Genetic control of the innate immune response.
BACKGROUND
Susceptibility to infectious diseases is directed, in part, by the interaction between the invading pathogen and host macrophages. This study examines the influence of genetic background on host-pathogen interactions, by assessing the transcriptional responses of macrophages from five inbred mouse strains to lipopolysaccharide (LPS), a major determinant of responses to gram-negative microorganisms.


RESULTS
The mouse strains examined varied greatly in the number, amplitude and rate of induction of genes expressed in response to LPS. The response was attenuated in the C3H/HeJlpsd strain, which has a mutation in the LPS receptor Toll-like receptor 4 (TLR4). Variation between mouse strains allowed clustering into early (C57Bl/6J and DBA/2J) and delayed (BALB/c and C3H/ARC) transcriptional phenotypes. There was no clear correlation between gene induction patterns and variation at the Bcg locus (Slc11A1) or propensity to bias Th1 versus Th2 T cell activation responses.


CONCLUSIONS
Macrophages from each strain responded to LPS with unique gene expression profiles. The variation apparent between genetic backgrounds provides insights into the breadth of possible inflammatory responses, and paradoxically, this divergence was used to identify a common transcriptional program that responds to TLR4 signalling, irrespective of genetic background. Our data indicates that many additional genetic loci control the nature and the extent of transcriptional responses promoted by a single pathogen-associated molecular pattern (PAMP), such as LPS.
Wells
Christine A
CA
Institute for Molecular Biosciences, The University of Queensland, Brisbane, QLD, 4072, Australia. c.wells@imb.uq.edu.au
Ravasi
Timothy
T
Faulkner
Geoffrey J
GJ
Carninci
Piero
P
Okazaki
Yasushi
Y
Hayashizaki
Yoshihide
Y
Sweet
Matthew
M
Wainwright
Brandon J
BJ
Hume
David A
DA
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002874:Chromosome Mapping; D020869:Gene Expression Profiling; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000276:immunology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D009154:Mutation; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014158:Transcription, Genetic / Q000187:drug effects
D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors