Streptococcus pneumoniae synergizes with nontypeable Haemophilus influenzae to induce inflammation via upregulating TLR2.
BACKGROUND
Toll-like receptor 2 (TLR2) plays a critical role in mediating inflammatory/immune responses against bacterial pathogens in lung. Streptococcus pneumoniae (S. pneumoniae) and nontypeable Haemophilus influenzae (NTHi) were previously reported to synergize with each other to induce inflammatory responses. Despite the relatively known intracellular signaling pathways involved in the synergistic induction of inflammation, it is still unclear if both bacterial pathogens also synergistically induce expression of surface TLR2.


RESULTS
Here we provide direct evidence that S. pneumoniae synergizes with NTHi to upregulate TLR2 expression in lung and middle ear of the mice. Pneumolysin (PLY) appears to be the major virulence factor involved in this synergism. Moreover, S. pneumoniae PLY induces TLR2 expression via a TLR4-MyD88-NF-kappaB-dependent signaling pathway. Interestingly, tumor suppressor CYLD acts as a negative regulator of S. pneumoniae-induced TLR2 up-regulation via negative-crosstalk with NF-kappaB signaling.


CONCLUSIONS
Our study thus provides novel insights into the regulation of TLR2 expression in mixed bacterial infections.
Lim
Jae Hyang
JH
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, NY 14642, USA. Jae-Hyang_Lim@urmc.rochester.edu
Ha
Unhwan
U
Sakai
Akihiro
A
Woo
Chang-Hoon
CH
Kweon
Soo-Mi
SM
Xu
Haidong
H
Li
Jian-Dong
JD
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000494:pharmacology; D000074749:Deubiquitinating Enzyme CYLD; D006192:Haemophilus Infections / Q000276:immunology*; D006193:Haemophilus influenzae; D006367:HeLa Cells; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D011018:Pneumonia, Pneumococcal / Q000139:chemically induced / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects; D013296:Streptococcus pneumoniae; D013301:Streptolysins / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics
D001426:Bacterial Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D013301:Streptolysins; C495342:TLR2 protein, human; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C032290:plY protein, Streptococcus pneumoniae; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases