKi2hNsaECGHCqLG8bRgiD7HU2ZRvbHoyGIQXVHZke3wzuSm78tWRM1BWi2eD1ZBD8zxFikr2LGrpODeDH_btZIyhFOd-sePUPen91E7VRuYDcfp_z6r2pXLL81RVtaJOpxT1UXgby7_oBrMvxI8GbI0FmEvxKGzXGKNffvv4He3HM0gOrg48xgL3tHUZyP9A3Rcr9QMtpoLPsxd2-34puJpj8ATrT708</recordid><startdate>20190805</startdate><enddate>20190805</enddate><creator>Singh, Shakti</creator><creator>Uppuluri, Priya</creator><creator>Mamouei, Zeinab</creator><creator>Alqarihi, Abdullah</creator><creator>Elhassan, Hana</creator><creator>French, Samuel</creator><creator>Lockhart, Shawn R</creator><creator>Chiller, Tom</creator><creator>Edwards, Jr, John E</creator><creator>Ibrahim, Ashraf S</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-3642-5698</orcidid><orcidid>https://orcid.org/0000-0002-4383-5994</orcidid><orcidid>https://orcid.org/0000-0003-3787-8530</orcidid><orcidid>https://orcid.org/0000-0003-4408-6398</orcidid><orcidid>https://orcid.org/0000-0001-6521-0998</orcidid></search><sort><creationdate>20190805</creationdate><title>The NDV-3A vaccine protects mice from multidrug resistant Candida auris infection</title><author>Singh, Shakti ; Uppuluri, Priya ; Mamouei, Zeinab ; Alqarihi, Abdullah ; Elhassan, Hana ; French, Samuel ; Lockhart, Shawn R ; Chiller, Tom ; Edwards, Jr, John E ; Ibrahim, Ashraf S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c661t-802237453860fb4f9dc4e5bc139895ab6a7c63615e9d97332ba913efdd740caf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adhesins</topic><topic>Alum Compounds - chemistry</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Biofilms</topic><topic>Biofilms - growth & development</topic><topic>Biology and Life Sciences</topic><topic>Biomedical research</topic><topic>Candida</topic><topic>Candida - immunology</topic><topic>Candida auris</topic><topic>Candidemia</topic><topic>Candidiasis</topic><topic>Candidiasis - immunology</topic><topic>Candidiasis - microbiology</topic><topic>Candidiasis - prevention & control</topic><topic>CD4 antigen</topic><topic>CD4-Positive T-Lymphocytes - immunology</topic><topic>Clinical trials</topic><topic>Disease control</topic><topic>Disseminated infection</topic><topic>Drug resistance</topic><topic>Drug Resistance, Multiple - immunology</topic><topic>Effectiveness</topic><topic>Fungal infections</topic><topic>Fungal Proteins - immunology</topic><topic>Fungal Vaccines - administration & dosage</topic><topic>Fungi</topic><topic>Fungicides</topic><topic>Geffen, David</topic><topic>Helper cells</topic><topic>Homology</topic><topic>Hospitals</topic><topic>Immune response</topic><topic>Immune response (cell-mediated)</topic><topic>Immune response (humoral)</topic><topic>Immunosuppressive agents</topic><topic>Immunotherapy</topic><topic>Infection</topic><topic>Infections</topic><topic>Infectious diseases</topic><topic>Macrophages</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Micafungin</topic><topic>Mice</topic><topic>Mice, Inbred ICR</topic><topic>Microbial drug resistance</topic><topic>Multidrug resistance</topic><topic>Multidrug resistant organisms</topic><topic>N-Terminus</topic><topic>Nursing homes</topic><topic>People and Places</topic><topic>Prevention</topic><topic>Proteins</topic><topic>Research and Analysis Methods</topic><topic>Skin</topic><topic>Testing</topic><topic>Vaccination</topic><topic>Vaccines</topic><topic>Viral vaccines</topic><topic>Yeast</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Singh, Shakti</creatorcontrib><creatorcontrib>Uppuluri, Priya</creatorcontrib><creatorcontrib>Mamouei, Zeinab</creatorcontrib><creatorcontrib>Alqarihi, Abdullah</creatorcontrib><creatorcontrib>Elhassan, Hana</creatorcontrib><creatorcontrib>French, Samuel</creatorcontrib><creatorcontrib>Lockhart, Shawn R</creatorcontrib><creatorcontrib>Chiller, Tom</creatorcontrib><creatorcontrib>Edwards, Jr, John E</creatorcontrib><creatorcontrib>Ibrahim, Ashraf S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - 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Its predominant prevalence in hospitals and nursing homes indicates its ability to adhere to and colonize the skin, or persist in an environment outside the host-a trait unique from other Candida species. Besides being associated globally with life-threatening disseminated infections, C. auris also poses significant clinical challenges due to its ability to adhere to polymeric surfaces and form highly drug-resistant biofilms. Here, we performed bioinformatic studies to identify the presence of adhesin proteins in C. auris, with sequence as well as 3-D structural homologies to the major adhesin/invasin of C. albicans, Als3. Anti-Als3p antibodies generated by vaccinating mice with NDV-3A (a vaccine based on the N-terminus of Als3 protein formulated with alum) recognized C. auris in vitro, blocked its ability to form biofilms and enhanced macrophage-mediated killing of the fungus. Furthermore, NDV-3A vaccination induced significant levels of C. auris cross-reactive humoral and cellular immune responses, and protected immunosuppressed mice from lethal C. auris disseminated infection, compared to the control alum-vaccinated mice. The mechanism of protection is attributed to anti-Als3p antibodies and CD4+ T helper cells activating tissue macrophages. Finally, NDV-3A potentiated the protective efficacy of the antifungal drug micafungin, against C. auris candidemia. Identification of Als3-like adhesins in C. auris makes it a target for immunotherapeutic strategies using NDV-3A, a vaccine with known efficacy against other Candida species and safety as well as efficacy in clinical trials. Considering that C. auris can be resistant to almost all classes of antifungal drugs, such an approach has profound clinical relevance.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31381597</pmid><doi>10.1371/journal.ppat.1007460</doi><orcidid>https://orcid.org/0000-0002-3642-5698</orcidid><orcidid>https://orcid.org/0000-0002-4383-5994</orcidid><orcidid>https://orcid.org/0000-0003-3787-8530</orcidid><orcidid>https://orcid.org/0000-0003-4408-6398</orcidid><orcidid>https://orcid.org/0000-0001-6521-0998</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_2291477193 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; PubMed Central Open Access |
| subjects | Adhesins Alum Compounds - chemistry Animals Antibodies Biofilms Biofilms - growth & development Biology and Life Sciences Biomedical research Candida Candida - immunology Candida auris Candidemia Candidiasis Candidiasis - immunology Candidiasis - microbiology Candidiasis - prevention & control CD4 antigen CD4-Positive T-Lymphocytes - immunology Clinical trials Disease control Disseminated infection Drug resistance Drug Resistance, Multiple - immunology Effectiveness Fungal infections Fungal Proteins - immunology Fungal Vaccines - administration & dosage Fungi Fungicides Geffen, David Helper cells Homology Hospitals Immune response Immune response (cell-mediated) Immune response (humoral) Immunosuppressive agents Immunotherapy Infection Infections Infectious diseases Macrophages Medicine Medicine and Health Sciences Micafungin Mice Mice, Inbred ICR Microbial drug resistance Multidrug resistance Multidrug resistant organisms N-Terminus Nursing homes People and Places Prevention Proteins Research and Analysis Methods Skin Testing Vaccination Vaccines Viral vaccines Yeast |
| title | The NDV-3A vaccine protects mice from multidrug resistant Candida auris infection |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T01%3A41%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20NDV-3A%20vaccine%20protects%20mice%20from%20multidrug%20resistant%20Candida%20auris%20infection&rft.jtitle=PLoS%20pathogens&rft.au=Singh,%20Shakti&rft.date=2019-08-05&rft.volume=15&rft.issue=8&rft.spage=e1007460&rft.epage=e1007460&rft.pages=e1007460-e1007460&rft.issn=1553-7374&rft.eissn=1553-7374&rft_id=info:doi/10.1371/journal.ppat.1007460&rft_dat=%3Cgale_plos_%3EA600424848%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2291477193&rft_id=info:pmid/31381597&rft_galeid=A600424848&rft_doaj_id=oai_doaj_org_article_591776a7f04541d49e6e74af7b86336e&rfr_iscdi=true |