Flavin Reductase Contributes to Pneumococcal Virulence by Protecting from Oxidative Stress and Mediating Adhesion and Elicits Protection Against Pneumococcal Challenge
Pneumococcal flavin reductase (FlaR) is known to be cell-wall associated and possess age dependent antigenicity in children. This study aimed at characterizing FlaR and elucidating its involvement in pneumococcal physiology and virulence. Bioinformatic analysis of FlaR sequence identified three-cons...
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| creator | Morozov, Giora I. Porat, Nurith Kushnir, Tatyana Najmuldeen, Hastyar Adawi, Asad Chalifa-Caspi, Vered Benisty, Rachel Ohayon, Ariel Liron, Ofir Azriel, Shalhevet Malka, Itai Dotan, Shahar Portnoi, Maxim Piotrowski, Andrew A. Kafka, Daniel Hajaj, Barak Fishilevich, Tali Shagan, Marilou Tal, Michael Ellis, Ron Morrison, Donald A. Mitchell, Andrea M. Mitchell, Timothy J. Dagan, Ron Yesilkaya, Hasan Nebenzahl, Yaffa Mizrachi |
| description | Pneumococcal flavin reductase (FlaR) is known to be cell-wall associated and possess age dependent antigenicity in children. This study aimed at characterizing FlaR and elucidating its involvement in pneumococcal physiology and virulence. Bioinformatic analysis of FlaR sequence identified three-conserved cysteine residues, suggesting a transition metal-binding capacity. Recombinant FlaR (rFlaR) bound Fe
2+
and exhibited FAD-dependent NADP-reductase activity, which increased in the presence of cysteine or excess Fe
2+
and inhibited by divalent-chelating agents.
fla
R mutant was highly susceptible to H
2
O
2
compared to its wild type (WT) and complemented strains, suggesting a role for FlaR in pneumococcal oxidative stress resistance. Additionally,
fla
R mutant demonstrated significantly decreased mice mortality following intraperitoneal infection. Interestingly, lack of FlaR did not affect the extent of phagocytosis by primary mouse peritoneal macrophages but reduced adhesion to A549 cells compared to the WT and complemented strains. Noteworthy are the findings that immunization with rFlaR elicited protection in mice against intraperitoneal lethal challenge and anti-FlaR antisera neutralized bacterial virulence. Taken together, FlaR’s roles in pneumococcal physiology and virulence, combined with its lack of significant homology to human proteins, point towards rFlaR as a vaccine candidate. |
| doi_str_mv | 10.1038/s41598-017-18645-8 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5762878</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1993418184</sourcerecordid><originalsourceid>FETCH-LOGICAL-c511t-acec11eee2a10f3e7eb27ec77dc18fcd74715438c8654e1205cc71900c4d0443</originalsourceid><addsrcrecordid>eNp1UsFuEzEQXSEQrUp_gAOyxIXLgsdrx94LUhS1gFTUCiquluOdTVzt2sX2RvSL-E2cpEQpEr54NPP83sz4VdVroO-BNupD4iBaVVOQNagZF7V6Vp0yWgLWMPb8KD6pzlO6o-UI1nJoX1YnrG0YCOCn1e_LwWycJ9-wm2w2Ccki-BzdcsqYSA7kxuM0BhusNQP54eI0oLdIlg_kJoaMNju_In0MI7n-5TqT3QbJ9xwxJWJ8R75i58wOM-_WmFzwu_TF4KzL6cBR0vOVcT7lp4KLtRmK4ApfVS96MyQ8f7zPqtvLi9vF5_rq-tOXxfyqtgIg18aiBUBEZoD2DUpcMolWys6C6m0nuQTBG2XVTHAERoW1ElpKLe8o581Z9XFPez8tR-wsll2YQd9HN5r4oINx-mnFu7VehY0WcsaUVIXg3SNBDD8nTFmPLlkcBuMxTElDq1ohVTvbar39B3oXpujLdAXVNhwUqC2K7VE2hpQi9odmgOqtE_TeCbo4Qe-coLddvDke4_Dk778XQLMHpFIq641H2v-n_QNUOsMh</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1993418184</pqid></control><display><type>article</type><title>Flavin Reductase Contributes to Pneumococcal Virulence by Protecting from Oxidative Stress and Mediating Adhesion and Elicits Protection Against Pneumococcal Challenge</title><source>MEDLINE</source><source>Nature Free</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><source>Springer Nature OA/Free Journals</source><source>Free Full-Text Journals in Chemistry</source><creator>Morozov, Giora I. ; Porat, Nurith ; Kushnir, Tatyana ; Najmuldeen, Hastyar ; Adawi, Asad ; Chalifa-Caspi, Vered ; Benisty, Rachel ; Ohayon, Ariel ; Liron, Ofir ; Azriel, Shalhevet ; Malka, Itai ; Dotan, Shahar ; Portnoi, Maxim ; Piotrowski, Andrew A. ; Kafka, Daniel ; Hajaj, Barak ; Fishilevich, Tali ; Shagan, Marilou ; Tal, Michael ; Ellis, Ron ; Morrison, Donald A. ; Mitchell, Andrea M. ; Mitchell, Timothy J. ; Dagan, Ron ; Yesilkaya, Hasan ; Nebenzahl, Yaffa Mizrachi</creator><creatorcontrib>Morozov, Giora I. ; Porat, Nurith ; Kushnir, Tatyana ; Najmuldeen, Hastyar ; Adawi, Asad ; Chalifa-Caspi, Vered ; Benisty, Rachel ; Ohayon, Ariel ; Liron, Ofir ; Azriel, Shalhevet ; Malka, Itai ; Dotan, Shahar ; Portnoi, Maxim ; Piotrowski, Andrew A. ; Kafka, Daniel ; Hajaj, Barak ; Fishilevich, Tali ; Shagan, Marilou ; Tal, Michael ; Ellis, Ron ; Morrison, Donald A. ; Mitchell, Andrea M. ; Mitchell, Timothy J. ; Dagan, Ron ; Yesilkaya, Hasan ; Nebenzahl, Yaffa Mizrachi</creatorcontrib><description>Pneumococcal flavin reductase (FlaR) is known to be cell-wall associated and possess age dependent antigenicity in children. This study aimed at characterizing FlaR and elucidating its involvement in pneumococcal physiology and virulence. Bioinformatic analysis of FlaR sequence identified three-conserved cysteine residues, suggesting a transition metal-binding capacity. Recombinant FlaR (rFlaR) bound Fe
2+
and exhibited FAD-dependent NADP-reductase activity, which increased in the presence of cysteine or excess Fe
2+
and inhibited by divalent-chelating agents.
fla
R mutant was highly susceptible to H
2
O
2
compared to its wild type (WT) and complemented strains, suggesting a role for FlaR in pneumococcal oxidative stress resistance. Additionally,
fla
R mutant demonstrated significantly decreased mice mortality following intraperitoneal infection. Interestingly, lack of FlaR did not affect the extent of phagocytosis by primary mouse peritoneal macrophages but reduced adhesion to A549 cells compared to the WT and complemented strains. Noteworthy are the findings that immunization with rFlaR elicited protection in mice against intraperitoneal lethal challenge and anti-FlaR antisera neutralized bacterial virulence. Taken together, FlaR’s roles in pneumococcal physiology and virulence, combined with its lack of significant homology to human proteins, point towards rFlaR as a vaccine candidate.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-017-18645-8</identifier><identifier>PMID: 29321514</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>119/118 ; 13 ; 13/106 ; 13/31 ; 45/22 ; 631/326/421 ; 631/326/590/2294 ; 64/60 ; 692/420/254 ; 82 ; 82/1 ; 82/29 ; 82/58 ; 82/80 ; 82/83 ; Adhesion ; Animals ; Antigenicity ; Antisera ; Bacterial Adhesion ; Bacterial Proteins - genetics ; Bacterial Proteins - metabolism ; Cell Line, Tumor ; Cell walls ; Cells, Cultured ; Chelating agents ; Children ; Conserved sequence ; Cysteine ; Female ; Flavin reductase ; Flavin-adenine dinucleotide ; FMN Reductase - genetics ; FMN Reductase - metabolism ; Homology ; Humanities and Social Sciences ; Humans ; Hydrogen peroxide ; Immunization ; Iron ; Macrophages ; Macrophages, Peritoneal - microbiology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred CBA ; multidisciplinary ; Mutation ; NADP ; Oxidative Stress ; Peritoneum ; Phagocytosis ; Physiology ; Science ; Science (multidisciplinary) ; Strains (organisms) ; Streptococcus infections ; Streptococcus pneumoniae - enzymology ; Streptococcus pneumoniae - genetics ; Streptococcus pneumoniae - pathogenicity ; Virulence ; Virulence - genetics</subject><ispartof>Scientific reports, 2018-01, Vol.8 (1), p.314-314, Article 314</ispartof><rights>The Author(s) 2017</rights><rights>2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-acec11eee2a10f3e7eb27ec77dc18fcd74715438c8654e1205cc71900c4d0443</citedby><cites>FETCH-LOGICAL-c511t-acec11eee2a10f3e7eb27ec77dc18fcd74715438c8654e1205cc71900c4d0443</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762878/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762878/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29321514$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Morozov, Giora I.</creatorcontrib><creatorcontrib>Porat, Nurith</creatorcontrib><creatorcontrib>Kushnir, Tatyana</creatorcontrib><creatorcontrib>Najmuldeen, Hastyar</creatorcontrib><creatorcontrib>Adawi, Asad</creatorcontrib><creatorcontrib>Chalifa-Caspi, Vered</creatorcontrib><creatorcontrib>Benisty, Rachel</creatorcontrib><creatorcontrib>Ohayon, Ariel</creatorcontrib><creatorcontrib>Liron, Ofir</creatorcontrib><creatorcontrib>Azriel, Shalhevet</creatorcontrib><creatorcontrib>Malka, Itai</creatorcontrib><creatorcontrib>Dotan, Shahar</creatorcontrib><creatorcontrib>Portnoi, Maxim</creatorcontrib><creatorcontrib>Piotrowski, Andrew A.</creatorcontrib><creatorcontrib>Kafka, Daniel</creatorcontrib><creatorcontrib>Hajaj, Barak</creatorcontrib><creatorcontrib>Fishilevich, Tali</creatorcontrib><creatorcontrib>Shagan, Marilou</creatorcontrib><creatorcontrib>Tal, Michael</creatorcontrib><creatorcontrib>Ellis, Ron</creatorcontrib><creatorcontrib>Morrison, Donald A.</creatorcontrib><creatorcontrib>Mitchell, Andrea M.</creatorcontrib><creatorcontrib>Mitchell, Timothy J.</creatorcontrib><creatorcontrib>Dagan, Ron</creatorcontrib><creatorcontrib>Yesilkaya, Hasan</creatorcontrib><creatorcontrib>Nebenzahl, Yaffa Mizrachi</creatorcontrib><title>Flavin Reductase Contributes to Pneumococcal Virulence by Protecting from Oxidative Stress and Mediating Adhesion and Elicits Protection Against Pneumococcal Challenge</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Pneumococcal flavin reductase (FlaR) is known to be cell-wall associated and possess age dependent antigenicity in children. This study aimed at characterizing FlaR and elucidating its involvement in pneumococcal physiology and virulence. Bioinformatic analysis of FlaR sequence identified three-conserved cysteine residues, suggesting a transition metal-binding capacity. Recombinant FlaR (rFlaR) bound Fe
2+
and exhibited FAD-dependent NADP-reductase activity, which increased in the presence of cysteine or excess Fe
2+
and inhibited by divalent-chelating agents.
fla
R mutant was highly susceptible to H
2
O
2
compared to its wild type (WT) and complemented strains, suggesting a role for FlaR in pneumococcal oxidative stress resistance. Additionally,
fla
R mutant demonstrated significantly decreased mice mortality following intraperitoneal infection. Interestingly, lack of FlaR did not affect the extent of phagocytosis by primary mouse peritoneal macrophages but reduced adhesion to A549 cells compared to the WT and complemented strains. Noteworthy are the findings that immunization with rFlaR elicited protection in mice against intraperitoneal lethal challenge and anti-FlaR antisera neutralized bacterial virulence. Taken together, FlaR’s roles in pneumococcal physiology and virulence, combined with its lack of significant homology to human proteins, point towards rFlaR as a vaccine candidate.</description><subject>119/118</subject><subject>13</subject><subject>13/106</subject><subject>13/31</subject><subject>45/22</subject><subject>631/326/421</subject><subject>631/326/590/2294</subject><subject>64/60</subject><subject>692/420/254</subject><subject>82</subject><subject>82/1</subject><subject>82/29</subject><subject>82/58</subject><subject>82/80</subject><subject>82/83</subject><subject>Adhesion</subject><subject>Animals</subject><subject>Antigenicity</subject><subject>Antisera</subject><subject>Bacterial Adhesion</subject><subject>Bacterial Proteins - genetics</subject><subject>Bacterial Proteins - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell walls</subject><subject>Cells, Cultured</subject><subject>Chelating agents</subject><subject>Children</subject><subject>Conserved sequence</subject><subject>Cysteine</subject><subject>Female</subject><subject>Flavin reductase</subject><subject>Flavin-adenine dinucleotide</subject><subject>FMN Reductase - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Morozov, Giora I.</au><au>Porat, Nurith</au><au>Kushnir, Tatyana</au><au>Najmuldeen, Hastyar</au><au>Adawi, Asad</au><au>Chalifa-Caspi, Vered</au><au>Benisty, Rachel</au><au>Ohayon, Ariel</au><au>Liron, Ofir</au><au>Azriel, Shalhevet</au><au>Malka, Itai</au><au>Dotan, Shahar</au><au>Portnoi, Maxim</au><au>Piotrowski, Andrew A.</au><au>Kafka, Daniel</au><au>Hajaj, Barak</au><au>Fishilevich, Tali</au><au>Shagan, Marilou</au><au>Tal, Michael</au><au>Ellis, Ron</au><au>Morrison, Donald A.</au><au>Mitchell, Andrea M.</au><au>Mitchell, Timothy J.</au><au>Dagan, Ron</au><au>Yesilkaya, Hasan</au><au>Nebenzahl, Yaffa Mizrachi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Flavin Reductase Contributes to Pneumococcal Virulence by Protecting from Oxidative Stress and Mediating Adhesion and Elicits Protection Against Pneumococcal Challenge</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2018-01-10</date><risdate>2018</risdate><volume>8</volume><issue>1</issue><spage>314</spage><epage>314</epage><pages>314-314</pages><artnum>314</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Pneumococcal flavin reductase (FlaR) is known to be cell-wall associated and possess age dependent antigenicity in children. This study aimed at characterizing FlaR and elucidating its involvement in pneumococcal physiology and virulence. Bioinformatic analysis of FlaR sequence identified three-conserved cysteine residues, suggesting a transition metal-binding capacity. Recombinant FlaR (rFlaR) bound Fe
2+
and exhibited FAD-dependent NADP-reductase activity, which increased in the presence of cysteine or excess Fe
2+
and inhibited by divalent-chelating agents.
fla
R mutant was highly susceptible to H
2
O
2
compared to its wild type (WT) and complemented strains, suggesting a role for FlaR in pneumococcal oxidative stress resistance. Additionally,
fla
R mutant demonstrated significantly decreased mice mortality following intraperitoneal infection. Interestingly, lack of FlaR did not affect the extent of phagocytosis by primary mouse peritoneal macrophages but reduced adhesion to A549 cells compared to the WT and complemented strains. Noteworthy are the findings that immunization with rFlaR elicited protection in mice against intraperitoneal lethal challenge and anti-FlaR antisera neutralized bacterial virulence. Taken together, FlaR’s roles in pneumococcal physiology and virulence, combined with its lack of significant homology to human proteins, point towards rFlaR as a vaccine candidate.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29321514</pmid><doi>10.1038/s41598-017-18645-8</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2045-2322 |
| ispartof | Scientific reports, 2018-01, Vol.8 (1), p.314-314, Article 314 |
| issn | 2045-2322 2045-2322 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5762878 |
| source | MEDLINE; Nature Free; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection; Springer Nature OA/Free Journals; Free Full-Text Journals in Chemistry |
| subjects | 119/118 13 13/106 13/31 45/22 631/326/421 631/326/590/2294 64/60 692/420/254 82 82/1 82/29 82/58 82/80 82/83 Adhesion Animals Antigenicity Antisera Bacterial Adhesion Bacterial Proteins - genetics Bacterial Proteins - metabolism Cell Line, Tumor Cell walls Cells, Cultured Chelating agents Children Conserved sequence Cysteine Female Flavin reductase Flavin-adenine dinucleotide FMN Reductase - genetics FMN Reductase - metabolism Homology Humanities and Social Sciences Humans Hydrogen peroxide Immunization Iron Macrophages Macrophages, Peritoneal - microbiology Mice Mice, Inbred BALB C Mice, Inbred CBA multidisciplinary Mutation NADP Oxidative Stress Peritoneum Phagocytosis Physiology Science Science (multidisciplinary) Strains (organisms) Streptococcus infections Streptococcus pneumoniae - enzymology Streptococcus pneumoniae - genetics Streptococcus pneumoniae - pathogenicity Virulence Virulence - genetics |
| title | Flavin Reductase Contributes to Pneumococcal Virulence by Protecting from Oxidative Stress and Mediating Adhesion and Elicits Protection Against Pneumococcal Challenge |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-12T20%3A36%3A03IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Flavin%20Reductase%20Contributes%20to%20Pneumococcal%20Virulence%20by%20Protecting%20from%20Oxidative%20Stress%20and%20Mediating%20Adhesion%20and%20Elicits%20Protection%20Against%20Pneumococcal%20Challenge&rft.jtitle=Scientific%20reports&rft.au=Morozov,%20Giora%20I.&rft.date=2018-01-10&rft.volume=8&rft.issue=1&rft.spage=314&rft.epage=314&rft.pages=314-314&rft.artnum=314&rft.issn=2045-2322&rft.eissn=2045-2322&rft_id=info:doi/10.1038/s41598-017-18645-8&rft_dat=%3Cproquest_pubme%3E1993418184%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1993418184&rft_id=info:pmid/29321514&rfr_iscdi=true |