D R Cameron1, Y-H Lin2, S Trouillet-Assant3, V Tafani3, X Kostoulias1, E Mouhtouris4, N Skinner5, K Visvanathan5, S L Baines2, B Howden2, I R Monk2, F Laurent3, T P Stinear2, B P Howden6, A Y Peleg7. 1. Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Australia. 2. Department of Microbiology and Immunology, The University of Melbourne at the Doherty Institute of Infection & Immunity, Australia. 3. Department of Microbiology, French National Reference Centre for Staphylococci, Hospices Civils de Lyon, International Centre of Infectiology Research, France. 4. Department of Surgery, The University of Melbourne, Australia. 5. Department of Medicine, The University of Melbourne, Australia. 6. Department of Microbiology and Immunology, The University of Melbourne at the Doherty Institute of Infection & Immunity, Australia; Infectious Diseases and Microbiology Departments, Austin Health, Australia. Electronic address: bhowden@unimelb.edu.au. 7. Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Australia; Department of Infectious Diseases, The Alfred Hospital and Central Clinical School, Monash University, Australia. Electronic address: anton.peleg@monash.edu.
Abstract
OBJECTIVES: Vancomycin-intermediate Staphylococcus aureus (VISA) is associated with genetic changes that may also impact upon pathogenicity. In the current study, we compared the virulence of clinical VISA strains with their isogenic vancomycin-susceptible progenitors (VSSA). METHODS: Production of the critical virulence protein, α toxin, was assessed using Western blot analysis and was correlated to agr activity using a bioluminescent agr-reporter. Cytotoxicity and intracellular persistence were compared ex vivo for VSSA and VISA within non-professional phagocytes (NPP). Virulence and host immune responses were further explored in vivo using a murine model of bacteraemia. RESULTS: VISA isolates produced up to 20-fold less α toxin compared with VSSA, and this was corroborated by either loss of agr activity due to agr mutation, or altered agr activity in the absence of mutation. VISA were less cytotoxic towards NPP and were associated with enhanced intracellular persistence, suggesting that NPP may act as a reservoir for VISA. Infection with VSSA strains produced higher mortality in a murine bacteraemia model (≥90% 7-day mortality) compared with infection with VISA isolates (20% to 50%, p <0.001). Mice infected with VISA produced a dampened immune response (4.6-fold reduction in interleukin-6, p <0.001) and persistent organ bacterial growth was observed for VISA strains out to 7 days. CONCLUSIONS: These findings highlight the remarkable adaptability of S. aureus, whereby, in addition to having reduced antibiotic susceptibility, VISA alter the expression of pathogenic factors to circumvent the host immune response to favour persistent infection over acute virulence.
OBJECTIVES:Vancomycin-intermediate Staphylococcus aureus (VISA) is associated with genetic changes that may also impact upon pathogenicity. In the current study, we compared the virulence of clinical VISA strains with their isogenic vancomycin-susceptible progenitors (VSSA). METHODS: Production of the critical virulence protein, α toxin, was assessed using Western blot analysis and was correlated to agr activity using a bioluminescent agr-reporter. Cytotoxicity and intracellular persistence were compared ex vivo for VSSA and VISA within non-professional phagocytes (NPP). Virulence and host immune responses were further explored in vivo using a murine model of bacteraemia. RESULTS: VISA isolates produced up to 20-fold less α toxin compared with VSSA, and this was corroborated by either loss of agr activity due to agr mutation, or altered agr activity in the absence of mutation. VISA were less cytotoxic towards NPP and were associated with enhanced intracellular persistence, suggesting that NPP may act as a reservoir for VISA. Infection with VSSA strains produced higher mortality in a murinebacteraemia model (≥90% 7-day mortality) compared with infection with VISA isolates (20% to 50%, p <0.001). Mice infected with VISA produced a dampened immune response (4.6-fold reduction in interleukin-6, p <0.001) and persistent organ bacterial growth was observed for VISA strains out to 7 days. CONCLUSIONS: These findings highlight the remarkable adaptability of S. aureus, whereby, in addition to having reduced antibiotic susceptibility, VISA alter the expression of pathogenic factors to circumvent the host immune response to favour persistent infection over acute virulence.
Authors: Cecilia F Volk; Sarah Burgdorf; Graham Edwardson; Victor Nizet; George Sakoulas; Warren E Rose Journal: Clin Infect Dis Date: 2020-06-10 Impact factor: 9.079
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Authors: Lloyd S Miller; Vance G Fowler; Sanjay K Shukla; Warren E Rose; Richard A Proctor Journal: FEMS Microbiol Rev Date: 2020-01-01 Impact factor: 16.408