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).
Ubol
Sukathida
S
Department of Microbiology, Faculty of Science, Mahidol University, Rathchatewee, Bangkok, Thailand. scsul@mahidol.ac.th
Phuklia
Weerawat
W
Kalayanarooj
Siripen
S
Modhiran
Naphak
N
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