Chlamydia trachomatis induces expression of IFN-gamma-inducible protein 10 and IFN-beta independent of TLR2 and TLR4, but largely dependent on MyD88.
IFN-gamma-inducible protein 10 (IP-10) is a chemokine important in the attraction of T cells, which are essential for resolution of chlamydial genital tract infection. During infections with Gram-negative bacteria, the IP-10 response mediated through type I IFNs usually occurs as a result of TLR4 stimulation by bacterial LPS. However, we found that levels of IP-10 in genital tract secretions of Chlamydia trachomatis-infected female wild-type mice were similar to those of infected TLR2- and TLR4-deficient mice but significantly greater than those of infected MyD88-deficient mice. We investigated the mechanism of IP-10 and IFN-beta induction during chlamydial infection using mouse macrophages and fibroblasts infected ex vivo. The induction of IP-10 and IFN-beta was unchanged in Chlamydia-infected TLR2- and TLR4-deficient cells compared with wild-type cells. However, infection of MyD88-deficient cells resulted in significantly decreased responses. These results suggest a role for MyD88-dependent pathways in induction of IP-10 and IFN-beta during chlamydial infection. Furthermore, treatment of infected macrophages with an endosomal maturation inhibitor significantly reduced chlamydial-induced IFN-beta. Because endosomal maturation is required for MyD88-dependent intracellular pathogen recognition receptors to function, our data suggest a role for the intracellular pathogen recognition receptor(s) in induction of IFN-beta and IP-10 during chlamydial infection. Furthermore, the intracellular pathways that lead to chlamydial-induced IFN-beta function through TANK-binding kinase mediated phosphorylation and nuclear translocation of IFN regulatory factor-3.
Division of Pediatric Infectious Diseases, Arkansas Children's Hospital, Little Rock, AR 72202, USA. nagarajanuma@uams.edu
Uma M
UM
Nagarajan
David M
DM
Ojcius
Lynn
L
Stahl
Roger G
RG
Rank
Toni
T
Darville
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics*; D002690:Chlamydia Infections / Q000235:genetics / Q000276:immunology; D002692:Chlamydia trachomatis / Q000276:immunology* / Q000472:pathogenicity*; D004247:DNA / Q000235:genetics; D011992:Endosomes / Q000276:immunology; D005260:Female; D015870:Gene Expression; D066298:In Vitro Techniques; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics*; D007371:Interferon-gamma / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; D007371:Interferon-gamma; D004247:DNA