Extending the host range of Listeria monocytogenes by rational protein design

Thomas Wollert, Bastian Pasche, Maike Rochon, Stefanie Deppenmeier, Joop van den Heuvel, Achim D Gruber, Dirk W Heinz, Andreas Lengeling, Wolf-Dieter Schubert

Research output: Contribution to journalArticlepeer-review

Abstract

In causing disease, pathogens outmaneuver host defenses through a dedicated arsenal of virulence determinants that specifically bind or modify individual host molecules. This dedication limits the intruder to a defined range of hosts. Newly emerging diseases mostly involve existing pathogens whose arsenal has been altered to allow them to infect previously inaccessible hosts. We have emulated this chance occurrence by extending the host range accessible to the human pathogen Listeria monocytogenes by the intestinal route to include the mouse. Analyzing the recognition complex of the listerial invasion protein InlA and its human receptor E-cadherin, we postulated and verified amino acid substitutions in InlA to increase its affinity for E-cadherin. Two single substitutions increase binding affinity by four orders of magnitude and extend binding specificity to include formerly incompatible murine E-cadherin. By rationally adapting a single protein, we thus create a versatile murine model of human listeriosis.
Original languageEnglish
Pages (from-to)891-902
Number of pages12
JournalCell
Volume129
Issue number5
DOIs
Publication statusPublished - 2007

Keywords

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Bacterial Proteins/chemistry
  • Bacterial Proteins/genetics
  • Bacterial Proteins/metabolism
  • Caco-2 Cells
  • Cadherins/metabolism
  • Female
  • Humans
  • Listeria monocytogenes/pathogenicity
  • Listeriosis/metabolism
  • Listeriosis/microbiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Models, Molecular
  • Molecular Sequence Data
  • Placenta
  • Pregnancy
  • Protein Binding
  • Protein Engineering
  • Specific Pathogen-Free Organisms
  • Virulence Factors

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