title: Antibody-Based Immunotherapy To Treat and Prevent Infection with Hypervirulent Klebsiella pneumoniae.
abstract: Hypervirulent Klebsiella pneumoniae (hvKp) strains are predicted to become a major threat in Asia if antibiotic resistance continues to spread. Anticapsular antibodies (Abs) were developed because disseminated infections caused by hvKp are associated with significant morbidity and mortality, even with antibiotic-sensitive strains. K1-serotype polysaccharide capsules (K1-CPS) are expressed by the majority of hvKp strains. In this study, K1-CPS-specific IgG Abs were generated by conjugation of K1-CPS to immunogenic anthrax protective antigen (PA) protein. Opsonophagocytic efficacy was measured in vitro and in vivo by intravital microscopy in murine livers. In vivo protection was tested in murine models, including a novel model for dissemination in hvKp-colonized mice. Protective efficacy of monoclonal antibodies (MAbs) 4C5 (IgG1) and 19A10 (IgG3) was demonstrated both in murine sepsis and pulmonary infection. In hvKp-colonized mice, MAb treatment significantly decreased dissemination of hvKp from the gut to mesenteric lymph nodes and organs. Intravital microscopy confirmed efficient opsonophagocytosis and clearance of bacteria from the liver. In vitro studies demonstrate that MAbs work predominantly by promoting FcR-mediated phagocytosis but also indicate that MAbs enhance the release of neutrophil extracellular traps (NETs). In anticipation of increasing antibiotic resistance, we propose further development of these and other Klebsiella-specific MAbs for therapeutic use.
authors: Department of Medicine (Division of Infectious Diseases), Stony Brook University, Stony Brook, New York, USA.
authors: Elizabeth
authors: E
authors: Diago-Navarro
authors: Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain.
authors: Isabel
authors: I
authors: Calatayud-Baselga
authors: Department of Veterinary Medicine, University of Maryland at College Park, College Park, Maryland, USA.
authors: Donglei
authors: D
authors: Sun
authors: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA.
authors: Camille
authors: C
authors: Khairallah
authors: Department of Medicine (Division of Infectious Diseases), Stony Brook University, Stony Brook, New York, USA.
authors: Inderjit
authors: I
authors: Mann
authors: Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain.
authors: Amaia
authors: A
authors: Ulacia-Hernando
authors: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA.
authors: Brian
authors: B
authors: Sheridan
authors: Department of Veterinary Medicine, University of Maryland at College Park, College Park, Maryland, USA.
authors: Meiqing
authors: M
authors: Shi
authors: Department of Medicine (Division of Infectious Diseases), Stony Brook University, Stony Brook, New York, USA bettina.fries@stonybrookmedicine.edu.|Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA.
authors: Bettina C
authors: BC
authors: Fries
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D016667:Bacterial Capsules / Q000276:immunology; D018890:Chemoprevention / Q000379:methods*; D004195:Disease Models, Animal; D005260:Female; D007167:Immunotherapy / Q000379:methods*; D007710:Klebsiella Infections / Q000517:prevention & control* / Q000628:therapy*; D007711:Klebsiella pneumoniae / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010587:Phagocytosis; D018410:Pneumonia, Bacterial / Q000517:prevention & control / Q000628:therapy; D018805:Sepsis / Q000517:prevention & control / Q000628:therapy; D016896:Treatment Outcome
chemical_list: D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal
keywords: Klebsiella pneumoniae; adjuvant therapy; colonization; hypervirulence; intestinal colonization; monoclonal antibodies; opsonophagocytosis