Development of Streptococcal Pyrogenic Exotoxin C Vaccine Toxoids That Are Protective in the Rabbit Model of Toxic Shock Syndrome
Streptococcal pyrogenic exotoxin C (SPE C) is a superantigen produced by many strains of Streptococcus pyogenes that (along with streptococcal pyrogenic exotoxin A) is highly associated with streptococcal toxic shock syndrome (STSS) and other invasive streptococcal diseases. Based on the three-dimen...
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| Veröffentlicht in: | The Journal of immunology (1950) 2000-08, Vol.165 (4), p.2306-2312 |
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| container_title | The Journal of immunology (1950) |
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| creator | McCormick, John K Tripp, Timothy J Olmsted, Stephen B Matsuka, Yury V Gahr, Pamala J Ohlendorf, Douglas H Schlievert, Patrick M |
| description | Streptococcal pyrogenic exotoxin C (SPE C) is a superantigen produced by many strains of Streptococcus pyogenes that (along with streptococcal pyrogenic exotoxin A) is highly associated with streptococcal toxic shock syndrome (STSS) and other invasive streptococcal diseases. Based on the three-dimensional structure of SPE C, solvent-exposed residues predicted to be important for binding to the TCR or the MHC class II molecule, or important for dimerization, were generated. Based on decreased mitogenic activity of various single-site mutants, the double-site mutant Y15A/N38D and the triple-site mutant Y15A/H35A/N38D were constructed and analyzed for superantigenicity, toxicity (lethality), immunogenicity, and the ability to protect against wild-type SPE C-induced STSS. The Y15A/N38D and Y15A/H35A/N38D mutants were nonmitogenic for rabbit splenocytes and human PBMCs and nonlethal in two rabbit models of STSS, yet both mutants were highly immunogenic. Animals vaccinated with the Y15A/N38D or Y15A/H35A/N38D toxoids were protected from challenge with wild-type SPE C. Collectively, these data indicate that the Y15A/N38D and Y15A/H35A/N38D mutants may be useful as toxoid vaccine candidates. |
| doi_str_mv | 10.4049/jimmunol.165.4.2306 |
| format | Article |
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Based on the three-dimensional structure of SPE C, solvent-exposed residues predicted to be important for binding to the TCR or the MHC class II molecule, or important for dimerization, were generated. Based on decreased mitogenic activity of various single-site mutants, the double-site mutant Y15A/N38D and the triple-site mutant Y15A/H35A/N38D were constructed and analyzed for superantigenicity, toxicity (lethality), immunogenicity, and the ability to protect against wild-type SPE C-induced STSS. The Y15A/N38D and Y15A/H35A/N38D mutants were nonmitogenic for rabbit splenocytes and human PBMCs and nonlethal in two rabbit models of STSS, yet both mutants were highly immunogenic. Animals vaccinated with the Y15A/N38D or Y15A/H35A/N38D toxoids were protected from challenge with wild-type SPE C. Collectively, these data indicate that the Y15A/N38D and Y15A/H35A/N38D mutants may be useful as toxoid vaccine candidates.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.165.4.2306</identifier><identifier>PMID: 10925320</identifier><language>eng</language><publisher>United States: Am Assoc Immnol</publisher><subject>Animals ; Bacterial Proteins ; Bacterial Vaccines - administration & dosage ; Bacterial Vaccines - chemical synthesis ; Bacterial Vaccines - genetics ; Bacterial Vaccines - immunology ; Cells, Cultured ; Dimerization ; Disease Models, Animal ; exotoxin C ; Exotoxins - administration & dosage ; Exotoxins - chemical synthesis ; Exotoxins - genetics ; Exotoxins - immunology ; Humans ; Infusion Pumps, Implantable ; Lymphocyte Activation ; Membrane Proteins ; Models, Molecular ; Mutagenesis, Site-Directed ; Pyrogens - administration & dosage ; Pyrogens - chemical synthesis ; Pyrogens - genetics ; Pyrogens - immunology ; Rabbits ; Shock, Septic - immunology ; Shock, Septic - prevention & control ; Streptococcal pyrogenic exotoxin C ; streptococcal toxic shock syndrome ; Streptococcus pyogenes ; Streptococcus pyogenes - genetics ; Streptococcus pyogenes - immunology ; Structure-Activity Relationship ; Toxoids - administration & dosage ; Toxoids - chemical synthesis ; Toxoids - genetics ; Toxoids - immunology ; Vaccines, Synthetic - chemistry ; Vaccines, Synthetic - genetics ; Vaccines, Synthetic - immunology</subject><ispartof>The Journal of immunology (1950), 2000-08, Vol.165 (4), p.2306-2312</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c409t-9349294b11a06e16b1986cba6bdd447702e98d92876284bb58bf25608b5392a23</citedby><cites>FETCH-LOGICAL-c409t-9349294b11a06e16b1986cba6bdd447702e98d92876284bb58bf25608b5392a23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10925320$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McCormick, John K</creatorcontrib><creatorcontrib>Tripp, Timothy J</creatorcontrib><creatorcontrib>Olmsted, Stephen B</creatorcontrib><creatorcontrib>Matsuka, Yury V</creatorcontrib><creatorcontrib>Gahr, Pamala J</creatorcontrib><creatorcontrib>Ohlendorf, Douglas H</creatorcontrib><creatorcontrib>Schlievert, Patrick M</creatorcontrib><title>Development of Streptococcal Pyrogenic Exotoxin C Vaccine Toxoids That Are Protective in the Rabbit Model of Toxic Shock Syndrome</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>Streptococcal pyrogenic exotoxin C (SPE C) is a superantigen produced by many strains of Streptococcus pyogenes that (along with streptococcal pyrogenic exotoxin A) is highly associated with streptococcal toxic shock syndrome (STSS) and other invasive streptococcal diseases. Based on the three-dimensional structure of SPE C, solvent-exposed residues predicted to be important for binding to the TCR or the MHC class II molecule, or important for dimerization, were generated. Based on decreased mitogenic activity of various single-site mutants, the double-site mutant Y15A/N38D and the triple-site mutant Y15A/H35A/N38D were constructed and analyzed for superantigenicity, toxicity (lethality), immunogenicity, and the ability to protect against wild-type SPE C-induced STSS. The Y15A/N38D and Y15A/H35A/N38D mutants were nonmitogenic for rabbit splenocytes and human PBMCs and nonlethal in two rabbit models of STSS, yet both mutants were highly immunogenic. Animals vaccinated with the Y15A/N38D or Y15A/H35A/N38D toxoids were protected from challenge with wild-type SPE C. Collectively, these data indicate that the Y15A/N38D and Y15A/H35A/N38D mutants may be useful as toxoid vaccine candidates.</description><subject>Animals</subject><subject>Bacterial Proteins</subject><subject>Bacterial Vaccines - administration & dosage</subject><subject>Bacterial Vaccines - chemical synthesis</subject><subject>Bacterial Vaccines - genetics</subject><subject>Bacterial Vaccines - immunology</subject><subject>Cells, Cultured</subject><subject>Dimerization</subject><subject>Disease Models, Animal</subject><subject>exotoxin C</subject><subject>Exotoxins - administration & dosage</subject><subject>Exotoxins - chemical synthesis</subject><subject>Exotoxins - genetics</subject><subject>Exotoxins - immunology</subject><subject>Humans</subject><subject>Infusion Pumps, Implantable</subject><subject>Lymphocyte Activation</subject><subject>Membrane Proteins</subject><subject>Models, Molecular</subject><subject>Mutagenesis, Site-Directed</subject><subject>Pyrogens - administration & dosage</subject><subject>Pyrogens - chemical synthesis</subject><subject>Pyrogens - genetics</subject><subject>Pyrogens - immunology</subject><subject>Rabbits</subject><subject>Shock, Septic - immunology</subject><subject>Shock, Septic - prevention & control</subject><subject>Streptococcal pyrogenic exotoxin C</subject><subject>streptococcal toxic shock syndrome</subject><subject>Streptococcus pyogenes</subject><subject>Streptococcus pyogenes - genetics</subject><subject>Streptococcus pyogenes - immunology</subject><subject>Structure-Activity Relationship</subject><subject>Toxoids - administration & dosage</subject><subject>Toxoids - chemical synthesis</subject><subject>Toxoids - genetics</subject><subject>Toxoids - immunology</subject><subject>Vaccines, Synthetic - chemistry</subject><subject>Vaccines, Synthetic - genetics</subject><subject>Vaccines, Synthetic - immunology</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkEFv0zAYhi0EYt3gFyAhn-CU8tlxnPg4lcGQhpho4WrZztfFI4k7213bI_-cVB3STu_leZ_DQ8g7BnMBQn2698OwHUM_Z7KaizkvQb4gM1ZVUEgJ8iWZAXBesFrWZ-Q8pXsAkMDFa3LGQPGq5DAjfz_jI_ZhM-CYaVjTZY64ycEF50xPbw8x3OHoHb3ahxz2fqQL-ts450ekq7APvk101ZlMLyPS2xgyuuwfkU5g7pD-NNb6TL-HFvujfbpMrmUX3B-6PIxtDAO-Ia_Wpk_49mkvyK8vV6vFdXHz4-u3xeVN4QSoXKhSKK6EZcyARCYtU4101kjbtkLUNXBUTat4U0veCGurxq55JaGxVam44eUF-XDybmJ42GLKevDJYd-bEcM26akTE6KCCSxPoIshpYhrvYl-MPGgGehjef2_vJ7Ka6GP5afX-yf91g7YPvucUk_AxxPQ-btu5yPqNJi-n3Cmd7vdM9U_bW-PWw</recordid><startdate>20000815</startdate><enddate>20000815</enddate><creator>McCormick, John K</creator><creator>Tripp, Timothy J</creator><creator>Olmsted, Stephen B</creator><creator>Matsuka, Yury V</creator><creator>Gahr, Pamala J</creator><creator>Ohlendorf, Douglas H</creator><creator>Schlievert, Patrick M</creator><general>Am Assoc Immnol</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>7QL</scope><scope>7T5</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope></search><sort><creationdate>20000815</creationdate><title>Development of Streptococcal Pyrogenic Exotoxin C Vaccine Toxoids That Are Protective in the Rabbit Model of Toxic Shock Syndrome</title><author>McCormick, John K ; Tripp, Timothy J ; Olmsted, Stephen B ; Matsuka, Yury V ; Gahr, Pamala J ; Ohlendorf, Douglas H ; Schlievert, Patrick M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c409t-9349294b11a06e16b1986cba6bdd447702e98d92876284bb58bf25608b5392a23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Animals</topic><topic>Bacterial Proteins</topic><topic>Bacterial Vaccines - administration & dosage</topic><topic>Bacterial Vaccines - chemical synthesis</topic><topic>Bacterial Vaccines - genetics</topic><topic>Bacterial Vaccines - immunology</topic><topic>Cells, Cultured</topic><topic>Dimerization</topic><topic>Disease Models, Animal</topic><topic>exotoxin C</topic><topic>Exotoxins - administration & dosage</topic><topic>Exotoxins - chemical synthesis</topic><topic>Exotoxins - genetics</topic><topic>Exotoxins - immunology</topic><topic>Humans</topic><topic>Infusion Pumps, Implantable</topic><topic>Lymphocyte Activation</topic><topic>Membrane Proteins</topic><topic>Models, Molecular</topic><topic>Mutagenesis, Site-Directed</topic><topic>Pyrogens - administration & dosage</topic><topic>Pyrogens - chemical synthesis</topic><topic>Pyrogens - genetics</topic><topic>Pyrogens - immunology</topic><topic>Rabbits</topic><topic>Shock, Septic - immunology</topic><topic>Shock, Septic - prevention & control</topic><topic>Streptococcal pyrogenic exotoxin C</topic><topic>streptococcal toxic shock syndrome</topic><topic>Streptococcus pyogenes</topic><topic>Streptococcus pyogenes - genetics</topic><topic>Streptococcus pyogenes - immunology</topic><topic>Structure-Activity Relationship</topic><topic>Toxoids - administration & dosage</topic><topic>Toxoids - chemical synthesis</topic><topic>Toxoids - genetics</topic><topic>Toxoids - immunology</topic><topic>Vaccines, Synthetic - chemistry</topic><topic>Vaccines, Synthetic - genetics</topic><topic>Vaccines, Synthetic - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McCormick, John K</creatorcontrib><creatorcontrib>Tripp, Timothy J</creatorcontrib><creatorcontrib>Olmsted, Stephen B</creatorcontrib><creatorcontrib>Matsuka, Yury V</creatorcontrib><creatorcontrib>Gahr, Pamala J</creatorcontrib><creatorcontrib>Ohlendorf, Douglas H</creatorcontrib><creatorcontrib>Schlievert, Patrick M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Immunology Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McCormick, John K</au><au>Tripp, Timothy J</au><au>Olmsted, Stephen B</au><au>Matsuka, Yury V</au><au>Gahr, Pamala J</au><au>Ohlendorf, Douglas H</au><au>Schlievert, Patrick M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of Streptococcal Pyrogenic Exotoxin C Vaccine Toxoids That Are Protective in the Rabbit Model of Toxic Shock Syndrome</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2000-08-15</date><risdate>2000</risdate><volume>165</volume><issue>4</issue><spage>2306</spage><epage>2312</epage><pages>2306-2312</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>Streptococcal pyrogenic exotoxin C (SPE C) is a superantigen produced by many strains of Streptococcus pyogenes that (along with streptococcal pyrogenic exotoxin A) is highly associated with streptococcal toxic shock syndrome (STSS) and other invasive streptococcal diseases. Based on the three-dimensional structure of SPE C, solvent-exposed residues predicted to be important for binding to the TCR or the MHC class II molecule, or important for dimerization, were generated. Based on decreased mitogenic activity of various single-site mutants, the double-site mutant Y15A/N38D and the triple-site mutant Y15A/H35A/N38D were constructed and analyzed for superantigenicity, toxicity (lethality), immunogenicity, and the ability to protect against wild-type SPE C-induced STSS. The Y15A/N38D and Y15A/H35A/N38D mutants were nonmitogenic for rabbit splenocytes and human PBMCs and nonlethal in two rabbit models of STSS, yet both mutants were highly immunogenic. Animals vaccinated with the Y15A/N38D or Y15A/H35A/N38D toxoids were protected from challenge with wild-type SPE C. Collectively, these data indicate that the Y15A/N38D and Y15A/H35A/N38D mutants may be useful as toxoid vaccine candidates.</abstract><cop>United States</cop><pub>Am Assoc Immnol</pub><pmid>10925320</pmid><doi>10.4049/jimmunol.165.4.2306</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of immunology (1950), 2000-08, Vol.165 (4), p.2306-2312 |
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| subjects | Animals Bacterial Proteins Bacterial Vaccines - administration & dosage Bacterial Vaccines - chemical synthesis Bacterial Vaccines - genetics Bacterial Vaccines - immunology Cells, Cultured Dimerization Disease Models, Animal exotoxin C Exotoxins - administration & dosage Exotoxins - chemical synthesis Exotoxins - genetics Exotoxins - immunology Humans Infusion Pumps, Implantable Lymphocyte Activation Membrane Proteins Models, Molecular Mutagenesis, Site-Directed Pyrogens - administration & dosage Pyrogens - chemical synthesis Pyrogens - genetics Pyrogens - immunology Rabbits Shock, Septic - immunology Shock, Septic - prevention & control Streptococcal pyrogenic exotoxin C streptococcal toxic shock syndrome Streptococcus pyogenes Streptococcus pyogenes - genetics Streptococcus pyogenes - immunology Structure-Activity Relationship Toxoids - administration & dosage Toxoids - chemical synthesis Toxoids - genetics Toxoids - immunology Vaccines, Synthetic - chemistry Vaccines, Synthetic - genetics Vaccines, Synthetic - immunology |
| title | Development of Streptococcal Pyrogenic Exotoxin C Vaccine Toxoids That Are Protective in the Rabbit Model of Toxic Shock Syndrome |
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