title: Limitations of Murine Models for Assessment of Antibody-Mediated Therapies or Vaccine Candidates against Staphylococcus epidermidis Bloodstream Infection.
abstract: Staphylococcus epidermidis is normally a commensal colonizer of human skin and mucus membranes, but, due to its ability to form biofilms on indwelling medical devices, it has emerged as a leading cause of nosocomial infections. Bacteremia or bloodstream infection is a frequent and costly complication resulting from biofilm fouling of medical devices. Our goal was to develop a murine model of S. epidermidis infection to identify potential vaccine targets for the prevention of S. epidermidis bacteremia. However, assessing the contribution of adaptive immunity to protection against S. epidermidis challenge was complicated by a highly efficacious innate immune response in mice. Naive mice rapidly cleared S. epidermidis infections from blood and solid organs, even when the animals were immunocompromised. Cyclophosphamide-mediated leukopenia reduced the size of the bacterial challenge dose required to cause lethality but did not impair clearance after a nonlethal challenge. Nonspecific innate immune stimulation, such as treatment with a Toll-like receptor 4 (TLR4) agonist, enhanced bacterial clearance. TLR2 signaling was confirmed to accelerate the clearance of S. epidermidis bacteremia, but TLR2(-/-)mice could still resolve a bloodstream infection. Furthermore, TLR2 signaling played no role in the clearance of bacteria from the spleen. In conclusion, these data suggest that S. epidermidis bloodstream infection is cleared in a highly efficient manner that is mediated by both TLR2-dependent and -independent innate immune mechanisms. The inability to establish a persistent infection in mice, even in immunocompromised animals, rendered these murine models unsuitable for meaningful assessment of antibody-mediated therapies or vaccine candidates.
authors: Sanofi Pasteur, Cambridge, Massachusetts, USA Leah.Cole@sanofipasteur.com.
authors: Leah E
authors: LE
authors: Cole
authors: Sanofi Pasteur, Cambridge, Massachusetts, USA.
authors: Jinrong
authors: J
authors: Zhang
authors: Sanofi Pasteur, Cambridge, Massachusetts, USA.
authors: Augustus
authors: A
authors: Kesselly
authors: Sanofi Pasteur, Cambridge, Massachusetts, USA.
authors: Natalie G
authors: http://orcid.org/0000-0002-1920-8245
authors: NG
authors: Anosova
authors: Sanofi Pasteur, Cambridge, Massachusetts, USA.
authors: Hubert
authors: H
authors: Lam
authors: Sanofi Pasteur, Cambridge, Massachusetts, USA.
authors: Harry
authors: H
authors: Kleanthous
authors: Sanofi Pasteur, Cambridge, Massachusetts, USA.
authors: Jeremy A
authors: JA
authors: Yethon
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000627:therapeutic use*; D016470:Bacteremia / Q000517:prevention & control*; D003520:Cyclophosphamide / Q000633:toxicity; D004195:Disease Models, Animal; D007113:Immunity, Innate; D007970:Leukopenia / Q000139:chemically induced; D051379:Mice; D018345:Mice, Knockout; D013203:Staphylococcal Infections / Q000097:blood / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D013209:Staphylococcal Vaccines / Q000276:immunology*; D013212:Staphylococcus epidermidis / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D000907:Antibodies, Bacterial; D013209:Staphylococcal Vaccines; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D003520:Cyclophosphamide