Novel, Broadly Reactive Anticapsular Antibodies against Carbapenem-Resistant Klebsiella pneumoniae Protect from Infection

Abstract

Carbapenem-resistant (CR) sequence type 258 (ST258) Klebsiella pneumoniae has become an urgent health care threat, causing an increasing number of high-mortality infections. Its resistance to numerous antibiotics and threat to immunocompromised patients necessitate finding new therapies to combat these infections. Previous successes in the laboratory, as well as the conservation of capsular polysaccharide (CPS) among the members of the ST258 clone, suggest that monoclonal antibody (MAb) therapy targeting the outer polysaccharide capsule of K. pneumoniae could serve as a valuable treatment alternative for afflicted patients. Here, we isolated several IgG antibodies from mice inoculated with a mixture of CR K. pneumoniae CPS conjugated to anthrax protective antigen. Two of these MAbs, 17H12 and 8F12, bind whole and oligosaccharide epitopes of the CPS of clade 2 ST258 CR K. pneumoniae, which is responsible for the most virulent CR K. pneumoniae infections in the United States. These antibodies were shown to agglutinate all clade 2 strains and were also shown to promote extracellular processes killing these bacteria, including biofilm inhibition, complement deposition, and deployment of neutrophil extracellular traps. Additionally, they promoted opsonophagocytosis and intracellular killing of CR K. pneumoniae by human-derived neutrophils and cultured murine macrophages. Finally, when mice were intratracheally infected with preopsonized clade 2 CR K. pneumoniae, these MAbs reduced bacterial dissemination to organs. Our data suggest that broadly reactive anticapsular antibodies and vaccines against clade 2 ST258 CR K. pneumoniae are possible. Such MAbs and vaccines would benefit those susceptible populations at risk of infection with this group of multidrug-resistant bacteria.

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.…”

A Front Line on Klebsiella pneumoniae Capsular Polysaccharide Knowledge: Fourier Transform Infrared Spectroscopy as an Accurate and Fast Typing Tool

“…The capsule, an extracellular polysaccharide matrix, is one of the most striking virulence mechanisms considered essential for establishment of infection and for its protective effect against desiccation, phages, and protists predation (1). Though it renders attractive properties as a target for vaccine development, the success of immunotherapeutic approaches depends on a complete understanding of bacterial surface structures circulating in the clinical setting (3,4). Whereas it is known that the expression of specific virulence factors and capsular (K) types (mainly K1 and K2) is related to severe infections caused by HV strains, much larger variation of K types has been described among clinical MDR strains, providing a higher resolution than multilocus sequence typing (MLST) and specific capsule-lineage associations that might be useful for typing (5)(6)(7).…”

The Role of IgG Subclass in Antibody-Mediated Protection against Carbapenem-ResistantKlebsiella pneumoniae

“…With the recent rise of multidrug resistant gram-negative bacteria, such as carbapenemresistant Klebsiella pneumoniae (CR-Kp) (13), several laboratories have been focusing on developing antibodies against these pathogens (3,(14)(15)(16)(17). These bacteria frequently infect immunocompromised populations that lack robust innate and adaptive immune responses (18,19).…”