Cross-specificity of protective human antibodies against Klebsiella pneumoniae LPS O-antigen

Abstract

Humoral immune responses to microbial polysaccharide surface antigens can prevent bacterial infection but are typically strain specific and fail to mediate broad protection against different serotypes. Here we describe a panel of affinity-matured monoclonal human antibodies from peripheral blood immunoglobulin M-positive (IgM) and IgA memory B cells and clonally related intestinal plasmablasts, directed against the lipopolysaccharide (LPS) O-antigen of Klebsiella pneumoniae, an opportunistic pathogen and major cause of antibiotic-resistant nosocomial infections. The antibodies showed distinct patterns of in vivo cross-specificity and protection against different clinically relevant K. pneumoniae serotypes. However, cross-specificity was not limited to K. pneumoniae, as K. pneumoniae-specific antibodies recognized diverse intestinal microbes and neutralized not only K. pneumoniae LPS but also non-K. pneumoniae LPS. Our data suggest that the recognition of minimal glycan epitopes abundantly expressed on microbial surfaces might serve as an efficient humoral immunological mechanism to control invading pathogens and the large diversity of the human microbiota with a limited set of cross-specific antibodies.

Human IgA binds a diverse array of commensal bacteria

“…We therefore hypothesize that somatic mutations contribute to the breadth of commensals bound by intestinal IgA, even though reverted murine mAbs were reported to remain poly-and microbiota reactive (Bunker et al, 2017). Consistent with this hypothesis, germline counterparts of human cross-reactive antibodies against Klebsiella pneumoniae reportedly lose their binding signature (Rollenske et al, 2018).…”

“…Of note, IgA cross-reactivity does not imply random interactions; on the contrary, IgA interactions appeared rather selective, since, for instance, S. haemolyticus evaded some, but not all, IgA antibodies that target S. aureus. Recent studies report the identification of highly abundant clonotypes in peripheral memory, as well as lamina propria, B cells that are cross-reactive Rollenske et al, 2018). Quite remarkably, these antibodies are extensively mutated.…”

Complement and Bacterial Infections: From Molecular Mechanisms to Therapeutic Applications

“…The main challenge is still to identify antibodies and bacterial antigens that drive potent complement activation, but the first successes have been made in the field of Klebsiella pneumoniae [61,62] and N. gonorrhoeae [63]. With the advancement of new antibody-discovery technologies (immune receptor identification), we believe that this promises to be a rapidly growing field in the near future.…”

Organoid Polymer Functionality and Mode ofKlebsiella PneumoniaeMembrane Antigen Presentation Regulates Ex Vivo Germinal Center Epigenetics in Young and Aged B Cells

“…Effective vaccination also requires identification of bacterial antigens, their immunogenicity, and the mode of presentation of these antigens -as embedded bacterial antigens in outer membranes or in soluble purified forms, making successful vaccination challenging. New immunotherapies using monoclonal antibodies targeting bacterial antigens are emerging as promising alternatives to passive immunization to tackle antibiotic-resistant bacteria, including K. pneumoniae 4,5 , but often fail to mediate broad protection against different serotypes.…”