Immune stealth-driven O2 serotype prevalence and potential for therapeutic antibodies against multidrug resistant Klebsiella pneumoniae

Meghan E Pennini,Mark Pelletier,Antonio Lanzavecchia,Anna De Marco,Wei Zhao,Elisabetta Cameroni,Е А Семенова ,Maria Clara Coelho Câmara ,Martina Beltramello,Qun Wang,Joann Suzich,Jessica Bonnell,Davide Corti,Xiaodong Xiao,Paul Warrener,Siro Bianchi,Fabrizia Zatta,Romana Cvitkovic,Antonio Digiandomenico,C Kendall Stover

doi:10.1038/s41467-017-02223-7

Meghan E Pennini, Mark Pelletier + Show 18 more

Open Access

https://doi.org/10.1038/s41467-017-02223-7

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Abstract

Emerging multidrug-resistant bacteria are a challenge for modern medicine, but how these pathogens are so successful is not fully understood. Robust antibacterial vaccines have prevented and reduced resistance suggesting a pivotal role for immunity in deterring antibiotic resistance. Here, we show the increased prevalence of Klebsiella pneumoniae lipopolysaccharide O2 serotype strains in all major drug resistance groups correlating with a paucity of anti-O2 antibodies in human B cell repertoires. We identify human monoclonal antibodies to O-antigens that are highly protective in mouse models of infection, even against heavily encapsulated strains. These antibodies, including a rare anti-O2 specific antibody, synergistically protect against drug-resistant strains in adjunctive therapy with meropenem, a standard-of-care antibiotic, confirming the importance of immune assistance in antibiotic therapy. These findings support an antibody-based immunotherapeutic strategy even for highly resistant K. pneumoniae infections, and underscore the effect humoral immunity has on evolving drug resistance.

Highlights

Emerging multidrug-resistant bacteria are a challenge for modern medicine, but how these pathogens are so successful is not fully understood
We find that LPS O2 antigen serotype has increased two to threefold in prevalence in both K. pneumoniae extended spectrum betalactamases (ESBL) and carbapenemresistant enteric bacteria (CRE) multidrug-resistant strain groups relative to the susceptible group
While we found the vast majority (85%) of sequence type 258 (ST258) isolates to be of the O2 serotype, only 49% of the CRE O2 isolates and just 5% of ESBL O2 isolates typed as ST258 (Fig. 1c)

Summary

Introduction

Emerging multidrug-resistant bacteria are a challenge for modern medicine, but how these pathogens are so successful is not fully understood. We identify human monoclonal antibodies to O-antigens that are highly protective in mouse models of infection, even against heavily encapsulated strains These antibodies, including a rare anti-O2 specific antibody, synergistically protect against drug-resistant strains in adjunctive therapy with meropenem, a standard-of-care antibiotic, confirming the importance of immune assistance in antibiotic therapy. We find that LPS O2 antigen serotype has increased two to threefold in prevalence in both K. pneumoniae ESBL and CRE multidrug-resistant strain groups relative to the susceptible group. This finding is surprising as strains expressing the O2-antigen, including ST258 strains, are more sensitive to human serum killing than the related O1 antigen expressing strains.

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