Dynamic Co-evolution of Host and Pathogen: HCMV Downregulates the Prevalent Allele MICA∗008 to Escape Elimination by NK Cells
Einat Seidel,
Vu Thuy Khanh Le,
Yotam Bar-On,
Pinchas Tsukerman,
Jonatan Enk,
Rachel Yamin,
Natan Stein,
Dominik Schmiedel,
Esther Oiknine Djian,
Yiska Weisblum,
Boaz Tirosh,
Peter Stastny,
Dana G. Wolf,
Hartmut Hengel,
Ofer Mandelboim
Affiliations
Einat Seidel
The Lautenberg Center for General and Tumor Immunology, The Faculty of Medicine, The Hebrew University Medical School, IMRIC, Jerusalem 9112001, Israel
Vu Thuy Khanh Le
Institute for Virology of the University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
Yotam Bar-On
The Lautenberg Center for General and Tumor Immunology, The Faculty of Medicine, The Hebrew University Medical School, IMRIC, Jerusalem 9112001, Israel
Pinchas Tsukerman
The Lautenberg Center for General and Tumor Immunology, The Faculty of Medicine, The Hebrew University Medical School, IMRIC, Jerusalem 9112001, Israel
Jonatan Enk
The Lautenberg Center for General and Tumor Immunology, The Faculty of Medicine, The Hebrew University Medical School, IMRIC, Jerusalem 9112001, Israel
Rachel Yamin
The Lautenberg Center for General and Tumor Immunology, The Faculty of Medicine, The Hebrew University Medical School, IMRIC, Jerusalem 9112001, Israel
Natan Stein
The Lautenberg Center for General and Tumor Immunology, The Faculty of Medicine, The Hebrew University Medical School, IMRIC, Jerusalem 9112001, Israel
Dominik Schmiedel
The Lautenberg Center for General and Tumor Immunology, The Faculty of Medicine, The Hebrew University Medical School, IMRIC, Jerusalem 9112001, Israel
Esther Oiknine Djian
Clinical Virology Unit, Hadassah Hebrew University Medical Center and Department of Biochemistry and the Chanock Center for Virology, IMRIC, Jerusalem 9112001, Israel
Yiska Weisblum
Clinical Virology Unit, Hadassah Hebrew University Medical Center and Department of Biochemistry and the Chanock Center for Virology, IMRIC, Jerusalem 9112001, Israel
Boaz Tirosh
The Institute for Drug Research, Hebrew University Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, Israel
Peter Stastny
Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390-8886, USA
Dana G. Wolf
Clinical Virology Unit, Hadassah Hebrew University Medical Center and Department of Biochemistry and the Chanock Center for Virology, IMRIC, Jerusalem 9112001, Israel
Hartmut Hengel
Institute of Virology, University Medical Center, Albert-Ludwigs-University Freiburg, Hermann-Herder Strasse 11, Freiburg 79104, Germany
Ofer Mandelboim
The Lautenberg Center for General and Tumor Immunology, The Faculty of Medicine, The Hebrew University Medical School, IMRIC, Jerusalem 9112001, Israel
Natural killer (NK) cells mediate innate immune responses against hazardous cells and are particularly important for the control of human cytomegalovirus (HCMV). NKG2D is a key NK activating receptor that recognizes a family of stress-induced ligands, including MICA, MICB, and ULBP1-6. Notably, most of these ligands are targeted by HCMV proteins and a miRNA to prevent the killing of infected cells by NK cells. A particular highly prevalent MICA allele, MICA∗008, is considered to be an HCMV-resistant “escape variant” that confers advantage to human NK cells in recognizing infected cells. However, here we show that HCMV uses its viral glycoprotein US9 to specifically target MICA∗008 and thus escapes NKG2D attack. The finding that HCMV evolved a protein dedicated to countering a single host allele illustrates the dynamic co-evolution of host and pathogen.
