Abstract
Tumour necrosis factor (TNF) is an inflammatory cytokine produced in response to viral infections that promotes the recruitment and activation of leukocytes to sites of infection. This TNF-based host response is essential to limit virus spreading, thus poxviruses have evolutionarily adopted diverse molecular mechanisms to counteract TNF antiviral action. These include the expression of poxvirus-encoded soluble receptors or proteins able to bind and neutralize TNF and other members of the TNF ligand superfamily, acting as decoy receptors. This article reviews in detail the various TNF decoy receptors identified to date in the genomes from different poxvirus species, with a special focus on their impact on poxvirus pathogenesis and their potential use as therapeutic molecules.
Highlights
Campus de Cantoblanco, Universidad Autónoma de Madrid, Nicolás Cabrera 1, 28049 Madrid, Spain; Abstract: Tumour necrosis factor (TNF) is an inflammatory cytokine produced in response to viral infections that promotes the recruitment and activation of leukocytes to sites of infection
Whereas sTNF binds preferentially to the ubiquitous TNFR1, tmTNF is the main activating ligand for TNFR2, which is only expressed in certain endothelial and immune cell types [8]. Both cell surface TNF receptor (TNFR) are type I membrane glycoproteins and similar in their extracellular domains involved in ligand binding, which comprise four cysteine-rich domains (CRDs), each of them containing about 40 residues including six conserved cysteines involved in the formation of internal disulfide bridges
Regarding LTα, both cytokine response modifier B (CrmB) and CrmD are able to interact with human LTα and murine LTα, but CrmB shows higher affinity for the human ligand while CrmD prefers the murine one, supporting again the hypothesis that variola virus (VARV) and ectromelia virus (ECTV)
Summary
TNF is a potent pro-inflammatory cytokine with a broad range of biological effects, ranging from the activation of inflammatory gene programs to cell differentiation or apoptosis induction while playing an essential role in the host control of many viral infections [1,2]. Whereas sTNF binds preferentially to the ubiquitous TNFR1 ( known as p55/p60), tmTNF is the main activating ligand for TNFR2 ( known as p75/p80), which is only expressed in certain endothelial and immune cell types [8] Both cell surface TNFRs are type I membrane glycoproteins and similar in their extracellular domains involved in ligand binding, which comprise four cysteine-rich domains (CRDs), each of them containing about 40 residues including six conserved cysteines involved in the formation of internal disulfide bridges. The intracellular part of TNFR2 does not contain a death domain and promotes cell survival after TNF binding through recruitment of TNF receptor-associated proteins (TRAF) that trigger activation of transcription factor nuclear factor-kB (NF-kB). TNF pro-survival action required for cell proliferation or differentiation can be executed either through TNFR1 or TNFR2, while TNF-mediated cell death mainly occurs through TNFR1 signalling (Figure 1)
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