The mechanism of action of a serotype-specific natural human antibody against dengue virus has been identified.

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...

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IntroductionFragment crystallizable receptors (FcRs) are receptors on immune cells that bind to the Fc region of immunoglobulins. Fc␥Rs that bind to the most common type of immunoglobulin (IgG), are expressed on the surface of many different immune cell types including monocytes, macrophages, dendritic cells, and neutrophils. [1][2][3] In humans, 3 different classes of activatory IgG receptors have been defined: Fc␥RI (CD64), Fc␥RIIa (CD32a), and Fc␥RIII (CD16), each of which has a variety of isoforms with differing affinities for IgG, tissue distribution, and level of expression. [1][2][3][4][5][6] The high affinity IgG receptor, Fc␥RI, is a 72-kD type-I membrane glycoprotein constitutively expressed on monocyte and macrophage lineage cells. 4 Fc␥RI is a member of the multichain immune recognition receptor family, comprising hetero-oligomeric complexes of a ligand-binding ␣-chain and a signaling ␥-chain usually found in association with other immune receptors. [1][2][3][4][5][6] The ␥-chain contains a signaling motif termed the "immunoreceptor tyrosinebased activation motif" (ITAM): it is through the ITAM-bearing chain that most FcRs trigger intracellular signal transduction cascades. The low-affinity receptor, Fc␥RIIa, is the most broadly distributed human Fc␥R and is expressed on many cell types, such as monocytes, neutrophils, and platelets. 1,7 This low-affinity receptor preferentially binds complexes of IgG and is the only Fc receptor that contains an ITAM of its own. Thus, it is the only Fc receptor that does not need to oligomerize with a ␥-chain in order to signal. 4,8,9 There is no identified murine equivalent of Fc␥RIIa. 1 On myeloid cells, aggregation of Fc␥Rs during the early stages of infection leads to several cellular responses, including the internalization of immune complexes by endocytosis or opsonized particles through phagocytosis, degranulation with the release of proteases, activation of respiratory burst, and secretion of cytokines. 5,[10][11][12] The presentation of antigens derived from internalized complexes forms an important component of our adaptive immune response, and dysregulation of this pathway is reported to be linked to increased susceptibility to bacterial sepsis. 13 The safe clearance of immune complexes toward the latter stages of infection is also dependent on FcR expressing mononuclear phagocytes. Dysfunction in the clearance of immune complexes is reported to be associated with immunopathology, autoimmunity, and allergic disease. 9,14 This represents one of the critical but poorly understood functions of Fc receptors, ie, the determination of the antigenic fate of immune complexes; specifically, whether to internalize and digest them in a way that is noninflammatory or to reinforce antigen presentation combined with immune activation and associated proinflammatory signaling.Studies on differential functions mediated by individual Fc receptors in immune activation/homeostasis are complicated by the coexistence of several FcRs on phagocytic cells-it is difficult to identi...

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Dendritic cell (DC) immunogenicity correlates with its maturation, which can be induced by toxic microbial products such as LPS. In this study, we report that a nontoxic polysaccharide-protein complex isolated from a Chinese medicinal herb, Lycium barbarum (LBP), induces phenotypic and functional maturation of DCs with strong immunogenicity. LBP up-regulated DC expression of CD40, CD80, CD86, and MHC class II molecules; down-regulated DC uptake of Ag; enhanced DC allostimulatory activity; and induced IL-12p40 and p70 production. All of its five fractions were active. LBP developed enhanced Th1 response, and LBP-treated DCs enhanced Th1 and Th2 responses in vitro and in vivo. Our study provides evidence and rationale on using LBP in various clinical conditions to enhance host immunity and suggests LBP as a potent adjuvant for the design of DC-based vaccines.