tetano
Editor, Senior Moderator
Blood. 2019 Feb 5. pii: blood-2018-09-873984. doi: 10.1182/blood-2018-09-873984. [Epub ahead of print]
[h=1]Human megakaryocytes possess intrinsic anti-viral immunity through regulated induction of IFITM3.[/h] Campbell RA[SUP]1[/SUP], Schwertz H[SUP]2[/SUP], Hottz ED[SUP]3[/SUP], Rowley JW[SUP]1[/SUP], Manne BK[SUP]1[/SUP], Washington AV[SUP]4[/SUP], Hunter-Mellado R[SUP]5[/SUP], Tolley ND[SUP]1[/SUP], Christensen M[SUP]6[/SUP], Eustes AS[SUP]1[/SUP], Montenont E[SUP]1[/SUP], Bhatlekar S[SUP]1[/SUP], Ventrone CH[SUP]7[/SUP], Kirkpatrick BD[SUP]7[/SUP], Pierce KK[SUP]7[/SUP], Whitehead SS[SUP]8[/SUP], Diehl SA[SUP]7[/SUP], Bray PF[SUP]1[/SUP], Zimmerman GA[SUP]1[/SUP], Kosaka Y[SUP]1[/SUP], Bozza PT[SUP]3[/SUP], Bozza FA[SUP]3[/SUP], Weyrich AS[SUP]1[/SUP], Rondina MT[SUP]9[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
Copyright ? 2019 American Society of Hematology.
PMID: 30723081 DOI: 10.1182/blood-2018-09-873984
[h=1]Human megakaryocytes possess intrinsic anti-viral immunity through regulated induction of IFITM3.[/h] Campbell RA[SUP]1[/SUP], Schwertz H[SUP]2[/SUP], Hottz ED[SUP]3[/SUP], Rowley JW[SUP]1[/SUP], Manne BK[SUP]1[/SUP], Washington AV[SUP]4[/SUP], Hunter-Mellado R[SUP]5[/SUP], Tolley ND[SUP]1[/SUP], Christensen M[SUP]6[/SUP], Eustes AS[SUP]1[/SUP], Montenont E[SUP]1[/SUP], Bhatlekar S[SUP]1[/SUP], Ventrone CH[SUP]7[/SUP], Kirkpatrick BD[SUP]7[/SUP], Pierce KK[SUP]7[/SUP], Whitehead SS[SUP]8[/SUP], Diehl SA[SUP]7[/SUP], Bray PF[SUP]1[/SUP], Zimmerman GA[SUP]1[/SUP], Kosaka Y[SUP]1[/SUP], Bozza PT[SUP]3[/SUP], Bozza FA[SUP]3[/SUP], Weyrich AS[SUP]1[/SUP], Rondina MT[SUP]9[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
Copyright ? 2019 American Society of Hematology.
PMID: 30723081 DOI: 10.1182/blood-2018-09-873984