Comparative Biochemical and Functional Analysis of Viral and Human Secreted Tumor Necrosis Factor (TNF) Decoy Receptors.
The blockade of tumor necrosis factor (TNF) by etanercept, a soluble version of the human TNF receptor 2 (hTNFR2), is a well established strategy to inhibit adverse TNF-mediated inflammatory responses in the clinic. A similar strategy is employed by poxviruses, encoding four viral TNF decoy receptor homologues (vTNFRs) named cytokine response modifier B (CrmB), CrmC, CrmD, and CrmE. These vTNFRs are differentially expressed by poxviral species, suggesting distinct immunomodulatory properties. Whereas the human variola virus and mouse ectromelia virus encode one vTNFR, the broad host range cowpox virus encodes all vTNFRs. We report the first comprehensive study of the functional and binding properties of these four vTNFRs, providing an explanation for their expression profile among different poxviruses. In addition, the vTNFRs activities were compared with the hTNFR2 used in the clinic. Interestingly, CrmB from variola virus, the causative agent of smallpox, is the most potent TNFR of those tested here including hTNFR2. Furthermore, we demonstrate a new immunomodulatory activity of vTNFRs, showing that CrmB and CrmD also inhibit the activity of lymphotoxin β. Similarly, we report for the first time that the hTNFR2 blocks the biological activity of lymphotoxin β. The characterization of vTNFRs optimized during virus-host evolution to modulate the host immune response provides relevant information about their potential role in pathogenesis and may be used to improve anti-inflammatory therapies based on soluble decoy TNFRs.
From the Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain and.
Sergio M
SM
Pontejo
Centro de Investigacion en Sanidad Animal, Instituto Nacional de Investigacion y Tecnologia Agraria y Alimentaria, Valdeolmos, 28130 Madrid, Spain.
Ali
A
Alejo
From the Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain and aalcami@cbm.csic.es.
Antonio
A
Alcami
D000595:Amino Acid Sequence; D000818:Animals; D015608:Cowpox virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053308:Lymphotoxin-beta / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011212:Poxviridae / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D053319:Tumor Necrosis Factor Decoy Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D053308:Lymphotoxin-beta; D047889:Receptors, Tumor Necrosis Factor, Type II; C415902:TNFRSF1B protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D048069:Tumor Necrosis Factors; D014764:Viral Proteins
TNF ligand superfamily; etanercept; immune evasion; inflammation; poxvirus; receptor; tumor necrosis factor (TNF); vTNFR; virus