PMID- 28507028 OWN - NLM STAT- MEDLINE DCOM- 20170927 LR - 20231213 IS - 1550-6606 (Electronic) IS - 0022-1767 (Linking) VI - 198 IP - 12 DP - 2017 Jun 15 TI - RIG-I-like Receptor Triggering by Dengue Virus Drives Dendritic Cell Immune Activation and T(H)1 Differentiation. PG - 4764-4771 LID - 10.4049/jimmunol.1602121 [doi] AB - Dengue virus (DENV) causes 400 million infections annually and is one of several viruses that can cause viral hemorrhagic fever, which is characterized by uncontrolled immune activation resulting in high fever and internal bleeding. Although the underlying mechanisms are unknown, massive cytokine secretion is thought to be involved. Dendritic cells (DCs) are the main target cells of DENV, and we investigated their role in DENV-induced cytokine production and adaptive immune responses. DENV infection induced DC maturation and secretion of IL-1beta, IL-6, and TNF. Inhibition of DENV RNA replication abrogated these responses. Notably, silencing of RNA sensors RIG-I or MDA5 abrogated DC maturation, as well as cytokine responses by DENV-infected DCs. DC maturation was induced by type I IFN responses because inhibition of IFN-alpha/beta receptor signaling abrogated DENV-induced DC maturation. Moreover, DENV infection of DCs resulted in CCL2, CCL3, and CCL4 expression, which was abrogated after RIG-I and MDA5 silencing. DCs play an essential role in T(H) cell differentiation, and we show that RIG-I and MDA5 triggering by DENV leads to T(H)1 polarization, which is characterized by high levels of IFN-gamma. Notably, cytokines IL-6, TNF, and IFN-gamma and chemokines CCL2, CCL3, and CCL4 have been associated with disease severity, endothelial dysfunction, and vasodilation. Therefore, we identified RIG-I and MDA5 as critical players in innate and adaptive immune responses against DENV, and targeting these receptors has the potential to decrease hemorrhagic fever in patients. CI - Copyright (c) 2017 by The American Association of Immunologists, Inc. FAU - Sprokholt, Joris K AU - Sprokholt JK AD - Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and. AD - Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands. FAU - Kaptein, Tanja M AU - Kaptein TM AD - Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and. AD - Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands. FAU - van Hamme, John L AU - van Hamme JL AUID- ORCID: 0000-0003-0765-9441 AD - Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and. AD - Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands. FAU - Overmars, Ronald J AU - Overmars RJ AD - Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and. AD - Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands. FAU - Gringhuis, Sonja I AU - Gringhuis SI AD - Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and. AD - Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands. FAU - Geijtenbeek, Teunis B H AU - Geijtenbeek TBH AD - Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and t.b.geijtenbeek@amc.uva.nl. AD - Amsterdam Infection & Immunity Institute, 1105 AZ Amsterdam, the Netherlands t.b.geijtenbeek@amc.uva.nl. LA - eng PT - Journal Article DEP - 20170515 PL - United States TA - J Immunol JT - Journal of immunology (Baltimore, Md. : 1950) JID - 2985117R RN - 0 (CCL2 protein, human) RN - 0 (CCL3 protein, human) RN - 0 (CCL4 protein, human) RN - 0 (Chemokine CCL2) RN - 0 (Chemokine CCL3) RN - 0 (Chemokine CCL4) RN - 0 (IL6 protein, human) RN - 0 (Interleukin-1beta) RN - 0 (Interleukin-6) RN - 0 (Receptors, Immunologic) RN - 0 (Tumor Necrosis Factor-alpha) RN - 82115-62-6 (Interferon-gamma) RN - EC 3.6.1.- (RIGI protein, human) RN - EC 3.6.1.- (IFIH1 protein, human) RN - EC 3.6.4.13 (DEAD Box Protein 58) RN - EC 3.6.4.13 (Interferon-Induced Helicase, IFIH1) SB - IM MH - Cell Differentiation MH - Chemokine CCL2/genetics/immunology MH - Chemokine CCL3/genetics/immunology MH - Chemokine CCL4/genetics/immunology MH - DEAD Box Protein 58/deficiency/genetics/*immunology/metabolism MH - Dendritic Cells/*immunology/virology MH - Dengue Virus/*immunology MH - Humans MH - Interferon-Induced Helicase, IFIH1/deficiency/immunology/metabolism MH - Interferon-gamma/immunology/metabolism MH - Interleukin-1beta/immunology/metabolism MH - Interleukin-6/immunology/metabolism MH - Receptors, Immunologic MH - Th1 Cells/*immunology/physiology MH - Tumor Necrosis Factor-alpha/immunology/metabolism EDAT- 2017/05/17 06:00 MHDA- 2017/09/28 06:00 CRDT- 2017/05/17 06:00 PHST- 2016/12/19 00:00 [received] PHST- 2017/04/13 00:00 [accepted] PHST- 2017/05/17 06:00 [pubmed] PHST- 2017/09/28 06:00 [medline] PHST- 2017/05/17 06:00 [entrez] AID - jimmunol.1602121 [pii] AID - 10.4049/jimmunol.1602121 [doi] PST - ppublish SO - J Immunol. 2017 Jun 15;198(12):4764-4771. doi: 10.4049/jimmunol.1602121. Epub 2017 May 15.