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Sepsis Alters the Transcriptional and Translational Landscape of Human and Murine Platelets

Elizabeth A Middleton, Jesse W Rowley, Robert A. Campbell, Colin K Grissom, Samuel M Brown, Sarah J Beesley, Hansjörg Schwertz, Yasuhiro Kosaka, Bhanu Kanth Manne, Krystin Krauel, Neal D. Tolley, Alicia S Eustes, Li Guo, Robert Paine III, Estelle Harris, Guy A. Zimmerman, Andrew S Weyrich and Matthew T. Rondina

Key Points

  • 1) Sepsis triggers transcriptional and translational alterations in platelets.

  • 2) Sepsis-induced upregulation of ITGA2B predicts mortality.

Abstract

There is increasing recognition that platelets have a functional role in the pathophysiology of sepsis though it has not been precisely defined. Whether sepsis alters the human platelet transcriptome and translational landscape has never been established. We utilized parallel techniques of RNA-sequencing and ribosome footprint profiling to interrogate the platelet transcriptome and translatome in septic patients and healthy donors. We identified 1,806 significantly differentially expressed (FDR<0.05) transcripts in platelets from septic patients. Platelet translational events during sepsis were also upregulated. To explore relevance of a murine model of sepsis, cecal ligation and puncture (CLP), we compared sepsis-induced changes in platelet gene expression between septic patients and mice subjected to CLP. Platelet transcriptional (rho=0.42, p=3.2x10-285) and translational (0.65, p=1.09x10-56) changes were significantly correlated between septic patients and mice. We focused on ITGA2B, tracking and validating the expression, regulation, and functional impact of changes in ITGA2B during sepsis. Increased ITGA2B was identified in bone marrow megakaryocytes within 24 hours of sepsis onset. Subsequent increases in ITGA2B were seen in circulating platelets, suggesting dynamic trafficking of the mRNA. Transcriptional changes in ITGA2B were accompanied by de novo protein synthesis of aIIb and integrin aIIbb3 activation. Increased aIIb was associated with mortality in humans and mice. These findings provide previously unrecognized evidence that human and murine sepsis similarly alters the platelet transcriptional and translational landscape. Moreover, ITGA2B is upregulated and functional in sepsis due to trafficking from megakaryocytes and de novo synthesis in platelets, and is associated with increased mortality.

  • Submitted January 31, 2019.
  • Revision received July 30, 2019.
  • Accepted July 10, 2019.