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Blood. 2019 Feb 5. pii: blood-2018-09-873984. doi: 10.1182/blood-2018-09-873984. [Epub ahead of print]

Human megakaryocytes possess intrinsic anti-viral immunity through regulated induction of IFITM3.

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University of Utah Molecular Medicine Program, Salt Lake City, UT, United States.
Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States.
Instituto Nacional de Infectologia Evandro Chagas (INI), Fundacao Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil.
University of Puerto Rico-Rio Piedras, Department of Biology, Puerto Rico.
Department of Internal Medicine, Universidad Central del Caribe, Bayamon, Puerto Rico.
University of Utah, Salt Lake City, UT, United States.
Vaccine Testing Center and Department of Microbiology and Molecular Genetics, University of Vermont Larner College of Medicine, Burlington, VT, United States.
National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States.
University of Utah Molecular Medicine Program, Salt Lake City, UT, United States;


Evolving evidence indicates that platelets and megakaryocytes (MKs) have unexpected activities in inflammation and infection; but whether viral infections upregulate biologically active, anti-viral immune genes in platelets and MKs is unknown. We examined anti-viral 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 anti-viral 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 (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 (IFNs) 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 SNP in areas of the world where DENV is endemic) were significantly more susceptible to DENV infection. DENV-induced MK secretion of IFNs prevented infection of bystander MKs and hematopoietic stem cells (HSCs). 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 anti-viral functions, preventing DENV infection of MKs and HSCs following local immune signaling.

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