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.early innate immune response | innate immune signaling | immune evasion D espite long-lived serotype-specific immunity upon initial infection, predicted global prevalence of dengue now surpasses World Health Organization estimates by more than threefold with 390 million cases annually (1). Furthermore, the risk of severe disease is augmented by cross-reactive or subneutralizing levels of antibody (2, 3), which opsonize dengue virus (DENV) to ligate Fc-gamma receptor (FcγR) for entry into monocytes, macrophages, and dendritic cells, a phenomenon known as antibody-dependent enhancement (ADE) of DENV infection (4, 5). The resultant greater viral burden leads to increased systemic inflammation that precipitates plasma leakage, a hallmark of dengue hemorrhagic fever (6). However, ligation of the activating FcγRs by immune complexes has been shown to induce type-I IFN stimulated genes (ISGs), independent of autocrine or paracrine IFN activity, unless the inhibitory FcγRIIB is coligated (7). We and others reported recently that coligation of FcγRIIB by DENV immune complexes requires high antibody concentration, and such coligation inhibited the entry of DENV immune complexes into monocytes (8, 9). At low antibody concentrations where ADE occurs, the inhibitory FcγRIIB is not coligated (9). Ligation of the activating FcγRs by DENV opsonized with subneutralizing levels of antibody would thus induce the expression of ISGs and hinder DENV replication (10). Here, we demonstrate that DENV employs a unique evasive mechanism by coligating LILRB1 to down-regulate the early antiviral responses triggered by activating FcγRs for ADE.Results ADE Differs in THP-1 Subclones. Our work was enabled by the isolation of subclones of THP-1 cells with different phenotypes to ADE. The low rate of...

Formation of Infectious Dengue Virus–Antibody Immune Complex In Vivo in Marmosets (Callithrix jacchus) After Passive Transfer of Anti-Dengue Virus Monoclonal Antibodies and Infection with Dengue Virus

“…Because Callithrix jacchus marmosets possess Ig receptors, including FcγRs and leukocyte immunoglobin-like receptors (LILRs), 34 the marmoset model is potentially useful in ADE and therapeutic Ab studies. 35,36 Our results confirm that DENV cross-reactive antibodies form virus-Ab immune complexes in vivo and that these immune complexes are infectious only to FcγR-bearing cells. Our results also concur with those of prior studies, which show that infectious virusAb immune complexes occur in the presence of DENV crossreactive infection-enhancing Abs before DENV infection or with transfer of maternal Ab.…”

“…[27][28][29][30][31] In the absence of an anamnestic immune response, passive Ab transfer, including maternal Abs, is speculated to be more effective at enhancing DENV infection than infection-acquired immunity. 12,32 However, the presence of DENV-immune complex formation in vivo has not been fully defined.…”

Research on Dengue During World War II Revisited

“…Alternatively, the high levels of heterotypic and homotypic IgG against dengue could either aggregate DENV to form immune complexes of sufficient size to co-ligate the inhibitory Fc gamma receptor IIB 27 or inhibit the co-ligation of leukocyte immunoglobulin-like receptor B1). 28 Both receptors have an immunoreceptor tyrosine inhibitory motif that signals to either inhibit phagocytosis and thus entry of heterologous DENV 27,29,30 or inhibit interferon stimulated gene expression that would otherwise limit viral replication. 28,31 The secondary dengue infections in subjects tested by Sabin were clinically less severe than the primary infections.…”

“…28 Both receptors have an immunoreceptor tyrosine inhibitory motif that signals to either inhibit phagocytosis and thus entry of heterologous DENV 27,29,30 or inhibit interferon stimulated gene expression that would otherwise limit viral replication. 28,31 The secondary dengue infections in subjects tested by Sabin were clinically less severe than the primary infections. Patients who showed development of a clinical infection after secondary inoculation with dengue had a lower maximum temperature and an approximately two-day shorter duration of fever compared with primary infection.…”

The Expanding Spectrum of Ligands for Leukocyte Ig-like Receptors

“…Dengue virus is a second virus reported to exploit LILRB1 during infection, but in this case, it is through an interaction with the intact virus. The discovery was made through screening derivatives of a monocyte cell line with altered susceptibility for Ab-mediated infection (48). Dengue virus is a major pathogen that causes serious illness in subsets of patients, and severe forms of dengue infection are associated with new infection in the face of pre-existing Ab to related strains that facilitate infection of monocytes.…”