Subversion of cytokine networks by virally encoded decoy receptors

Abstract

During the course of evolution, viruses have captured or created a diverse array of open reading frames, which encode for proteins that serve to evade and sabotage the host innate and adaptive immune responses that 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.

Fig. 1. Viral decoy receptor inhibition of chemokines

Herpesviruses and poxviruses encode chemokine binding proteins (vCKBPs) that sequester chemokines and block their biological function. vCCI and Evm1 block chemokine-receptor interactions. A41, E163, and the SECRET domain inhibit the ability of chemokines to interact with cell surface GAGs. M3 blocks both. EHV/BHV gG blocks both receptor and GAG interactions. HSV gG blocks GAG interactions. pUL21.5 blocks hCCL5 receptor interaction. The structures of viral CKBPs are shown in ribbon, while the chemokines structures are represented by molecular surface. The proteins whose structures are not known are shown as cartoons. Molecular surface of chemokines colored in shades of red have been solved in complex with the viral protein while chemokines in neutral shade have been modeled in for illustration purposes. PDB codes for the structures are as follows: M3-hCCL2 complex (2NZI), GAG (1HPN), vCCI-hCCL4 (2FFK), SECRET-hCX3CL1 (3ONA), Evm1 (2GRK), and A41 (2VGA).

Fig. 2. Structural mimicry of chemokine receptor and GAG interactions by viral decoys

(A) Herpesvirus M3 engages both receptor binding and GAG binding epitopes on hCCL2 or hXCL1 chemokines. (B) The NMR solution structure of vCCI in complex with hCCL4 outlines the overlap between the vCCI chemokine binding site and the receptor interaction region. (C) The footprint of the SECRET domain of poxviral protein CrmD on hCX3CL1 points to inhibition of chemokine-GAG interactions as the likely mechanism for chemokine inhibition. The SECRET domain contacts this chemokine using the opposite face, or β sheet I instead of β sheet II, which is utilized by all other characterized vCKBPs. PDB codes for the structures are as follows: M3-hCCL2 (2NZI), M-hXCL1 (2NYZ), vC-hCCL4 (2FFK), SECRET-hCX3CL1 (3ONA).

Fig. 3. Viral decoy receptor inhibition of TNF

Poxviruses encode multiple proteins that inhibit TNF. Orthopoxviruses and leporipoxviruses encode for vTNFRs that resemble the extracellular domain of host TNFRs. Yatapoxviruses encode for a TNFbp that resembles MHC class I heavy chain. The 2L, CrmC, and CrmE decoys are specific TNFα inhibitors, while CrmB and CrmD are able to inhibit both TNFα as well as LTα. vCD30 inhibits receptor binding to CD30L and signals through CD30L. Inhibition of TNF cytokines blocks downstream signaling cascades. For each component of this figure, structures that are known are represented by a ribbon (receptors), or surface representation (cytokines) of the solved structure, while molecules whose structures are still unknown are represented by a cartoon illustration. PDB codes for the structures are as follows: TNFR2-TNFα, TNFR1-LTα (1TNR), TNFα (2TNF), 2L-TNFα (3IT8), CrmE (2UWI), CrmD SECRET (3ON9).

Fig. 4. Viral decoy receptor inhibition of the IL-1 family

Poxviruses encode many proteins to inhibit members of the IL-1 family of cytokines, specifically IL- 1β and IL-18. In the extracellular milieu, viral IL-1βR and viral IL-18bp prevent cytokine recognition by their respective host receptors. Inhibition of the IL-1 family interferes with IFNγ secretion and thus activation of NK, T, and B cells. For each component of this figure, structures that are known are represented by a ribbon (receptors), or surface representation of the solved structure (cytokines), while molecules whose structures are still unknown are represented by a cartoon illustration. IL-1RacP has been separately modeled in next to IL-1R1 and IL-1R2 for better viewing. PDB codes for the structures are as follows: IL-1β (1ITB), IL-1R2-IL-1β (3O4O), IL-1R1 signaling complex (4DEP), IL-1RA (1ILR), and vIL-18bp-IL-18 (3F62).

Fig. 5. Viral decoy receptor inhibition of IFNs

Poxviruses encode for secreted IFNbps that bind to Type I, II, or III IFNs and prevent recognition by host receptors. Inhibition of IFNs prevents activation of the JAK/STAT pathway and thus the establishment of an antiviral state. Yaba136 has been shown to inhibit both Type I and Type III IFNS, while vIFNα/βbps such as B18R or EVM166 have been shown to inhibit only Type I IFNs. Additionally, the vIFNα/βbp is positioned near the cell surface, as these proteins have been shown to bind to the surface of cells. For each component of this figure, structures that are known are represented by a ribbon (receptors), or surface representation of the solved structure (cytokines), while molecules whose structures are still unknown are represented by a cartoon illustration. PDB codes for the structures are as follows: IFNλR1-IFNλ (3OG6), IL-10R2 (3O4O), IFNAR1/2-IFNα2 (3SE3), IFNγR1-IFNγ (1FG9), and vIFNγbp:IFNγ complex.