Fc receptors in antibody-dependent enhancement of viral infections

Abstract

Sensitization of the humoral immune response to invading viruses and production of antiviral antibodies forms part of the host antiviral repertoire. Paradoxically, for a number of viral pathogens, under certain conditions, antibodies provide an attractive means of enhanced virus entry and replication in a number of cell types. Known as antibody-dependent enhancement (ADE) of infection, the phenomenon occurs when virus-antibody immunocomplexes interact with cells bearing complement or Fc receptors, promoting internalization of the virus and increasing infection. Frequently associated with exacerbation of viral disease, ADE of infection presents a major obstacle to the prevention of viral disease by vaccination and is thought to be partly responsible for the adverse effects of novel antiviral therapeutics such as intravenous immunoglobulins. There is a growing body of work examining the intracellular signaling pathways and epitopes responsible for mediating ADE, with a view to aiding rational design of antiviral strategies. With in vitro studies also confirming ADE as a feature of infection for a growing number of viruses, challenges remain in understanding the multilayered molecular mechanisms of ADE and its effect on viral pathogenesis.

Keywords: Fc receptors; antibody-dependent enhancement; intravenous immunoglobulins; virus.

Figure 1

Antiviral responses under normal conditions. The TLR‐dependent, RIG‐1/MDA5 and TLR‐independent pathways induce IFN‐α/β production and the expression of ISG (interferon‐stimulated gene) to tailor the innate anti‐viral response to DENV infection. dsRNA, double‐stranded RNA; 5′‐pppRNA, 5′ triphosphate single‐stranded RNA; STING, stimulator of IFN genes; MAVS, mitochondrial antiviral signaling; TRIF, TIR‐domain‐containing adapter‐inducing interferon‐β; TRAF, TNF receptor‐associated factor; IKK, inhibitor of nuclear factor kappa‐B kinase; JAK/STAT, janus kinase/signal transducer and activator of transcription; IRF, interferon regulatory factor.

Figure 2

Dengue virus subversion of host innate immune responses during ADE can occur via three pathways. (A) Infectious DENV‐sub‐neutralizing antibody complexes internalized via phagocytic FcγRIIa pathway is uncoated within the endosome, where viral RNA is recognized by TLR. FcγR synergize with TLR to orchestrate the induction of cytokines: promoting DAK (dihydroxy acetone kinase), Atg5/12 (autophagy‐related 5/12 protein), SARM (Sterile‐alpha and Armadillo motif‐containing protein), and TANK (TRAF family member‐associated nuclear factor kappa‐B activator), down‐regulating RIG‐I and MDA5 expression, sabotaging the TLR‐independent antiviral pathway, subsequently suppressing production of type I IFNs. (B) Co‐ligation of FcγR and LILRB1 (leukocyte immunoglobulin‐like receptor‐B1) to DENV‐immune complexes and the DENV virion, respectively, inhibits the activation of Syk and abrogate the expression of ISGs. (C) Ligation of FcγR to immune complexes also induces upregulation of IL‐10 via Syk (spleen tyrosine kinase‐mediated PI3K/PKB (phosphoinositide 3 kinase) activation. The activation of IL‐10 as well as IL‐6 triggers SOCS (suppressor of cytokine signaling) pathway, inhibiting the JAK/STAT signaling pathway, decreasing pro‐inflammatory cytokine production. ITIM, immunoreceptor tyrosine‐based inhibitory motif; ITAM, immunoreceptor tyrosine‐based activation motif; SHP‐1, Src homology 2‐containing protein tyrosine phosphatase‐1; PKB, protein kinase B; GSK‐3β, glycogen synthase kinase; CREB, cyclic adenosine monophosphate response element‐binding; Tyk, tyrosine kinase.