Subversion of cytokine networks by virally encoded decoy receptors

Abstract

Summary During the course of evolution, viruses have captured or created a diverse array of open reading frames that encode for proteins that serve to evade and sabotage the host innate and adaptive immune responses, which would otherwise lead to their elimination. These viral genomes are some of the best textbooks of immunology ever written. The established arsenal of immunomodulatory proteins encoded by viruses is large and growing and includes specificities for virtually all known inflammatory pathways and targets. The focus of this review is on herpes and poxvirus-encoded cytokine and chemokine binding proteins that serve to undermine the coordination of host immune surveillance. Structural and mechanistic studies of these decoy receptors have provided a wealth of information, not only about viral pathogenesis but also about the inner workings of cytokine signaling networks.

Rodent Herpesvirus Peru Encodes a Secreted Chemokine Decoy Receptor

“…Based on the known mechanisms of viral immune evasion, we hypothesized that R17 may function as a viral decoy that prevents chemokine recruitment of immune cells to sites of infection (8). To address the functional consequences of R17-chemokine interactions, we performed experiments evaluating the migration of the human monocytic cell line THP-1 in response to hCCL2, a fast dissociating R17 ligand (K D,eq ϭ 12 nM, t 1/2 ϭ 2.1 s), and human PBMCs in response to hCCL3, a slow off-rate R17 ligand (K D,eq ϭ 1.4 nM, t 1/2,app Ͼ 1,000 s).…”

“…To function properly, chemokines need to interact with their cognate G protein-coupled receptor as well as glycosaminoglycans (GAGs) on extracellular surfaces where they establish their gradients (9,40). The viral chemokine binding proteins described to date have been shown to interfere with chemokine-GPCR interactions, chemokine-GAG interactions, or both (8). To assess the ability of R17 to block chemokine-GAG interactions, we conducted cell surface binding and competition assays.…”

“…Not surprisingly, these and related factors are favorite targets for viral sabotage (5)(6)(7). An immune evasion strategy commonly employed by large-DNA viruses is based on the secretion of high-affinity binding proteins that act as cytokine scavengers (8,9). Frequently, these decoy receptors correspond to soluble versions of their host cellular counterparts.…”

“…A wide variety of secreted chemokine binding proteins with the ability to subvert chemokine signaling have been identified, including those encoded by schistosoma parasites, bloodsucking ticks, and herpes-and poxviruses (8,9). The M3 protein of MHV68 is abundantly secreted during infection and is capable of promiscuously sequestering members of all four chemokine classes with subnanomolar affinities.…”

A tumour necrosis factor receptor-like protein encoded by Singapore grouper iridovirus modulates cell proliferation, apoptosis and viral replication

“…Large DNA viruses usually encode certain viral products to suppress or delay apoptosis of infected cells until abundant progeny viruses are produced (Cuconati and White, 2002;Meseda et al, 2000). Increasing reports showed that viral TNFR homologues were capable of affecting the cellular TNF/TNFR pathway by regulating the host apoptotic response (Benedict et al TNFRs (vTNFRs) can bind to and inhibit the signalling induced by distinct host TNF super family members (Alejo et al, 2011;Epperson et al, 2012). Moreover, vaccinia virus encoded cytokine response modifier E (CrmE) was demonstrated to protect infected cells from apoptosis induced by TNF-a (Graham et al, 2007).…”