Matthew K Howe1, Kennichi Dowdell1, Hye Sun Kuehn2, Qingxue Li1, Geoffrey T Hart3, Doreen Garabedian4, Kelly Liepshutz4, Amy P Hsu5, Hua Su5, Julie E Niemela2, Jennifer L Stoddard2, Gulbu Uzel5, Evan Shereck6, Laura Schulz7, Tatyana Feldman8, Sergio D Rosenzweig2, Eric O Long3, Lesia Dropulic1, Jeffrey I Cohen1. 1. Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. 2. Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA. 3. Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA. 4. Leidos Biomedical Research, Inc, Frederick National Laboratory, Frederick, Maryland, USA. 5. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. 6. Doembecker Children's Hospital, Oregon Health and Science University, Portland, Oregon, USA. 7. Pediatric Hematology and Oncology, Providence Alaska Medical Center, Anchorage, Alaska, USA. 8. John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey, USA.
Abstract
BACKGROUND: Chronic active Epstein-Barr virus (CAEBV) presents with high levels of viral genomes in blood and tissue infiltration with Epstein-Barr virus (EBV)-positive lymphocytes. The pathogenesis of CAEBV is poorly understood. METHODS: We evaluated 2 patients with natural killer (NK) cell CAEBV and studied their NK cell phenotype and signaling pathways in cells. RESULTS: Both patients had increased numbers of NK cells, EBV predominantly in NK cells, and immature NK cells in the blood. Both patients had increased phosphorylation of Akt, S6, and STAT1 in NK cells, and increased total STAT1. Treatment of 1 patient with sirolimus reduced phosphorylation of S6 in T and B cells, but not in NK cells and did not reduce levels of NK cells or EBV DNA in the blood. Treatment of both patients' cells with JAK inhibitors in vitro reduced phosphorylated STAT1 to normal. Patients with T- or B-cell CAEBV had increased phosphorylation of Akt and S6 in NK cells, but no increase in total STAT1. CONCLUSIONS: The increase in phosphorylated Akt, S6, and STAT1, as well as immature NK cells describe a new phenotype for NK cell CAEBV. The reduction of STAT1 phosphorylation in their NK cells with JAK inhibitors suggests a novel approach to therapy. Published by Oxford University Press for the Infectious Diseases Society of America 2020.
BACKGROUND: Chronic active Epstein-Barr virus (CAEBV) presents with high levels of viral genomes in blood and tissue infiltration with Epstein-Barr virus (EBV)-positive lymphocytes. The pathogenesis of CAEBV is poorly understood. METHODS: We evaluated 2 patients with natural killer (NK) cell CAEBV and studied their NK cell phenotype and signaling pathways in cells. RESULTS: Both patients had increased numbers of NK cells, EBV predominantly in NK cells, and immature NK cells in the blood. Both patients had increased phosphorylation of Akt, S6, and STAT1 in NK cells, and increased total STAT1. Treatment of 1 patient with sirolimus reduced phosphorylation of S6 in T and B cells, but not in NK cells and did not reduce levels of NK cells or EBV DNA in the blood. Treatment of both patients' cells with JAK inhibitors in vitro reduced phosphorylated STAT1 to normal. Patients with T- or B-cell CAEBV had increased phosphorylation of Akt and S6 in NK cells, but no increase in total STAT1. CONCLUSIONS: The increase in phosphorylated Akt, S6, and STAT1, as well as immature NK cells describe a new phenotype for NK cell CAEBV. The reduction of STAT1 phosphorylation in their NK cells with JAK inhibitors suggests a novel approach to therapy. Published by Oxford University Press for the Infectious Diseases Society of America 2020.
Entities:
Keywords:
Akt; Epstein-Barr virus; NK cells; STAT1; chronic active EBV
Authors: Katja G Weinacht; Louis-Marie Charbonnier; Fayhan Alroqi; Ashley Plant; Qi Qiao; Hao Wu; Clement Ma; Troy R Torgerson; Sergio D Rosenzweig; Thomas A Fleisher; Luigi D Notarangelo; Imelda C Hanson; Lisa R Forbes; Talal A Chatila Journal: J Allergy Clin Immunol Date: 2017-01-27 Impact factor: 10.793
Authors: Jeffrey I Cohen; Elaine S Jaffe; Janet K Dale; Stefania Pittaluga; Helen E Heslop; Cliona M Rooney; Stephen Gottschalk; Catherine M Bollard; V Koneti Rao; Adriana Marques; Peter D Burbelo; Siu-Ping Turk; Rachael Fulton; Alan S Wayne; Richard F Little; Mitchell S Cairo; Nader K El-Mallawany; Daniel Fowler; Claude Sportes; Michael R Bishop; Wyndham Wilson; Stephen E Straus Journal: Blood Date: 2011-03-31 Impact factor: 22.113
Authors: Gulbu Uzel; Elizabeth P Sampaio; Monica G Lawrence; Amy P Hsu; Mary Hackett; Morna J Dorsey; Richard J Noel; James W Verbsky; Alexandra F Freeman; Erin Janssen; Francisco A Bonilla; Joseph Pechacek; Prabha Chandrasekaran; Sarah K Browne; Anahita Agharahimi; Ahmed M Gharib; Sara C Mannurita; Jae Joon Yim; Eleonora Gambineri; Troy Torgerson; Dat Q Tran; Joshua D Milner; Steven M Holland Journal: J Allergy Clin Immunol Date: 2013-03-25 Impact factor: 10.793
Authors: Lies Boelen; Bisrat Debebe; Marcos Silveira; Arafa Salam; Julia Makinde; Chrissy H Roberts; Eddie C Y Wang; John Frater; Jill Gilmour; Katie Twigger; Kristin Ladell; Kelly L Miners; Jyothi Jayaraman; James A Traherne; David A Price; Ying Qi; Maureen P Martin; Derek C Macallan; Chloe L Thio; Jacquie Astemborski; Gregory Kirk; Sharyne M Donfield; Susan Buchbinder; Salim I Khakoo; James J Goedert; John Trowsdale; Mary Carrington; Simon Kollnberger; Becca Asquith Journal: Sci Immunol Date: 2018-11-09
Authors: Ivan Angulo; Oscar Vadas; Fabien Garçon; Edward Banham-Hall; Vincent Plagnol; Timothy R Leahy; Helen Baxendale; Tanya Coulter; James Curtis; Changxin Wu; Katherine Blake-Palmer; Olga Perisic; Deborah Smyth; Mailis Maes; Christine Fiddler; Jatinder Juss; Deirdre Cilliers; Gašper Markelj; Anita Chandra; George Farmer; Anna Kielkowska; Jonathan Clark; Sven Kracker; Marianne Debré; Capucine Picard; Isabelle Pellier; Nada Jabado; James A Morris; Gabriela Barcenas-Morales; Alain Fischer; Len Stephens; Phillip Hawkins; Jeffrey C Barrett; Mario Abinun; Menna Clatworthy; Anne Durandy; Rainer Doffinger; Edwin R Chilvers; Andrew J Cant; Dinakantha Kumararatne; Klaus Okkenhaug; Roger L Williams; Alison Condliffe; Sergey Nejentsev Journal: Science Date: 2013-10-17 Impact factor: 47.728