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Title: Antibody-Mediated Killing of Carbapenem-Resistant ST258 Klebsiella pneumoniae by Human Neutrophils

Abstract

ABSTRACT Carbapenem-resistant Klebsiella pneumoniae is a problem worldwide. A carbapenem-resistant K. pneumoniae lineage classified as multilocus sequence type 258 (ST258) is prominent in the health care setting in many regions of the world, including the United States. ST258 strains can be resistant to virtually all clinically useful antibiotics; treatment of infections caused by these organisms is difficult, and mortality is high. As a step toward promoting development of new therapeutics for ST258 infections, we tested the ability of rabbit antibodies specific for ST258 capsule polysaccharide to enhance human serum bactericidal activity and promote phagocytosis and killing of these bacteria by human neutrophils. We first demonstrated that an isogenic wzy deletion strain is significantly more susceptible to killing by human heparinized blood, serum, and neutrophils than a wild-type ST258 strain. Consistent with the importance of capsule as an immune evasion molecule, rabbit immune serum and purified IgG specific for ST258 capsule polysaccharide type 2 (CPS2) enhanced killing by human blood and serum in vitro. Moreover, antibodies specific for CPS2 promoted phagocytosis and killing of ST258 by human neutrophils. Collectively, our findings suggest that ST258 CPS2 is a viable target for immunoprophylactics and/or therapeutics. IMPORTANCEInfections caused by carbapenem-resistant K. pneumoniae are difficult tomore » treat, and mortality is high. New prophylactic approaches and/or therapeutic measures are needed to prevent or treat infections caused by these multidrug-resistant bacteria. A strain of carbapenem-resistant K. pneumoniae, classified by multilocus sequence typing as ST258, is present in many regions of the world and is the most prominent carbapenem-resistant K. pneumoniae lineage in the United States. Here we show that rabbit antibodies specific for capsule polysaccharide of ST258 significantly enhance human serum bactericidal activity and promote phagocytosis and killing of this pathogen by human neutrophils. These studies have provided strong support for the idea that development of an immunotherapy (vaccine) for carbapenem-resistant K. pneumoniae infections is feasible and has merit.« less

Authors:
 [1];  [1];  [1];  [2];  [2];  [2];  [1];  [3]
  1. National Inst. of Health (NIH), Hamilton, MT (United States). Rocky Mountain Lab.
  2. Rutgers Univ., Newark, NJ (United States). New Jersey Medical School
  3. Northern Arizona Univ., Flagstaff, AZ (United States)
Publication Date:
Research Org.:
Univ. of Georgia, Athens, GA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1510500
Grant/Contract Number:  
SC0015662
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
mBio (Online)
Additional Journal Information:
Journal Volume: 9; Journal Issue: 2; Journal ID: ISSN 2150-7511
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Klebsiella; antibiotic resistance; antibody; carbapenems; neutrophils; vaccines

Citation Formats

Kobayashi, Scott D., Porter, Adeline R., Freedman, Brett, Pandey, Ruchi, Chen, Liang, Kreiswirth, Barry N., DeLeo, Frank R., and Keim, Paul. Antibody-Mediated Killing of Carbapenem-Resistant ST258 Klebsiella pneumoniae by Human Neutrophils. United States: N. p., 2018. Web. doi:10.1128/mbio.00297-18.
Kobayashi, Scott D., Porter, Adeline R., Freedman, Brett, Pandey, Ruchi, Chen, Liang, Kreiswirth, Barry N., DeLeo, Frank R., & Keim, Paul. Antibody-Mediated Killing of Carbapenem-Resistant ST258 Klebsiella pneumoniae by Human Neutrophils. United States. doi:10.1128/mbio.00297-18.
Kobayashi, Scott D., Porter, Adeline R., Freedman, Brett, Pandey, Ruchi, Chen, Liang, Kreiswirth, Barry N., DeLeo, Frank R., and Keim, Paul. Tue . "Antibody-Mediated Killing of Carbapenem-Resistant ST258 Klebsiella pneumoniae by Human Neutrophils". United States. doi:10.1128/mbio.00297-18. https://www.osti.gov/servlets/purl/1510500.
@article{osti_1510500,
title = {Antibody-Mediated Killing of Carbapenem-Resistant ST258 Klebsiella pneumoniae by Human Neutrophils},
author = {Kobayashi, Scott D. and Porter, Adeline R. and Freedman, Brett and Pandey, Ruchi and Chen, Liang and Kreiswirth, Barry N. and DeLeo, Frank R. and Keim, Paul},
abstractNote = {ABSTRACT Carbapenem-resistant Klebsiella pneumoniae is a problem worldwide. A carbapenem-resistant K. pneumoniae lineage classified as multilocus sequence type 258 (ST258) is prominent in the health care setting in many regions of the world, including the United States. ST258 strains can be resistant to virtually all clinically useful antibiotics; treatment of infections caused by these organisms is difficult, and mortality is high. As a step toward promoting development of new therapeutics for ST258 infections, we tested the ability of rabbit antibodies specific for ST258 capsule polysaccharide to enhance human serum bactericidal activity and promote phagocytosis and killing of these bacteria by human neutrophils. We first demonstrated that an isogenic wzy deletion strain is significantly more susceptible to killing by human heparinized blood, serum, and neutrophils than a wild-type ST258 strain. Consistent with the importance of capsule as an immune evasion molecule, rabbit immune serum and purified IgG specific for ST258 capsule polysaccharide type 2 (CPS2) enhanced killing by human blood and serum in vitro. Moreover, antibodies specific for CPS2 promoted phagocytosis and killing of ST258 by human neutrophils. Collectively, our findings suggest that ST258 CPS2 is a viable target for immunoprophylactics and/or therapeutics. IMPORTANCEInfections caused by carbapenem-resistant K. pneumoniae are difficult to treat, and mortality is high. New prophylactic approaches and/or therapeutic measures are needed to prevent or treat infections caused by these multidrug-resistant bacteria. A strain of carbapenem-resistant K. pneumoniae, classified by multilocus sequence typing as ST258, is present in many regions of the world and is the most prominent carbapenem-resistant K. pneumoniae lineage in the United States. Here we show that rabbit antibodies specific for capsule polysaccharide of ST258 significantly enhance human serum bactericidal activity and promote phagocytosis and killing of this pathogen by human neutrophils. These studies have provided strong support for the idea that development of an immunotherapy (vaccine) for carbapenem-resistant K. pneumoniae infections is feasible and has merit.},
doi = {10.1128/mbio.00297-18},
journal = {mBio (Online)},
issn = {2150-7511},
number = 2,
volume = 9,
place = {United States},
year = {2018},
month = {3}
}

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