title: Cowpox virus employs a two-pronged strategy to outflank MHCI antigen presentation.
abstract: Smallpox decimated humanity for thousands of years before being eradicated by vaccination, a success facilitated by the fact that humans are the only host of variola virus. In contrast, other orthopoxviruses such as cowpox virus can infect a variety of mammalian species, although its dominant reservoir appears to be rodents. This difference in host specificity suggests that cowpox may have developed promiscuous immune evasion strategies to facilitate zoonosis. Recent experiments have established that cowpox can disrupt MHCI antigen presentation during viral infection of both human and murine cells, a process enabled by two unique proteins, CPXV012 and CPXV203. While CPXV012 inhibits antigenic peptide transport from the cytosol to the ER, CPXV203 blocks MHCI trafficking to the cell surface by exploiting the KDEL-receptor recycling pathway. Our recent investigations of CPXV203 reveal that it binds a diverse array of classical and non-classical MHCI proteins with dramatically increased affinities at the lower pH of the Golgi relative to the ER, thereby providing mechanistic insight into how it works synergistically with KDEL receptors to block MHCI surface expression. The strategy used by cowpox to both limit peptide supply and disrupt trafficking of fully assembled MHCI acts as a dual-edged sword that effectively disables adaptive immune surveillance of infected cells.
authors: Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States. mccoyw@wusm.wustl.edu
authors: William H
authors: WH
authors: McCoy
authors: Xiaoli
authors: X
authors: Wang
authors: Wayne M
authors: WM
authors: Yokoyama
authors: Ted H
authors: TH
authors: Hansen
authors: Daved H
authors: DH
authors: Fremont
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D015605:Cowpox / Q000276:immunology*; D015608:Cowpox virus / Q000276:immunology*; D006056:Golgi Apparatus / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D057131:Immune Evasion; D051379:Mice; D017433:Protein Structure, Secondary; D021381:Protein Transport; D018000:Receptors, Peptide / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; C064459:KDEL receptor; D018000:Receptors, Peptide; D014764:Viral Proteins