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Colistin resistance mutations in phoQ can sensitize Klebsiella pneumoniae to IgM-mediated complement killing

Sjors P A van der Lans1, Manon Janet-Maitre2,3, Frerich M Masson1

  • 1Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Scientific Reports
|August 3, 2023
PubMed

Insights

Colistin resistance in Klebsiella pneumoniae alters its interaction with the immune system. Developing resistance can unexpectedly increase susceptibility to complement-mediated killing by human serum.

Area of Science:

  • Microbiology
  • Immunology
  • Genetics

Background:

  • Multi-drug resistant Klebsiella pneumoniae necessitates colistin use.
  • Colistin resistance in K. pneumoniae presents complex immune evasion and susceptibility challenges.
  • Colistin resistance can paradoxically increase bacterial sensitivity to human serum complement.

Purpose of the Study:

  • Investigate mechanisms of increased serum sensitivity in colistin-resistant K. pneumoniae.
  • Elucidate the role of the human complement system, specifically the membrane attack complex (MAC).
  • Identify genetic and immunological factors contributing to altered serum susceptibility.

Main Methods:

  • In vitro evolution of colistin-resistant K. pneumoniae strains.
  • Fluorescent MAC-mediated permeabilization assay to assess serum sensitivity.
  • Transcriptomic analysis and immunological assays (IgM binding) to identify mechanisms.

Main Results:

  • Two of three colistin-resistant strains (Kp209_CSTR, Kp257_CSTR) showed increased sensitivity to MAC.
  • A phoQ gene mutation in Kp209_CSTR locked PhoQ in an active state, conferring colistin resistance and MAC sensitivity.
  • Complement activation on Kp209_CSTR required specific IgM antibodies not found against the wild-type strain.

Conclusions:

  • Colistin resistance development impacts K. pneumoniae recognition by the immune system.
  • Specific mutations, like in phoQ, can link colistin resistance to complement-mediated killing.
  • Altered bacterial surface properties due to colistin resistance affect antibody binding and immune clearance.

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