Patients With Natural Killer (NK) Cell Chronic Active Epstein-Barr Virus Have Immature NK Cells and Hyperactivation of PI3K/Akt/mTOR and STAT1 Pathways

Matthew K Howe; Kennichi Dowdell; Hye Sun Kuehn; Qingxue Li; Geoffrey T Hart; Doreen Garabedian; Kelly Liepshutz; Amy P Hsu; Hua Su; Julie E Niemela; Jennifer L Stoddard; Gulbu Uzel; Evan Shereck; Laura Schulz; Tatyana Feldman; Sergio D Rosenzweig; Eric O Long; Lesia Dropulic; Jeffrey I Cohen

doi:10.1093/infdis/jiaa232

Patients With Natural Killer (NK) Cell Chronic Active Epstein-Barr Virus Have Immature NK Cells and Hyperactivation of PI3K/Akt/mTOR and STAT1 Pathways

Matthew K Howe, Kennichi Dowdell, Hye Sun Kuehn, Qingxue Li, Geoffrey T Hart, Doreen Garabedian, Kelly Liepshutz, Amy P Hsu, Hua Su, Julie E Niemela, Jennifer L Stoddard, Gulbu Uzel, Evan Shereck, Laura Schulz, Tatyana Feldman, Sergio D Rosenzweig, Eric O Long, Lesia Dropulic, Jeffrey I Cohen

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1170-1179
Number of pages	10
Journal	The Journal of infectious diseases
Volume	222
Issue number	7
DOIs	https://doi.org/10.1093/infdis/jiaa232
State	Published - Oct 1 2020

Bibliographical note

Funding Information:
This work was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases and the NIH Clinical Center.

Publisher Copyright:
© Published by Oxford University Press for the Infectious Diseases Society of America 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Keywords

Akt
Chronic active EBV
Epstein-Barr virus
NK cells
STAT1

PubMed: MeSH publication types

Case Reports
Journal Article
Observational Study
Research Support, N.I.H., Intramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/infdis/jiaa232

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Howe, M. K., Dowdell, K., Kuehn, H. S., Li, Q., Hart, G. T., Garabedian, D., Liepshutz, K., Hsu, A. P., Su, H., Niemela, J. E., Stoddard, J. L., Uzel, G., Shereck, E., Schulz, L., Feldman, T., Rosenzweig, S. D., Long, E. O., Dropulic, L., & Cohen, J. I. (2020). Patients With Natural Killer (NK) Cell Chronic Active Epstein-Barr Virus Have Immature NK Cells and Hyperactivation of PI3K/Akt/mTOR and STAT1 Pathways. The Journal of infectious diseases, 222(7), 1170-1179. https://doi.org/10.1093/infdis/jiaa232

Howe, MK, Dowdell, K, Kuehn, HS, Li, Q, Hart, GT, Garabedian, D, Liepshutz, K, Hsu, AP, Su, H, Niemela, JE, Stoddard, JL, Uzel, G, Shereck, E, Schulz, L, Feldman, T, Rosenzweig, SD, Long, EO, Dropulic, L & Cohen, JI 2020, 'Patients With Natural Killer (NK) Cell Chronic Active Epstein-Barr Virus Have Immature NK Cells and Hyperactivation of PI3K/Akt/mTOR and STAT1 Pathways', The Journal of infectious diseases, vol. 222, no. 7, pp. 1170-1179. https://doi.org/10.1093/infdis/jiaa232

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title = "Patients With Natural Killer (NK) Cell Chronic Active Epstein-Barr Virus Have Immature NK Cells and Hyperactivation of PI3K/Akt/mTOR and STAT1 Pathways",

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.",

keywords = "Akt, Chronic active EBV, Epstein-Barr virus, NK cells, STAT1",

author = "Howe, {Matthew K} and Kennichi Dowdell and Kuehn, {Hye Sun} and Qingxue Li and Hart, {Geoffrey T} and Doreen Garabedian and Kelly Liepshutz and Hsu, {Amy P} and Hua Su and Niemela, {Julie E} and Stoddard, {Jennifer L} and Gulbu Uzel and Evan Shereck and Laura Schulz and Tatyana Feldman and Rosenzweig, {Sergio D} and Long, {Eric O} and Lesia Dropulic and Cohen, {Jeffrey I}",

note = "Funding Information: This work was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases and the NIH Clinical Center. Publisher Copyright: {\textcopyright} Published by Oxford University Press for the Infectious Diseases Society of America 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.",

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T1 - Patients With Natural Killer (NK) Cell Chronic Active Epstein-Barr Virus Have Immature NK Cells and Hyperactivation of PI3K/Akt/mTOR and STAT1 Pathways

AU - Howe, Matthew K

AU - Dowdell, Kennichi

AU - Kuehn, Hye Sun

AU - Li, Qingxue

AU - Hart, Geoffrey T

AU - Garabedian, Doreen

AU - Liepshutz, Kelly

AU - Hsu, Amy P

AU - Su, Hua

AU - Niemela, Julie E

AU - Stoddard, Jennifer L

AU - Uzel, Gulbu

AU - Shereck, Evan

AU - Schulz, Laura

AU - Feldman, Tatyana

AU - Rosenzweig, Sergio D

AU - Long, Eric O

AU - Dropulic, Lesia

AU - Cohen, Jeffrey I

N1 - Funding Information: This work was supported by the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases and the NIH Clinical Center. Publisher Copyright: © Published by Oxford University Press for the Infectious Diseases Society of America 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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.

AB - 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.

KW - Akt

KW - Chronic active EBV

KW - Epstein-Barr virus

KW - NK cells

KW - STAT1

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DO - 10.1093/infdis/jiaa232

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JO - The Journal of infectious diseases

JF - The Journal of infectious diseases

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Patients With Natural Killer (NK) Cell Chronic Active Epstein-Barr Virus Have Immature NK Cells and Hyperactivation of PI3K/Akt/mTOR and STAT1 Pathways

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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