Extending the Host Range of Listeria monocytogenes by Rational Protein Design

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 a...

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Bibliographic Details
Published in:Cell 2007-06, Vol.129 (5), p.891-902
Main Authors: Wollert, Thomas, Pasche, Bastian, Rochon, Maike, Deppenmeier, Stefanie, van den Heuvel, Joop, Gruber, Achim D., Heinz, Dirk W., Lengeling, Andreas, Schubert, Wolf-Dieter
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino Acid Substitution
Animals
Bacterial Proteins - chemistry
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
Caco-2 Cells
Cadherins - metabolism
Female
Humans
HUMDISEASE
Listeria monocytogenes
Listeria monocytogenes - pathogenicity
Listeriosis - metabolism
Listeriosis - microbiology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
MICROBIO
Models, Molecular
Molecular Sequence Data
Placenta
Pregnancy
Protein Binding
Protein Engineering
PROTEINS
Specific Pathogen-Free Organisms
Virulence Factors
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Summary: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.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2007.03.049