Overexpression of Toll-like receptor 4 amplifies the host response to lipopolysaccharide and provides a survival advantage in transgenic mice.
Toll-like receptors are transmembrane proteins that are involved in the innate immune recognition of microbial constituents. Among them, Toll-like receptor 4 (Tlr4) is a crucial signal transducer for LPS, the major component of Gram-negative bacteria outer cell membrane. The contribution of Tlr4 to the host response to LPS and to infection with virulent Salmonella typhimurium was studied in four transgenic (Tg) strains including three overexpressing Tlr4. There was a good correlation between the level of Tlr4 mRNA expression and the sensitivity to LPS both in vitro and in vivo: Tg mice possessing the highest number of Tlr4 copies respond the most to LPS. Overexpression of Tlr4 by itself appears to have a survival advantage in Tg mice early during infection: animals possessing more than two copies of the gene survived longer and in a greater percentage to Salmonella infection. The beneficial effect of Tlr4 overexpression is greatly enhanced when the mice present a wild-type allele at natural resistance-associated macrophage protein 1, another critical innate immune gene involved in resistance to infection with Salmonella. Tlr4 and natural resistance-associated macrophage protein 1 exhibit functional epistatic interaction to improve the capacity of the host to control bacterial replication. However, this early improvement in disease resistance is not conducted later during infection, because mice overexpressing Tlr4 developed an excessive inflammatory response detrimental to the host.
Bihl
Franck
F
Department of Human Genetics, McGill University, and Center for the Study of Host Resistance, Montreal General Hospital, Montréal, Québec, Canada.
Salez
Laurent
L
Beaubier
Magali
M
Torres
David
D
Larivière
Line
L
Laroche
Line
L
Benedetto
Alexandre
A
Martel
Dominic
D
Lapointe
Jean-Martin
JM
Ryffel
Bernhard
B
Malo
Danielle
D
D000276:Adjuvants, Immunologic / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003433:Crosses, Genetic; D005434:Flow Cytometry; D018628:Gene Dosage; D005786:Gene Expression Regulation / Q000276:immunology; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012481:Salmonella Infections, Animal / Q000235:genetics* / Q000276:immunology / Q000401:mortality* / Q000473:pathology; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology / Q000401:mortality; D015996:Survival Rate; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D019076:Transgenes / Q000276:immunology
D000276:Adjuvants, Immunologic; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors