Mechanisms of immune evasion induced by a complex of dengue virus and preexisting enhancing antibodies.
We have found that dengue virus (DENV) not only uses preexisting enhancing antibodies to promote its entry into Fc receptor-bearing cells but also exploits enhancing antibodies for intracellular immune evasion through 2 mechanisms. In the first mechanism, entry of DENV-antibody complexes into human monocytic cells activates negative regulators, dihydroxyacetone kinase and autophagy-related 5-autophagy-related 12, which then disrupt the retinoic acide incucible gene I and melanoma differentiation associated gene 5 signaling cascade and disable type 1 interferon production, leading to suppression of interferon-mediated antiviral responses. In the second mechanism, the immune evasion was found to be mediated by the suppressive cytokine interleukin 10 (IL-10). High levels of IL-10 activated expression of suppressor of cytokine signaling 3 gene, which subsequently inactivated the Janus kinase-signal transducer and activator of transcription pathway. Inhibition of IL-10 production by small interfering RNA down-regulated suppressor of cytokine signaling 3 gene expression, restored inducible nitric oxide synthase gene expression, and suppressed DENV replication. Importantly, we were able to demonstrate that these 2 loops of suppression occurred in patients with severe secondary dengue infection (dengue hemorrhagic fever) but not in patients with mild secondary dengue infection (dengue fever).
Department of Microbiology, Faculty of Science, Mahidol University, Rathchatewee, Bangkok, Thailand. scsul@mahidol.ac.th
Sukathida
S
Ubol
Weerawat
W
Phuklia
Siripen
S
Kalayanarooj
Naphak
N
Modhiran
D019138:Antibodies, Blocking / Q000097:blood / Q000276:immunology*; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis / Q000235:genetics; D003715:Dengue / Q000276:immunology / Q000821:virology; D003716:Dengue Virus / Q000235:genetics / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000502:physiology; D012367:RNA, Viral; D011971:Receptors, Immunologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013785:Thailand; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*
D019138:Antibodies, Blocking; D000914:Antibodies, Viral; D016207:Cytokines; D034741:RNA, Small Interfering; D012367:RNA, Viral; D011971:Receptors, Immunologic; D050794:STAT1 Transcription Factor; D016753:Interleukin-10; D016899:Interferon-beta; D053612:Janus Kinases; C452820:RIGI protein, human; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1