Human <italic toggle="yes">V<sub>H</sub>1-69</italic> Gene-Encoded Human Monoclonal Antibodies against <named-content content-type="genus-species">Staphylococcus aureus</named-content> IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis

ABSTRACT Staphylococcus aureus is an important human pathogen that infects nearly every human tissue. Like most organisms, the acquisition of nutrient iron is necessary for its survival. One route by which it obtains this metal is through the iron-regulated surface determinant (Isd) system that scav...

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Autores principales:	Monique R. Bennett, Jinhui Dong, Robin G. Bombardi, Cinque Soto, Helen M. Parrington, Rachel S. Nargi, Clara T. Schoeder, Marcus B. Nagel, Kevin L. Schey, Jens Meiler, Eric P. Skaar, James E. Crowe
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Staphylococcus aureus X-ray crystallography adaptive immunity antibody functions antibody repertoire computer modeling Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/633528a5968b43209963b3d7f2daa1df
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spelling	oai:doaj.org-article:633528a5968b43209963b3d7f2daa1df2021-11-15T15:59:42ZHuman <italic toggle="yes">V<sub>H</sub>1-69</italic> Gene-Encoded Human Monoclonal Antibodies against <named-content content-type="genus-species">Staphylococcus aureus</named-content> IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis10.1128/mBio.02473-192150-7511https://doaj.org/article/633528a5968b43209963b3d7f2daa1df2019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02473-19https://doaj.org/toc/2150-7511ABSTRACT Staphylococcus aureus is an important human pathogen that infects nearly every human tissue. Like most organisms, the acquisition of nutrient iron is necessary for its survival. One route by which it obtains this metal is through the iron-regulated surface determinant (Isd) system that scavenges iron from the hemoglobin of the host. We show that the heavy chain variable region IGHV1-69 gene commonly encodes human monoclonal antibodies (mAbs) targeting IsdB-NEAT2. Remarkably, these antibodies bind to multiple antigenic sites. One class of IGHV1-69-encoded mAbs blocks S. aureus heme acquisition by binding to the heme-binding site of NEAT2, while two additional classes reduce the bacterial burden in vivo by an alternative Fc receptor-mediated mechanism. We further identified clonal lineages of IGHV1-69-encoded mAbs using donor samples, showing that each lineage diversifies during infection by somatic hypermutation. These studies reveal that IGHV1-69-encoded antibodies contribute to a protective immune response, furthering our understanding of the correlates of protection against S. aureus infection. IMPORTANCE The human pathogen Staphylococcus aureus causes a wide range of infections, including skin abscesses and sepsis. There is currently no licensed vaccine to prevent S. aureus infection, and its treatment has become increasingly difficult due to antibiotic resistance. One potential way to inhibit S. aureus pathogenesis is to prevent iron acquisition. The iron-regulated surface determinant (Isd) system has evolved in S. aureus to acquire hemoglobin from the human host as a source of heme-iron. In this study, we investigated the molecular and structural basis for antibody-mediated correlates against a member of the Isd system, IsdB. The association of immunoglobulin heavy chain variable region IGHV1-69 gene-encoded human monoclonal antibodies with the response against S. aureus IsdB is described using structural and functional studies to define the importance of this antibody class. We also determine that somatic hypermutation in the development of these antibodies hinders rather than fine-tunes the immune response to IsdB.Monique R. BennettJinhui DongRobin G. BombardiCinque SotoHelen M. ParringtonRachel S. NargiClara T. SchoederMarcus B. NagelKevin L. ScheyJens MeilerEric P. SkaarJames E. CroweAmerican Society for MicrobiologyarticleStaphylococcus aureusX-ray crystallographyadaptive immunityantibody functionsantibody repertoirecomputer modelingMicrobiologyQR1-502ENmBio, Vol 10, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Staphylococcus aureus X-ray crystallography adaptive immunity antibody functions antibody repertoire computer modeling Microbiology QR1-502
spellingShingle	Staphylococcus aureus X-ray crystallography adaptive immunity antibody functions antibody repertoire computer modeling Microbiology QR1-502 Monique R. Bennett Jinhui Dong Robin G. Bombardi Cinque Soto Helen M. Parrington Rachel S. Nargi Clara T. Schoeder Marcus B. Nagel Kevin L. Schey Jens Meiler Eric P. Skaar James E. Crowe Human <italic toggle="yes">V<sub>H</sub>1-69</italic> Gene-Encoded Human Monoclonal Antibodies against <named-content content-type="genus-species">Staphylococcus aureus</named-content> IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis
description	ABSTRACT Staphylococcus aureus is an important human pathogen that infects nearly every human tissue. Like most organisms, the acquisition of nutrient iron is necessary for its survival. One route by which it obtains this metal is through the iron-regulated surface determinant (Isd) system that scavenges iron from the hemoglobin of the host. We show that the heavy chain variable region IGHV1-69 gene commonly encodes human monoclonal antibodies (mAbs) targeting IsdB-NEAT2. Remarkably, these antibodies bind to multiple antigenic sites. One class of IGHV1-69-encoded mAbs blocks S. aureus heme acquisition by binding to the heme-binding site of NEAT2, while two additional classes reduce the bacterial burden in vivo by an alternative Fc receptor-mediated mechanism. We further identified clonal lineages of IGHV1-69-encoded mAbs using donor samples, showing that each lineage diversifies during infection by somatic hypermutation. These studies reveal that IGHV1-69-encoded antibodies contribute to a protective immune response, furthering our understanding of the correlates of protection against S. aureus infection. IMPORTANCE The human pathogen Staphylococcus aureus causes a wide range of infections, including skin abscesses and sepsis. There is currently no licensed vaccine to prevent S. aureus infection, and its treatment has become increasingly difficult due to antibiotic resistance. One potential way to inhibit S. aureus pathogenesis is to prevent iron acquisition. The iron-regulated surface determinant (Isd) system has evolved in S. aureus to acquire hemoglobin from the human host as a source of heme-iron. In this study, we investigated the molecular and structural basis for antibody-mediated correlates against a member of the Isd system, IsdB. The association of immunoglobulin heavy chain variable region IGHV1-69 gene-encoded human monoclonal antibodies with the response against S. aureus IsdB is described using structural and functional studies to define the importance of this antibody class. We also determine that somatic hypermutation in the development of these antibodies hinders rather than fine-tunes the immune response to IsdB.
format	article
author	Monique R. Bennett Jinhui Dong Robin G. Bombardi Cinque Soto Helen M. Parrington Rachel S. Nargi Clara T. Schoeder Marcus B. Nagel Kevin L. Schey Jens Meiler Eric P. Skaar James E. Crowe
author_facet	Monique R. Bennett Jinhui Dong Robin G. Bombardi Cinque Soto Helen M. Parrington Rachel S. Nargi Clara T. Schoeder Marcus B. Nagel Kevin L. Schey Jens Meiler Eric P. Skaar James E. Crowe
author_sort	Monique R. Bennett
title	Human <italic toggle="yes">V<sub>H</sub>1-69</italic> Gene-Encoded Human Monoclonal Antibodies against <named-content content-type="genus-species">Staphylococcus aureus</named-content> IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis
title_short	Human <italic toggle="yes">V<sub>H</sub>1-69</italic> Gene-Encoded Human Monoclonal Antibodies against <named-content content-type="genus-species">Staphylococcus aureus</named-content> IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis
title_full	Human <italic toggle="yes">V<sub>H</sub>1-69</italic> Gene-Encoded Human Monoclonal Antibodies against <named-content content-type="genus-species">Staphylococcus aureus</named-content> IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis
title_fullStr	Human <italic toggle="yes">V<sub>H</sub>1-69</italic> Gene-Encoded Human Monoclonal Antibodies against <named-content content-type="genus-species">Staphylococcus aureus</named-content> IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis
title_full_unstemmed	Human <italic toggle="yes">V<sub>H</sub>1-69</italic> Gene-Encoded Human Monoclonal Antibodies against <named-content content-type="genus-species">Staphylococcus aureus</named-content> IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis
title_sort	human <italic toggle="yes">v<sub>h</sub>1-69</italic> gene-encoded human monoclonal antibodies against <named-content content-type="genus-species">staphylococcus aureus</named-content> isdb use at least three distinct modes of binding to inhibit bacterial growth and pathogenesis
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/633528a5968b43209963b3d7f2daa1df
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Human <italic toggle="yes">V<sub>H</sub>1-69</italic> Gene-Encoded Human Monoclonal Antibodies against <named-content content-type="genus-species">Staphylococcus aureus</named-content> IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis

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