There is an urgency to develop phage therapies for multi-drug resistant bacterial infections. However, although bacteria can be shown to be susceptible to phage therapy, it is not sufficient in some cases. PhiMR003 is a methicillin-resistant Staphylococcus aureus (MRSA) phage previously isolated from sewage influent and demonstrates a highly lytic activity and a broad host range to MRSA clinical isolates in vitro. To investigate the potential of phiMR003 for the treatment of MRSA infection, the effects of phiMR003 on immune responses in vivo were analyzed using phiMR003 susceptible MRSA strains in a mouse wound infection model. Additionally, we assessed whether phiMR003 affects the immune response to infection caused by a non-susceptible MRSA strain. Interestingly, cases with both susceptible and non-susceptible MRSA strains infected with phiMR003 demonstrated decreased bacterial load, repressed inflammation and acceleration of wound closure. Moreover, the infiltration of inflammatory cells in infected tissue was altered by phiMR003. All these effects required the phage virion suggesting a phage-specific recognition and signaling response. Induced transcripts of proinflammatory cytokines by lipopolysaccharide (LPS) were repressed in mouse peritoneal macrophages. These results show that immune modulation occurring as a response to the phage itself improves the clinical outcomes of phage therapy.
