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 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.
Wollert
Thomas
T
Molecular Host-Pathogen Interactions, Division of Structural Biology, Helmholtz Centre for Infection Research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
Pasche
Bastian
B
Rochon
Maike
M
Deppenmeier
Stefanie
S
van den Heuvel
Joop
J
Gruber
Achim D
AD
Heinz
Dirk W
DW
Lengeling
Andreas
A
Schubert
Wolf-Dieter
WD
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism; D005260:Female; D006801:Humans; D008089:Listeria monocytogenes / Q000472:pathogenicity*; D008088:Listeriosis / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010920:Placenta; D011247:Pregnancy; D011485:Protein Binding; D015202:Protein Engineering; D013047:Specific Pathogen-Free Organisms; D037521:Virulence Factors
D001426:Bacterial Proteins; D015820:Cadherins; D037521:Virulence Factors; C069761:internalin protein, Bacteria