Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2.
Human cytomegalovirus (CMV) is a ubiquitous opportunistic pathogen that causes significant morbidity and mortality in immunocompromised people. An understanding of how CMV induces and circumvents host immunity is of critical importance in efforts to design effective therapeutics. It was recently discovered that mere cell contact by CMV particles leads to profound modulation of cellular gene expression, including induction of inflammatory cytokines and interferon-stimulated genes characteristic of innate immune detection. These findings suggest that a membrane receptor recognizes a CMV envelope protein(s), leading to innate immune activation. Here, we show that the pattern recognition receptors Toll-like receptor 2 (TLR2) and CD14 recognize CMV virions and trigger inflammatory cytokine production. Induction of inflammatory cytokines is mediated via TLR2-dependent activation of NF-kappa B. Since many of the pathological processes associated with CMV disease are facilitated or directly mediated by inflammatory cytokines, identification of the host membrane detection machinery may ultimately lead to improved therapeutics.
Compton
Teresa
T
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison Medical School, Madison, Wisconsin 53706, USA. tcompton@wisc.edu
Kurt-Jones
Evelyn A
EA
Boehme
Karl W
KW
Belko
John
J
Latz
Eicke
E
Golenbock
Douglas T
DT
Finberg
Robert W
RW
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D003587:Cytomegalovirus / Q000276:immunology* / Q000472:pathogenicity; D029721:Drosophila Proteins; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors
D016207:Cytokines; D029721:Drosophila Proteins; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors