固有免疫应答的遗传控制

生物谷

Christine A Well et al

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.
Conclusion: 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.