title: Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue.
abstract: Viruses must evade the host innate defenses for replication and dengue is no exception. During secondary infection with a heterologous dengue virus (DENV) serotype, DENV is opsonized with sub- or nonneutralizing antibodies that enhance infection of monocytes, macrophages, and dendritic cells via the Fc-gamma receptor (FcγR), a process termed antibody-dependent enhancement of DENV infection. However, this enhancement of DENV infection is curious as cross-linking of activating FcγRs signals an early antiviral response by inducing the type-I IFN-stimulated genes (ISGs). Entry through activating FcγR would thus place DENV in an intracellular environment unfavorable for enhanced replication. Here we demonstrate that, to escape this antiviral response, antibody-opsonized DENV coligates leukocyte Ig-like receptor-B1 (LILRB1) to inhibit FcγR signaling for ISG expression. This immunoreceptor tyrosine-based inhibition motif-bearing receptor recruits Src homology phosphatase-1 to dephosphorylate spleen tyrosine kinase (Syk). As Syk is a key intermediate of FcγR signaling, LILRB1 coligation resulted in reduced ISG expression for enhanced DENV replication. Our findings suggest a unique mechanism for DENV to evade an early antiviral response for enhanced infection.
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore 169857.
authors.forename: Kuan Rong
authors.initials: KR
authors.lastname: Chan
authors.forename: Eugenia Z
authors.initials: EZ
authors.lastname: Ong
authors.forename: Hwee Cheng
authors.initials: HC
authors.lastname: Tan
authors.forename: Summer Li-Xin
authors.initials: SL
authors.lastname: Zhang
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Kin Fai
authors.initials: KF
authors.lastname: Tang
authors.forename: Nivashini
authors.initials: N
authors.lastname: Kaliaperumal
authors.forename: Angeline Pei Chiew
authors.initials: AP
authors.lastname: Lim
authors.forename: Martin L
authors.initials: ML
authors.lastname: Hibberd
authors.forename: Soh Ha
authors.initials: SH
authors.lastname: Chan
authors.forename: John E
authors.initials: JE
authors.lastname: Connolly
authors.forename: Manoj N
authors.initials: MN
authors.lastname: Krishnan
authors.forename: Shee Mei
authors.initials: SM
authors.lastname: Lok
authors.forename: Brendon J
authors.initials: BJ
authors.lastname: Hanson
authors.forename: Chao-Nan
authors.initials: CN
authors.lastname: Lin
authors.forename: Eng Eong
authors.initials: EE
authors.lastname: Ooi
mesh_terms: D019067:Antibody-Dependent Enhancement / Q000276:immunology / Q000502:physiology*; D015703:Antigens, CD / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D003715:Dengue / Q000276:immunology / Q000503:physiopathology*; D003716:Dengue Virus / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D046228:Microarray Analysis; D034741:RNA, Small Interfering / Q000235:genetics; D017452:Receptors, IgG / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D034741:RNA, Small Interfering; D017452:Receptors, IgG; D011971:Receptors, Immunologic
keywords: early innate immune response; immune evasion; innate immune signaling