Patients With Natural Killer (NK) Cell Chronic Active Epstein-Barr Virus Have Immature NK Cells and Hyperactivation of PI3K/Akt/mTOR and STAT1 Pathways.
Identifieur interne : 000074 ( Main/Exploration ); précédent : 000073; suivant : 000075Patients With Natural Killer (NK) Cell Chronic Active Epstein-Barr Virus Have Immature NK Cells and Hyperactivation of PI3K/Akt/mTOR and STAT1 Pathways.
Auteurs : Matthew K. Howe [États-Unis] ; Kennichi Dowdell [États-Unis] ; Hye Sun Kuehn [États-Unis] ; Qingxue Li [États-Unis] ; Geoffrey T. Hart [États-Unis] ; Doreen Garabedian [États-Unis] ; Kelly Liepshutz [États-Unis] ; Amy P. Hsu [États-Unis] ; Hua Su [États-Unis] ; Julie E. Niemela [États-Unis] ; Jennifer L. Stoddard [États-Unis] ; Gulbu Uzel [États-Unis] ; Evan Shereck [États-Unis] ; Laura Schulz [États-Unis] ; Tatyana Feldman [États-Unis] ; Sergio D. Rosenzweig [États-Unis] ; Eric O. Long [États-Unis] ; Lesia Dropulic [États-Unis] ; Jeffrey I. Cohen [États-Unis]Source :
- The Journal of infectious diseases [ 1537-6613 ] ; 2020.
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.
DOI: 10.1093/infdis/jiaa232
PubMed: 32386415
PubMed Central: PMC7459139
Affiliations:
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Howe</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Dowdell, Kennichi" sort="Dowdell, Kennichi" uniqKey="Dowdell K" first="Kennichi" last="Dowdell">Kennichi Dowdell</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Kuehn, Hye Sun" sort="Kuehn, Hye Sun" uniqKey="Kuehn H" first="Hye Sun" last="Kuehn">Hye Sun Kuehn</name><affiliation wicri:level="2"><nlm:affiliation>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Li, Qingxue" sort="Li, Qingxue" uniqKey="Li Q" first="Qingxue" last="Li">Qingxue Li</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Hart, Geoffrey T" sort="Hart, Geoffrey T" uniqKey="Hart G" first="Geoffrey T" last="Hart">Geoffrey T. 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Hsu</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Su, Hua" sort="Su, Hua" uniqKey="Su H" first="Hua" last="Su">Hua Su</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Niemela, Julie E" sort="Niemela, Julie E" uniqKey="Niemela J" first="Julie E" last="Niemela">Julie E. Niemela</name><affiliation wicri:level="2"><nlm:affiliation>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Stoddard, Jennifer L" sort="Stoddard, Jennifer L" uniqKey="Stoddard J" first="Jennifer L" last="Stoddard">Jennifer L. Stoddard</name><affiliation wicri:level="2"><nlm:affiliation>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Uzel, Gulbu" sort="Uzel, Gulbu" uniqKey="Uzel G" first="Gulbu" last="Uzel">Gulbu Uzel</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Shereck, Evan" sort="Shereck, Evan" uniqKey="Shereck E" first="Evan" last="Shereck">Evan Shereck</name><affiliation wicri:level="2"><nlm:affiliation>Doembecker Children's Hospital, Oregon Health and Science University, Portland, Oregon, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Doembecker Children's Hospital, Oregon Health and Science University, Portland, Oregon</wicri:regionArea><placeName><region type="state">Oregon</region></placeName></affiliation></author><author><name sortKey="Schulz, Laura" sort="Schulz, Laura" uniqKey="Schulz L" first="Laura" last="Schulz">Laura Schulz</name><affiliation wicri:level="2"><nlm:affiliation>Pediatric Hematology and Oncology, Providence Alaska Medical Center, Anchorage, Alaska, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pediatric Hematology and Oncology, Providence Alaska Medical Center, Anchorage, Alaska</wicri:regionArea><placeName><region type="state">Alaska</region></placeName></affiliation></author><author><name sortKey="Feldman, Tatyana" sort="Feldman, Tatyana" uniqKey="Feldman T" first="Tatyana" last="Feldman">Tatyana Feldman</name><affiliation wicri:level="2"><nlm:affiliation>John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Rosenzweig, Sergio D" sort="Rosenzweig, Sergio D" uniqKey="Rosenzweig S" first="Sergio D" last="Rosenzweig">Sergio D. Rosenzweig</name><affiliation wicri:level="2"><nlm:affiliation>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Long, Eric O" sort="Long, Eric O" uniqKey="Long E" first="Eric O" last="Long">Eric O. Long</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Dropulic, Lesia" sort="Dropulic, Lesia" uniqKey="Dropulic L" first="Lesia" last="Dropulic">Lesia Dropulic</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Cohen, Jeffrey I" sort="Cohen, Jeffrey I" uniqKey="Cohen J" first="Jeffrey I" last="Cohen">Jeffrey I. Cohen</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32386415</idno><idno type="pmid">32386415</idno><idno type="doi">10.1093/infdis/jiaa232</idno><idno type="pmc">PMC7459139</idno><idno type="wicri:Area/Main/Corpus">000077</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000077</idno><idno type="wicri:Area/Main/Curation">000077</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000077</idno><idno type="wicri:Area/Main/Exploration">000077</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Patients With Natural Killer (NK) Cell Chronic Active Epstein-Barr Virus Have Immature NK Cells and Hyperactivation of PI3K/Akt/mTOR and STAT1 Pathways.</title><author><name sortKey="Howe, Matthew K" sort="Howe, Matthew K" uniqKey="Howe M" first="Matthew K" last="Howe">Matthew K. Howe</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Dowdell, Kennichi" sort="Dowdell, Kennichi" uniqKey="Dowdell K" first="Kennichi" last="Dowdell">Kennichi Dowdell</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Kuehn, Hye Sun" sort="Kuehn, Hye Sun" uniqKey="Kuehn H" first="Hye Sun" last="Kuehn">Hye Sun Kuehn</name><affiliation wicri:level="2"><nlm:affiliation>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Li, Qingxue" sort="Li, Qingxue" uniqKey="Li Q" first="Qingxue" last="Li">Qingxue Li</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Hart, Geoffrey T" sort="Hart, Geoffrey T" uniqKey="Hart G" first="Geoffrey T" last="Hart">Geoffrey T. Hart</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Garabedian, Doreen" sort="Garabedian, Doreen" uniqKey="Garabedian D" first="Doreen" last="Garabedian">Doreen Garabedian</name><affiliation wicri:level="2"><nlm:affiliation>Leidos Biomedical Research, Inc, Frederick National Laboratory, Frederick, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Leidos Biomedical Research, Inc, Frederick National Laboratory, Frederick, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Liepshutz, Kelly" sort="Liepshutz, Kelly" uniqKey="Liepshutz K" first="Kelly" last="Liepshutz">Kelly Liepshutz</name><affiliation wicri:level="2"><nlm:affiliation>Leidos Biomedical Research, Inc, Frederick National Laboratory, Frederick, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Leidos Biomedical Research, Inc, Frederick National Laboratory, Frederick, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Hsu, Amy P" sort="Hsu, Amy P" uniqKey="Hsu A" first="Amy P" last="Hsu">Amy P. Hsu</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Su, Hua" sort="Su, Hua" uniqKey="Su H" first="Hua" last="Su">Hua Su</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Niemela, Julie E" sort="Niemela, Julie E" uniqKey="Niemela J" first="Julie E" last="Niemela">Julie E. Niemela</name><affiliation wicri:level="2"><nlm:affiliation>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Stoddard, Jennifer L" sort="Stoddard, Jennifer L" uniqKey="Stoddard J" first="Jennifer L" last="Stoddard">Jennifer L. Stoddard</name><affiliation wicri:level="2"><nlm:affiliation>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Uzel, Gulbu" sort="Uzel, Gulbu" uniqKey="Uzel G" first="Gulbu" last="Uzel">Gulbu Uzel</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Shereck, Evan" sort="Shereck, Evan" uniqKey="Shereck E" first="Evan" last="Shereck">Evan Shereck</name><affiliation wicri:level="2"><nlm:affiliation>Doembecker Children's Hospital, Oregon Health and Science University, Portland, Oregon, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Doembecker Children's Hospital, Oregon Health and Science University, Portland, Oregon</wicri:regionArea><placeName><region type="state">Oregon</region></placeName></affiliation></author><author><name sortKey="Schulz, Laura" sort="Schulz, Laura" uniqKey="Schulz L" first="Laura" last="Schulz">Laura Schulz</name><affiliation wicri:level="2"><nlm:affiliation>Pediatric Hematology and Oncology, Providence Alaska Medical Center, Anchorage, Alaska, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pediatric Hematology and Oncology, Providence Alaska Medical Center, Anchorage, Alaska</wicri:regionArea><placeName><region type="state">Alaska</region></placeName></affiliation></author><author><name sortKey="Feldman, Tatyana" sort="Feldman, Tatyana" uniqKey="Feldman T" first="Tatyana" last="Feldman">Tatyana Feldman</name><affiliation wicri:level="2"><nlm:affiliation>John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author><author><name sortKey="Rosenzweig, Sergio D" sort="Rosenzweig, Sergio D" uniqKey="Rosenzweig S" first="Sergio D" last="Rosenzweig">Sergio D. Rosenzweig</name><affiliation wicri:level="2"><nlm:affiliation>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Long, Eric O" sort="Long, Eric O" uniqKey="Long E" first="Eric O" last="Long">Eric O. Long</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Dropulic, Lesia" sort="Dropulic, Lesia" uniqKey="Dropulic L" first="Lesia" last="Dropulic">Lesia Dropulic</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Cohen, Jeffrey I" sort="Cohen, Jeffrey I" uniqKey="Cohen J" first="Jeffrey I" last="Cohen">Jeffrey I. Cohen</name><affiliation wicri:level="2"><nlm:affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author></analytic><series><title level="j">The Journal of infectious diseases</title><idno type="eISSN">1537-6613</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><b>BACKGROUND</b></p><p>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.</p></div><div type="abstract" xml:lang="en"><p><b>METHODS</b></p><p>We evaluated 2 patients with natural killer (NK) cell CAEBV and studied their NK cell phenotype and signaling pathways in cells.</p></div><div type="abstract" xml:lang="en"><p><b>RESULTS</b></p><p>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.</p></div><div type="abstract" xml:lang="en"><p><b>CONCLUSIONS</b></p><p>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.</p></div></front></TEI><pubmed><MedlineCitation Status="In-Data-Review" Owner="NLM"><PMID Version="1">32386415</PMID><DateRevised><Year>2020</Year><Month>09</Month><Day>04</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1537-6613</ISSN><JournalIssue CitedMedium="Internet"><Volume>222</Volume><Issue>7</Issue><PubDate><Year>2020</Year><Month>Sep</Month><Day>01</Day></PubDate></JournalIssue><Title>The Journal of infectious diseases</Title><ISOAbbreviation>J Infect Dis</ISOAbbreviation></Journal><ArticleTitle>Patients With Natural Killer (NK) Cell Chronic Active Epstein-Barr Virus Have Immature NK Cells and Hyperactivation of PI3K/Akt/mTOR and STAT1 Pathways.</ArticleTitle><Pagination><MedlinePgn>1170-1179</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1093/infdis/jiaa232</ELocationID><Abstract><AbstractText Label="BACKGROUND" NlmCategory="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.</AbstractText><AbstractText Label="METHODS" NlmCategory="METHODS">We evaluated 2 patients with natural killer (NK) cell CAEBV and studied their NK cell phenotype and signaling pathways in cells.</AbstractText><AbstractText Label="RESULTS" NlmCategory="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.</AbstractText><AbstractText Label="CONCLUSIONS" NlmCategory="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.</AbstractText><CopyrightInformation>Published by Oxford University Press for the Infectious Diseases Society of America 2020.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Howe</LastName><ForeName>Matthew K</ForeName><Initials>MK</Initials><AffiliationInfo><Affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dowdell</LastName><ForeName>Kennichi</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kuehn</LastName><ForeName>Hye Sun</ForeName><Initials>HS</Initials><AffiliationInfo><Affiliation>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Qingxue</ForeName><Initials>Q</Initials><AffiliationInfo><Affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hart</LastName><ForeName>Geoffrey T</ForeName><Initials>GT</Initials><AffiliationInfo><Affiliation>Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Garabedian</LastName><ForeName>Doreen</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Leidos Biomedical Research, Inc, Frederick National Laboratory, Frederick, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liepshutz</LastName><ForeName>Kelly</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Leidos Biomedical Research, Inc, Frederick National Laboratory, Frederick, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hsu</LastName><ForeName>Amy P</ForeName><Initials>AP</Initials><AffiliationInfo><Affiliation>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Su</LastName><ForeName>Hua</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Niemela</LastName><ForeName>Julie E</ForeName><Initials>JE</Initials><AffiliationInfo><Affiliation>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Stoddard</LastName><ForeName>Jennifer L</ForeName><Initials>JL</Initials><AffiliationInfo><Affiliation>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Uzel</LastName><ForeName>Gulbu</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shereck</LastName><ForeName>Evan</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Doembecker Children's Hospital, Oregon Health and Science University, Portland, Oregon, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schulz</LastName><ForeName>Laura</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Pediatric Hematology and Oncology, Providence Alaska Medical Center, Anchorage, Alaska, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Feldman</LastName><ForeName>Tatyana</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rosenzweig</LastName><ForeName>Sergio D</ForeName><Initials>SD</Initials><AffiliationInfo><Affiliation>Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Long</LastName><ForeName>Eric O</ForeName><Initials>EO</Initials><AffiliationInfo><Affiliation>Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dropulic</LastName><ForeName>Lesia</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cohen</LastName><ForeName>Jeffrey I</ForeName><Initials>JI</Initials><AffiliationInfo><Affiliation>Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Infect Dis</MedlineTA><NlmUniqueID>0413675</NlmUniqueID><ISSNLinking>0022-1899</ISSNLinking></MedlineJournalInfo><CitationSubset>AIM</CitationSubset><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Akt</Keyword><Keyword MajorTopicYN="N">Epstein-Barr virus</Keyword><Keyword MajorTopicYN="N">NK cells</Keyword><Keyword MajorTopicYN="N">STAT1</Keyword><Keyword MajorTopicYN="N">chronic active EBV</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2019</Year><Month>11</Month><Day>10</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>05</Month><Day>05</Day></PubMedPubDate><PubMedPubDate 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Howe</name></region><name sortKey="Cohen, Jeffrey I" sort="Cohen, Jeffrey I" uniqKey="Cohen J" first="Jeffrey I" last="Cohen">Jeffrey I. Cohen</name><name sortKey="Dowdell, Kennichi" sort="Dowdell, Kennichi" uniqKey="Dowdell K" first="Kennichi" last="Dowdell">Kennichi Dowdell</name><name sortKey="Dropulic, Lesia" sort="Dropulic, Lesia" uniqKey="Dropulic L" first="Lesia" last="Dropulic">Lesia Dropulic</name><name sortKey="Feldman, Tatyana" sort="Feldman, Tatyana" uniqKey="Feldman T" first="Tatyana" last="Feldman">Tatyana Feldman</name><name sortKey="Garabedian, Doreen" sort="Garabedian, Doreen" uniqKey="Garabedian D" first="Doreen" last="Garabedian">Doreen Garabedian</name><name sortKey="Hart, Geoffrey T" sort="Hart, Geoffrey T" uniqKey="Hart G" first="Geoffrey T" last="Hart">Geoffrey T. Hart</name><name sortKey="Hsu, Amy P" sort="Hsu, Amy P" uniqKey="Hsu A" first="Amy P" last="Hsu">Amy P. Hsu</name><name sortKey="Kuehn, Hye Sun" sort="Kuehn, Hye Sun" uniqKey="Kuehn H" first="Hye Sun" last="Kuehn">Hye Sun Kuehn</name><name sortKey="Li, Qingxue" sort="Li, Qingxue" uniqKey="Li Q" first="Qingxue" last="Li">Qingxue Li</name><name sortKey="Liepshutz, Kelly" sort="Liepshutz, Kelly" uniqKey="Liepshutz K" first="Kelly" last="Liepshutz">Kelly Liepshutz</name><name sortKey="Long, Eric O" sort="Long, Eric O" uniqKey="Long E" first="Eric O" last="Long">Eric O. Long</name><name sortKey="Niemela, Julie E" sort="Niemela, Julie E" uniqKey="Niemela J" first="Julie E" last="Niemela">Julie E. Niemela</name><name sortKey="Rosenzweig, Sergio D" sort="Rosenzweig, Sergio D" uniqKey="Rosenzweig S" first="Sergio D" last="Rosenzweig">Sergio D. Rosenzweig</name><name sortKey="Schulz, Laura" sort="Schulz, Laura" uniqKey="Schulz L" first="Laura" last="Schulz">Laura Schulz</name><name sortKey="Shereck, Evan" sort="Shereck, Evan" uniqKey="Shereck E" first="Evan" last="Shereck">Evan Shereck</name><name sortKey="Stoddard, Jennifer L" sort="Stoddard, Jennifer L" uniqKey="Stoddard J" first="Jennifer L" last="Stoddard">Jennifer L. Stoddard</name><name sortKey="Su, Hua" sort="Su, Hua" uniqKey="Su H" first="Hua" last="Su">Hua Su</name><name sortKey="Uzel, Gulbu" sort="Uzel, Gulbu" uniqKey="Uzel G" first="Gulbu" last="Uzel">Gulbu Uzel</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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