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HUMAN MEGAKARYOCYTES POSSESS INTRINSIC ANTIVIRAL IMMUNITY THROUGH REGULATED INDUCTION OF IFITM3
Campbell, Robert A. et al. | Date Issued: 2019
Author
Campbell, Robert A.
Schwertz, Hansjorg
Hottz, Eugenio D.
Rowley, Jesse W.
Manne, Bhanu Kanth
Washington, A. Valance
Hunter-Mellado, Robert
Tolley, Neal D.
Christensen, Miles
Eustes, Alicia S.
Montenont, Emilie
Bhatlekar, Seema
Ventrone, Cassandra H.
Kirkpatrick, Beth D.
Pierce, Kristen K.
Whitehead, Stephen S.
Diehl, Sean A.
Bray, Paul F.
Zimmerman, Guy A.
Kosaka, Yasuhiro
Bozza, Patrícia T.
Bozza, Fernando A.
Weyrich, Andrew S.
Rondina, Matthew T.
Affilliation
University of Utah Molecular Medicine Program. Salt Lake City, UT, USA / University of Utah. Department of Internal Medicine. Salt Lake City, UT, USA.
University of Utah Molecular Medicine Program. Salt Lake City, UT, USA / University of Utah. Rocky Mountain Center for Occupational and Environmental Health. Salt Lake City, UT, USA.
University of Utah Molecular Medicine Program. Salt Lake City, UT, USA / Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.
University of Utah Molecular Medicine Program. Salt Lake City, UT, USA / University of Utah. Department of Internal Medicine. Salt Lake City, UT, USA.
University of Utah Molecular Medicine Program. Salt Lake City, UT, USA.
University of Puerto Rico–Rio Piedras. Departmento of Biology. San Juan, Porto Rico / Universidad Central del Caribe. Department of Internal Medicine. Bayamon, Puerto Rico.
University of Puerto Rico–Rio Piedras. Departmento of Biology. San Juan, Porto Rico / Universidad Central del Caribe. Department of Internal Medicine. Bayamon, Puerto Rico.
University of Utah Molecular Medicine Program. Salt Lake City, UT, USA.
University of Utah. Department of Internal Medicine. Salt Lake City, UT, USA.
University of Utah Molecular Medicine Program. Salt Lake City, UT, USA.
University of Utah Molecular Medicine Program. Salt Lake City, UT, USA.
University of Utah Molecular Medicine Program. Salt Lake City, UT, USA.
University of Vermont Larner College of Medicine. Department of Microbiology and Molecular Genetics. Vaccine Testing Center. Burlington, VT, USA.
University of Vermont Larner College of Medicine. Department of Microbiology and Molecular Genetics. Vaccine Testing Center. Burlington, VT, USA.
University of Vermont Larner College of Medicine. Department of Microbiology and Molecular Genetics. Vaccine Testing Center. Burlington, VT, USA.
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Bethesda, MD, USA.
University of Vermont Larner College of Medicine. Department of Microbiology and Molecular Genetics. Vaccine Testing Center. Burlington, VT, USA.
University of Utah Molecular Medicine Program. Salt Lake City, UT, USA / University of Utah. Department of Internal Medicine. Salt Lake City, UT, USA.
University of Utah Molecular Medicine Program. Salt Lake City, UT, USA / University of Utah. Department of Internal Medicine. Salt Lake City, UT, USA.
University of Utah Molecular Medicine Program. Salt Lake City, UT, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil / Instituto D’Or de Pesquisa e Ensino. Rio de Janeiro, RJ, Brasil.
University of Utah Molecular Medicine Program. Salt Lake City, UT, USA / University of Utah. Department of Internal Medicine. Salt Lake City, UT, USA.
University of Utah Molecular Medicine Program. Salt Lake City, UT, USA / University of Utah. Department of Internal Medicine. Salt Lake City, UT, USA / George E. Wahlen Veterans Affairs Medical Center and Geriatric Research, Education, and Clinical Center. Department of Internal Medicine. Salt Lake City, UT, USA.
Abstract
Evolving evidence indicates that platelets and megakaryocytes (MKs) have unexpected activities in inflammation and infection; whether viral infections upregulate biologically active, antiviral immune genes in platelets and MKs is unknown, however. We examined antiviral immune genes in these cells in dengue and influenza infections, viruses that are global public health threats. Using complementary biochemical, pharmacological, and genetic approaches, we examined the regulation and function of interferon-induced transmembrane protein 3 (IFITM3), an antiviral immune effector gene not previously studied in human platelets and MKs. IFITM3 was markedly upregulated in platelets isolated from patients during clinical influenza and dengue virus (DENV) infections. Lower IFITM3 expression in platelets correlated with increased illness severity and mortality in patients. Administering a live, attenuated DENV vaccine to healthy subjects significantly increased platelet IFITM3 expression. Infecting human MKs with DENV selectively increased type I interferons and IFITM3. Overexpression of IFITM3 in MKs was sufficient to prevent DENV infection. In naturally occurring, genetic loss-of-function studies, MKs from healthy subjects harboring a homozygous mutation in IFITM3 (rs12252-C, a common single-nucleotide polymorphism in areas of the world where DENV is endemic) were significantly more susceptible to DENV infection. DENV-induced MK secretion of interferons prevented infection of bystander MKs and hematopoietic stem cells. Thus, viral infections upregulate IFITM3 in human platelets and MKs, and IFITM3 expression is associated with adverse clinical outcomes. These observations establish, for the first time, that human MKs possess antiviral functions, preventing DENV infection of MKs and hematopoietic stem cells after local immune signaling.
Keywords in Portuguese
Megacariócitos humanos
Antivirais intrínsecos
Imunidade antiviral
Indução regulada
IFITM3
 
Keywords
Human megakaryocytes
Intrinsic antiviral immunity
Regulated induction
IFITM3
 
Publisher
American Society of Hematology
Citation
CAMPBELL, Robert A. et al. Human megakaryocytes possess intrinsic antiviral immunity through regulated induction of IFITM3. Blood, v. 133, n. 19, p. 2013-2026, May 2019.
DOI
10.1182/blood-2018-09-873984
ISSN
0006-4971