title: Spleen Tyrosine Kinase (Syk) Mediates IL-1β Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection.
abstract: Approximately 500,000 people are hospitalized with severe dengue illness annually. Antibody-dependent enhancement (ADE) of dengue virus (DENV) infection is believed to contribute to the pathogenic cytokine storm described in severe dengue patients, but the precise signaling pathways contributing to elevated cytokine production are not elucidated. IL-1β is a potent inflammatory cytokine that is frequently elevated during severe dengue, and the unique dual regulation of IL-1β provides an informative model to study ADE-induced cytokines. This work utilizes patient-derived anti-DENV mAbs and primary human monocytes to study ADE-induced IL-1β and other cytokines. ADE of DENV serotype 2 (DENV-2) elevates mature IL-1β secretion by monocytes independent of DENV replication by 4 h postinoculation (hpi). Prior to this, DENV immune complexes activate spleen tyrosine kinase (Syk) within 1 hpi. Syk induces elevated IL1B, TNF, and IL6 mRNA by 2 hpi. Syk mediates elevated IL-1β secretion by activating ERK1/2, and both Syk and ERK1/2 inhibitors ablated ADE-induced IL-1β secretion. Maturation of pro-IL-1β during ADE requires caspase-1 and NLRP3, but caspase-1 is suboptimally increased by ADE and can be significantly enhanced by a typical inflammasome agonist, ATP. Importantly, this inflammatory Syk-ERK signaling axis requires DENV immune complexes, because DENV-2 in the presence of serotype-matched anti-DENV-2 mAb, but not anti-DENV-1 mAb, activates Syk, ERK, and IL-1β secretion. This study provides evidence that DENV-2 immune complexes activate Syk to mediate elevated expression of inflammatory cytokines. Syk and ERK may serve as new therapeutic targets for interfering with ADE-induced cytokine expression during severe dengue.
authors.affiliation: From the Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center.
authors.forename: Justin B
authors.initials: JB
authors.lastname: Callaway
authors.affiliation: the Vanderbilt Vaccine Center and the Departments of Medicine.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Smith
authors.affiliation: From the Department of Microbiology and Immunology.
authors.forename: Karen P
authors.initials: KP
authors.lastname: McKinnon
authors.affiliation: From the Department of Microbiology and Immunology.
authors.forename: Aravinda M
authors.initials: AM
authors.lastname: de Silva
authors.affiliation: the Vanderbilt Vaccine Center and Pathology, Microbiology, and Immunology, and Pediatrics, Vanderbilt Medical Center, Nashville, Tennessee 37232.
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
authors.affiliation: From the Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, Department of Genetics, and Institute of Inflammatory Diseases, University of North Carolina, Chapel Hill, North Carolina 27599 and jenny_ting@med.unc.edu.
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000914:Antibodies, Viral / Q000378:metabolism; D019067:Antibody-Dependent Enhancement; D000936:Antigen-Antibody Complex / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D003715:Dengue / Q000235:genetics / Q000276:immunology / Q000821:virology; D003716:Dengue Virus / Q000276:immunology* / Q000472:pathogenicity* / Q000502:physiology; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000821:virology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000072377:Syk Kinase; D014779:Virus Replication
chemical_list: D000914:Antibodies, Viral; D000936:Antigen-Antibody Complex; D002352:Carrier Proteins; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D020170:Caspase 1; D005905:Glyburide
keywords: Fc-gamma receptor; caspase 1 (CASP1); cytokine induction; extracellular signal-regulated kinase (ERK); flavivirus; inflammasome; innate immunity; interleukin 1 (IL-1); monocyte; spleen tyrosine kinase (Syk)