TLR2-dependent MyD88 signaling contributes to early host defense in murine Enterococcus faecium peritonitis.
The incidence of infections with Enterococcus faecium is increasing worldwide. TLRs have been implicated in the recognition of pathogens and the initiation of an adequate innate immune response. We here sought to determine the roles of MyD88, the common adaptor protein involved in TLR signaling, TLR2, TLR4, and CD14 in host defense against E. faecium peritonitis. MyD88 knockout (KO) mice demonstrated an impaired early response to E. faecium peritonitis, as reflected by higher bacterial loads in peritoneal fluid and liver accompanied by a markedly attenuated neutrophil influx into the abdominal cavity. In vitro, not only MyD88 KO macrophages but also TLR2 KO and CD14 KO macrophages displayed a reduced responsiveness to E. faecium. In accordance, transfection of TLR2 rendered human embryonic kidney 293 cells responsive to E. faecium, which was enhanced by cotransfection of CD14. TLR2 KO mice showed higher bacterial loads in peritoneal fluid after in vivo infection with E. faecium and a diminished influx of neutrophils, whereas CD14 KO mice had an unaltered host response. E. faecium phagocytosis and killing were not affected by MyD88, TLR2, or CD14 deficiency. TLR4 did not play a role in the immune response to E. faecium in vitro or in vivo. These data suggest that MyD88 contributes to the effective clearance of E. faecium during peritonitis at least in part via TLR2 and by facilitating neutrophil recruitment to the site of the infection.
Leendertse
Masja
M
Center for Infection and Immunity Amsterdam, Academic Medical Center, Amsterdam, The Netherlands. m.leendertse@amc.uva.nl
Willems
Rob J L
RJ
Giebelen
Ida A J
IA
van den Pangaart
Petra S
PS
Wiersinga
W Joost
WJ
de Vos
Alex F
AF
Florquin
Sandrine
S
Bonten
Marc J M
MJ
van der Poll
Tom
T
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D016984:Enterococcus faecium / Q000276:immunology*; D005260:Female; D006801:Humans; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D010538:Peritonitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010586:Phagocytes / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism*
D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2