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Title: Human VH1-69 Gene-Encoded Human Monoclonal Antibodies against Staphylococcus aureus 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 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 tomore » 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.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ORCiD logo;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIAID
OSTI Identifier:
1575023
Resource Type:
Journal Article
Journal Name:
mBio (Online)
Additional Journal Information:
Journal Volume: 10; Journal Issue: 5; Journal ID: ISSN 2150-7511
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Bennett, Monique R., Dong, Jinhui, Bombardi, Robin G., Soto, Cinque, Parrington, Helen M., Nargi, Rachel S., Schoeder, Clara T., Nagel, Marcus B., Schey, Kevin L., Meiler, Jens, Skaar, Eric P., Crowe, James E., and Rappuoli, Rino. Human VH1-69 Gene-Encoded Human Monoclonal Antibodies against Staphylococcus aureus IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis. United States: N. p., 2019. Web. doi:10.1128/mBio.02473-19.
Bennett, Monique R., Dong, Jinhui, Bombardi, Robin G., Soto, Cinque, Parrington, Helen M., Nargi, Rachel S., Schoeder, Clara T., Nagel, Marcus B., Schey, Kevin L., Meiler, Jens, Skaar, Eric P., Crowe, James E., & Rappuoli, Rino. Human VH1-69 Gene-Encoded Human Monoclonal Antibodies against Staphylococcus aureus IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis. United States. doi:10.1128/mBio.02473-19.
Bennett, Monique R., Dong, Jinhui, Bombardi, Robin G., Soto, Cinque, Parrington, Helen M., Nargi, Rachel S., Schoeder, Clara T., Nagel, Marcus B., Schey, Kevin L., Meiler, Jens, Skaar, Eric P., Crowe, James E., and Rappuoli, Rino. Tue . "Human VH1-69 Gene-Encoded Human Monoclonal Antibodies against Staphylococcus aureus IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis". United States. doi:10.1128/mBio.02473-19.
@article{osti_1575023,
title = {Human VH1-69 Gene-Encoded Human Monoclonal Antibodies against Staphylococcus aureus IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis},
author = {Bennett, Monique R. and Dong, Jinhui and Bombardi, Robin G. and Soto, Cinque and Parrington, Helen M. and Nargi, Rachel S. and Schoeder, Clara T. and Nagel, Marcus B. and Schey, Kevin L. and Meiler, Jens and Skaar, Eric P. and Crowe, James E. and Rappuoli, Rino},
abstractNote = {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.},
doi = {10.1128/mBio.02473-19},
journal = {mBio (Online)},
issn = {2150-7511},
number = 5,
volume = 10,
place = {United States},
year = {2019},
month = {10}
}

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