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      LysGH15 kills Staphylococcus aureus without being affected by the humoral immune response or inducing inflammation

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          Abstract

          The lysin LysGH15, derived from the staphylococcal phage GH15, exhibits a wide lytic spectrum and highly efficient lytic activity against methicillin-resistant Staphylococcus aureus (MRSA). Here, we found that LysGH15 did not induce resistance in MRSA or methicillin-sensitive S. aureus (MSSA) strains after repeated treatment. Although LysGH15 triggered the generation of LysGH15-specific antibodies in mice, these antibodies did not block lytic activity in vitro (nor the binding capacity of LysGH15). More importantly, when the antibody titre was highest in mice immunized with LysGH15, a single intravenous injection of LysGH15 was sufficient to protect mice against lethal infection with MRSA. These results indicated that LysGH15-specific antibodies did not affect the killing efficiency of LysGH15 against MRSA in vitro or in vivo. LysGH15 also reduced pro-inflammatory cytokines in mice with lethal infections. Furthermore, a high-dose LysGH15 injection did not cause significant adverse effects or pathological changes in the main organs of treated animals. These results provide further evidence for the administration of LysGH15 as an alternative strategy for the treatment of infections caused by MRSA.

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          Most cited references 38

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          Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus.

          Vancomycin is usually reserved for treatment of serious infections, including those caused by multidrug-resistant Staphylococcus aureus. A clinical isolate of S. aureus with high-level resistance to vancomycin (minimal inhibitory concentration = 1024 microg/ml) was isolated in June 2002. This isolate harbored a 57.9-kilobase multiresistance conjugative plasmid within which Tn1546 (vanA) was integrated. Additional elements on the plasmid encoded resistance to trimethoprim (dfrA), beta-lactams (blaZ), aminoglycosides (aacA-aphD), and disinfectants (qacC). Genetic analyses suggest that the long-anticipated transfer of vancomycin resistance to a methicillin-resistant S. aureus occurred in vivo by interspecies transfer of Tn1546 from a co-isolate of Enterococcus faecalis.
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            Staphylococcal manipulation of host immune responses.

            Staphylococcus aureus, a bacterial commensal of the human nares and skin, is a frequent cause of soft tissue and bloodstream infections. A hallmark of staphylococcal infections is their frequent recurrence, even when treated with antibiotics and surgical intervention, which demonstrates the bacterium's ability to manipulate innate and adaptive immune responses. In this Review, we highlight how S. aureus virulence factors inhibit complement activation, block and destroy phagocytic cells and modify host B cell and T cell responses, and we discuss how these insights might be useful for the development of novel therapies against infections with antibiotic resistant strains such as methicillin-resistant S. aureus.
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              Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles.

              Necrotizing fasciitis is a life-threatening infection requiring urgent surgical and medical therapy. Staphylococcus aureus has been a very uncommon cause of necrotizing fasciitis, but we have recently noted an alarming number of these infections caused by community-associated methicillin-resistant S. aureus (MRSA). We reviewed the records of 843 patients whose wound cultures grew MRSA at our center from January 15, 2003, to April 15, 2004. Among this cohort, 14 were identified as patients presenting from the community with clinical and intraoperative findings of necrotizing fasciitis, necrotizing myositis, or both. The median age of the patients was 46 years (range, 28 to 68), and 71 percent were men. Coexisting conditions or risk factors included current or past injection-drug use (43 percent); previous MRSA infection, diabetes, and chronic hepatitis C (21 percent each); and cancer and human immunodeficiency virus infection or the acquired immunodeficiency syndrome (7 percent each). Four patients (29 percent) had no serious coexisting conditions or risk factors. All patients received combined medical and surgical therapy, and none died, but they had serious complications, including the need for reconstructive surgery and prolonged stay in the intensive care unit. Wound cultures were monomicrobial for MRSA in 86 percent, and 40 percent of patients (4 of 10) for whom blood cultures were obtained had positive results. All MRSA isolates were susceptible in vitro to clindamycin, trimethoprim-sulfamethoxazole, and rifampin. All recovered isolates belonged to the same genotype (multilocus sequence type ST8, pulsed-field type USA300, and staphylococcal cassette chromosome mec type IV [SCCmecIV]) and carried the Panton-Valentine leukocidin (pvl), lukD, and lukE genes, but no other toxin genes were detected. Necrotizing fasciitis caused by community-associated MRSA is an emerging clinical entity. In areas in which community-associated MRSA infection is endemic, empirical treatment of suspected necrotizing fasciitis should include antibiotics predictably active against this pathogen. Copyright 2005 Massachusetts Medical Society.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                07 July 2016
                2016
                : 6
                Affiliations
                [1 ]College of Veterinary Medicine, Jilin University , Changchun 130062, P. R. China
                [2 ]Department of Immunology, College of Basic Medical Sciences, Jilin University , Changchun, 130021, P. R. China
                [3 ]Jiangsu Co-innovation Center for the Prevention and Control of important Animal Infectious Disease and Zoonoses , Yangzhou 225009, P. R. China
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                srep29344
                10.1038/srep29344
                4935890
                27385518
                a0532a0b-a0a1-44cc-a680-661631fa99c7
                Copyright © 2016, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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