Capsular Polysaccharide Is Essential for the Virulence of the Antimicrobial-Resistant Pathogen Enterobacter hormaechei
ABSTRACT Nosocomial infections caused by multidrug-resistant (MDR) Enterobacter cloacae complex (ECC) pathogens are on the rise. However, the virulence strategies employed by these pathogens remain elusive. Here, we study the interaction of ECC clinical isolates with human serum to define how this p...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-04-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.02590-22 |
| _version_ | 1797839632028663808 |
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| author | Amelia St. John Andrew I. Perault Sabrina I. Giacometti Alexis G. Sommerfield Ashley L. DuMont Keenan A. Lacey Xuhui Zheng Julia Sproch Chris Petzold Kristen Dancel-Manning Sandra Gonzalez Medini Annavajhala Colleen Beckford Nathalie Zeitouni Feng-Xia Liang Harm van Bakel Bo Shopsin Anne-Catrin Uhlemann Alejandro Pironti Victor J. Torres |
| author_facet | Amelia St. John Andrew I. Perault Sabrina I. Giacometti Alexis G. Sommerfield Ashley L. DuMont Keenan A. Lacey Xuhui Zheng Julia Sproch Chris Petzold Kristen Dancel-Manning Sandra Gonzalez Medini Annavajhala Colleen Beckford Nathalie Zeitouni Feng-Xia Liang Harm van Bakel Bo Shopsin Anne-Catrin Uhlemann Alejandro Pironti Victor J. Torres |
| author_sort | Amelia St. John |
| collection | DOAJ |
| description | ABSTRACT Nosocomial infections caused by multidrug-resistant (MDR) Enterobacter cloacae complex (ECC) pathogens are on the rise. However, the virulence strategies employed by these pathogens remain elusive. Here, we study the interaction of ECC clinical isolates with human serum to define how this pathogen evades the antimicrobial action of complement, one of the first lines of host-mediated immune defense. We identified a small number of serum-sensitive strains, including Enterobacter hormaechei strain NR3055, which we exploited for the in vitro selection of serum-resistant clones. Comparative genomics between the serum-sensitive NR3055 strain and the isolated serum-resistant clones revealed a premature stop codon in the wzy gene of the capsular polysaccharide biosynthesis locus of NR3055. The complementation of wzy conferred serum resistance to NR3055, prevented the deposition of complement proteins on the bacterial surface, inhibited phagocytosis by human neutrophils, and rendered the bacteria virulent in a mouse model of peritonitis. Mice exposed to a nonlethal dose of encapsulated NR3055 were protected from subsequent lethal infections by encapsulated NR3055, whereas mice that were previously exposed to unencapsulated NR3055 succumbed to infection. Thus, capsule is a key immune evasion determinant for E. hormaechei, and it is a potential target for prophylactics and therapeutics to combat these increasingly MDR human pathogens. IMPORTANCE Infections caused by antimicrobial resistant bacteria are of increasing concern, especially those due to carbapenem-resistant Enterobacteriaceae pathogens. Included in this group are species of the Enterobacter cloacae complex, regarding which there is a paucity of knowledge on the infection biology of the pathogens, despite their clinical relevance. In this study, we combine techniques in comparative genomics, bacterial genetics, and diverse models of infection to establish capsule as an important mechanism of Enterobacter pathogens to resist the antibacterial activity of serum, a first line of host defense against bacterial infections. We also show that immune memory targeting the Enterobacter capsule protects against lethal infection. The further characterization of Enterobacter infection biology and the immune response to infection are needed for the development of therapies and preventative interventions targeting these highly antibiotic resistant pathogens. |
| first_indexed | 2024-04-09T16:01:11Z |
| format | Article |
| id | doaj.art-d3aff886dd104f129b126519af1d6e50 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-09T16:01:11Z |
| publishDate | 2023-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-d3aff886dd104f129b126519af1d6e502023-04-25T13:04:56ZengAmerican Society for MicrobiologymBio2150-75112023-04-0114210.1128/mbio.02590-22Capsular Polysaccharide Is Essential for the Virulence of the Antimicrobial-Resistant Pathogen Enterobacter hormaecheiAmelia St. John0Andrew I. Perault1Sabrina I. Giacometti2Alexis G. Sommerfield3Ashley L. DuMont4Keenan A. Lacey5Xuhui Zheng6Julia Sproch7Chris Petzold8Kristen Dancel-Manning9Sandra Gonzalez10Medini Annavajhala11Colleen Beckford12Nathalie Zeitouni13Feng-Xia Liang14Harm van Bakel15Bo Shopsin16Anne-Catrin Uhlemann17Alejandro Pironti18Victor J. Torres19Department of Microbiology, New York University Grossman School of Medicine, New York, New York, USADepartment of Microbiology, New York University Grossman School of Medicine, New York, New York, USADepartment of Cell Biology, New York University Grossman School of Medicine, New York, New York, USADepartment of Microbiology, New York University Grossman School of Medicine, New York, New York, USADepartment of Microbiology, New York University Grossman School of Medicine, New York, New York, USADepartment of Microbiology, New York University Grossman School of Medicine, New York, New York, USADepartment of Microbiology, New York University Grossman School of Medicine, New York, New York, USADepartment of Microbiology, New York University Grossman School of Medicine, New York, New York, USAMicroscopy Laboratory, Division of Advanced Research Technologies, New York University Langone Health, New York, New York, USAMicroscopy Laboratory, Division of Advanced Research Technologies, New York University Langone Health, New York, New York, USADepartment of Microbiology, New York University Grossman School of Medicine, New York, New York, USADepartment of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USAIcahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USAMicroscopy Laboratory, Division of Advanced Research Technologies, New York University Langone Health, New York, New York, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USADepartment of Microbiology, New York University Grossman School of Medicine, New York, New York, USADepartment of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USADepartment of Microbiology, New York University Grossman School of Medicine, New York, New York, USADepartment of Microbiology, New York University Grossman School of Medicine, New York, New York, USAABSTRACT Nosocomial infections caused by multidrug-resistant (MDR) Enterobacter cloacae complex (ECC) pathogens are on the rise. However, the virulence strategies employed by these pathogens remain elusive. Here, we study the interaction of ECC clinical isolates with human serum to define how this pathogen evades the antimicrobial action of complement, one of the first lines of host-mediated immune defense. We identified a small number of serum-sensitive strains, including Enterobacter hormaechei strain NR3055, which we exploited for the in vitro selection of serum-resistant clones. Comparative genomics between the serum-sensitive NR3055 strain and the isolated serum-resistant clones revealed a premature stop codon in the wzy gene of the capsular polysaccharide biosynthesis locus of NR3055. The complementation of wzy conferred serum resistance to NR3055, prevented the deposition of complement proteins on the bacterial surface, inhibited phagocytosis by human neutrophils, and rendered the bacteria virulent in a mouse model of peritonitis. Mice exposed to a nonlethal dose of encapsulated NR3055 were protected from subsequent lethal infections by encapsulated NR3055, whereas mice that were previously exposed to unencapsulated NR3055 succumbed to infection. Thus, capsule is a key immune evasion determinant for E. hormaechei, and it is a potential target for prophylactics and therapeutics to combat these increasingly MDR human pathogens. IMPORTANCE Infections caused by antimicrobial resistant bacteria are of increasing concern, especially those due to carbapenem-resistant Enterobacteriaceae pathogens. Included in this group are species of the Enterobacter cloacae complex, regarding which there is a paucity of knowledge on the infection biology of the pathogens, despite their clinical relevance. In this study, we combine techniques in comparative genomics, bacterial genetics, and diverse models of infection to establish capsule as an important mechanism of Enterobacter pathogens to resist the antibacterial activity of serum, a first line of host defense against bacterial infections. We also show that immune memory targeting the Enterobacter capsule protects against lethal infection. The further characterization of Enterobacter infection biology and the immune response to infection are needed for the development of therapies and preventative interventions targeting these highly antibiotic resistant pathogens.https://journals.asm.org/doi/10.1128/mbio.02590-22Enterobacterserumcomplementcapsuleantimicrobial resistancepathogenesis |
| spellingShingle | Amelia St. John Andrew I. Perault Sabrina I. Giacometti Alexis G. Sommerfield Ashley L. DuMont Keenan A. Lacey Xuhui Zheng Julia Sproch Chris Petzold Kristen Dancel-Manning Sandra Gonzalez Medini Annavajhala Colleen Beckford Nathalie Zeitouni Feng-Xia Liang Harm van Bakel Bo Shopsin Anne-Catrin Uhlemann Alejandro Pironti Victor J. Torres Capsular Polysaccharide Is Essential for the Virulence of the Antimicrobial-Resistant Pathogen Enterobacter hormaechei mBio Enterobacter serum complement capsule antimicrobial resistance pathogenesis |
| title | Capsular Polysaccharide Is Essential for the Virulence of the Antimicrobial-Resistant Pathogen Enterobacter hormaechei |
| title_full | Capsular Polysaccharide Is Essential for the Virulence of the Antimicrobial-Resistant Pathogen Enterobacter hormaechei |
| title_fullStr | Capsular Polysaccharide Is Essential for the Virulence of the Antimicrobial-Resistant Pathogen Enterobacter hormaechei |
| title_full_unstemmed | Capsular Polysaccharide Is Essential for the Virulence of the Antimicrobial-Resistant Pathogen Enterobacter hormaechei |
| title_short | Capsular Polysaccharide Is Essential for the Virulence of the Antimicrobial-Resistant Pathogen Enterobacter hormaechei |
| title_sort | capsular polysaccharide is essential for the virulence of the antimicrobial resistant pathogen enterobacter hormaechei |
| topic | Enterobacter serum complement capsule antimicrobial resistance pathogenesis |
| url | https://journals.asm.org/doi/10.1128/mbio.02590-22 |
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