Gp05, a Prophage-Encoded Virulence Factor, Contributes to Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection
ABSTRACT Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections represent a serious public health threat. We recently demonstrated that the presence of a novel prophage ϕSA169 was associated with vancomycin (VAN) treatment failure in experimental MRSA endocarditis. In...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-08-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.00600-23 |
| _version_ | 1797741747640467456 |
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| author | Yi Li Fengli Zhu Adhar C. Manna Liang Chen Jason Jiang Jong-In Hong Richard A. Proctor Arnold S. Bayer Ambrose L. Cheung Yan Q. Xiong |
| author_facet | Yi Li Fengli Zhu Adhar C. Manna Liang Chen Jason Jiang Jong-In Hong Richard A. Proctor Arnold S. Bayer Ambrose L. Cheung Yan Q. Xiong |
| author_sort | Yi Li |
| collection | DOAJ |
| description | ABSTRACT Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections represent a serious public health threat. We recently demonstrated that the presence of a novel prophage ϕSA169 was associated with vancomycin (VAN) treatment failure in experimental MRSA endocarditis. In this study, we assessed the role of a ϕSA169 gene, ϕ80α_gp05 (gp05), in VAN-persistent outcome using gp05 isogenic MRSA strain sets. Of note, Gp05 significantly influences the intersection of MRSA virulence factors, host immune responses, and antibiotic treatment efficacy, including the following: (i) activity of the significant energy-yielding metabolic pathway (e.g., tricarboxylic acid cycle); (ii) carotenoid pigment production; (iii) (p)ppGpp (guanosine tetra- and pentaphosphate) production, which activates the stringent response and subsequent downstream functional factors (e.g., phenol-soluble modulins and polymorphonuclear neutrophil bactericidal activity); and (iv) persistence to VAN treatment in an experimental infective endocarditis model. These data suggest that Gp05 is a significant virulence factor which contributes to the persistent outcomes in MRSA endovascular infection by multiple pathways. IMPORTANCE Persistent endovascular infections are often caused by MRSA strains that are susceptible to anti-MRSA antibiotics in vitro by CLSI breakpoints. Thus, the persistent outcome represents a unique variant of traditional antibiotic resistance mechanisms and a significant therapeutic challenge. Prophage, a critical mobile genetic element carried by most MRSA isolates, provides their bacterial host with metabolic advantages and resistance mechanisms. However, how prophage-encoded virulence factors interact with the host defense system and antibiotics, driving the persistent outcome, is not well known. In the current study, we demonstrated that a novel prophage gene, gp05, significantly impacts tricarboxylic acid cycle activity, stringent response, and pigmentation, as well as vancomycin treatment outcome in an experimental endocarditis model using isogenic gp05 overexpression and chromosomal deletion mutant MRSA strain sets. The findings significantly advance our understanding of the role of Gp05 in persistent MRSA endovascular infection and provide a potential target for development of novel drugs against these life-threatening infections. |
| first_indexed | 2024-03-12T14:31:07Z |
| format | Article |
| id | doaj.art-2ebfbf0b3c694e2b87c6a3abf8df6716 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-03-12T14:31:07Z |
| publishDate | 2023-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-2ebfbf0b3c694e2b87c6a3abf8df67162023-08-17T13:04:14ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972023-08-0111410.1128/spectrum.00600-23Gp05, a Prophage-Encoded Virulence Factor, Contributes to Persistent Methicillin-Resistant Staphylococcus aureus Endovascular InfectionYi Li0Fengli Zhu1Adhar C. Manna2Liang Chen3Jason Jiang4Jong-In Hong5Richard A. Proctor6Arnold S. Bayer7Ambrose L. Cheung8Yan Q. Xiong9The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USAThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USADepartment of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USACenter for Discovery and Innovation, Nutley, New Jersey, USAThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USADepartment of Chemistry, Seoul National University, Seoul, South KoreaDepartment of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USAThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USADepartment of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USAThe Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USAABSTRACT Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections represent a serious public health threat. We recently demonstrated that the presence of a novel prophage ϕSA169 was associated with vancomycin (VAN) treatment failure in experimental MRSA endocarditis. In this study, we assessed the role of a ϕSA169 gene, ϕ80α_gp05 (gp05), in VAN-persistent outcome using gp05 isogenic MRSA strain sets. Of note, Gp05 significantly influences the intersection of MRSA virulence factors, host immune responses, and antibiotic treatment efficacy, including the following: (i) activity of the significant energy-yielding metabolic pathway (e.g., tricarboxylic acid cycle); (ii) carotenoid pigment production; (iii) (p)ppGpp (guanosine tetra- and pentaphosphate) production, which activates the stringent response and subsequent downstream functional factors (e.g., phenol-soluble modulins and polymorphonuclear neutrophil bactericidal activity); and (iv) persistence to VAN treatment in an experimental infective endocarditis model. These data suggest that Gp05 is a significant virulence factor which contributes to the persistent outcomes in MRSA endovascular infection by multiple pathways. IMPORTANCE Persistent endovascular infections are often caused by MRSA strains that are susceptible to anti-MRSA antibiotics in vitro by CLSI breakpoints. Thus, the persistent outcome represents a unique variant of traditional antibiotic resistance mechanisms and a significant therapeutic challenge. Prophage, a critical mobile genetic element carried by most MRSA isolates, provides their bacterial host with metabolic advantages and resistance mechanisms. However, how prophage-encoded virulence factors interact with the host defense system and antibiotics, driving the persistent outcome, is not well known. In the current study, we demonstrated that a novel prophage gene, gp05, significantly impacts tricarboxylic acid cycle activity, stringent response, and pigmentation, as well as vancomycin treatment outcome in an experimental endocarditis model using isogenic gp05 overexpression and chromosomal deletion mutant MRSA strain sets. The findings significantly advance our understanding of the role of Gp05 in persistent MRSA endovascular infection and provide a potential target for development of novel drugs against these life-threatening infections.https://journals.asm.org/doi/10.1128/spectrum.00600-23MRSAphage-encoded virulence factorvancomycin persistenceendovascular infection |
| spellingShingle | Yi Li Fengli Zhu Adhar C. Manna Liang Chen Jason Jiang Jong-In Hong Richard A. Proctor Arnold S. Bayer Ambrose L. Cheung Yan Q. Xiong Gp05, a Prophage-Encoded Virulence Factor, Contributes to Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection Microbiology Spectrum MRSA phage-encoded virulence factor vancomycin persistence endovascular infection |
| title | Gp05, a Prophage-Encoded Virulence Factor, Contributes to Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection |
| title_full | Gp05, a Prophage-Encoded Virulence Factor, Contributes to Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection |
| title_fullStr | Gp05, a Prophage-Encoded Virulence Factor, Contributes to Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection |
| title_full_unstemmed | Gp05, a Prophage-Encoded Virulence Factor, Contributes to Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection |
| title_short | Gp05, a Prophage-Encoded Virulence Factor, Contributes to Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection |
| title_sort | gp05 a prophage encoded virulence factor contributes to persistent methicillin resistant staphylococcus aureus endovascular infection |
| topic | MRSA phage-encoded virulence factor vancomycin persistence endovascular infection |
| url | https://journals.asm.org/doi/10.1128/spectrum.00600-23 |
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