Platelets are emerging as dynamic and versatile immune effector cells that mediate host responses to respiratory viral infections, including influenza. In the elderly, influenza infections are common and cause substantial morbidity and mortality. Our grant, entitled """"""""Platelet Immune Responses in Aging and Influenza"""""""" will examine age-related changes in newly-discovered platelet immune proteins and how impaired responses contribute to adverse clinical outcomes. This family of proteins, the interferon-induced transmembrane proteins (IFITMs), prevents influenza viral replication and infectivity. IFITM family members have not previously been described in human platelets.
Our specific aims and hypotheses are based on a rich pool of preliminary data demonstrating that platelets from older adults have diminished expression of IFITMs during influenza infection and following influenza vaccination. We also found that the inability to upregulate IFITM protein expression correlates with an increased risk of influenza-related mortality. In our preliminary studies, there is evidenc that expression of IFITM occurs at transcriptional and post-transcriptional checkpoints in platelet precursors (e.g., megakaryocytes) and mature platelets. In this application, we will determine, in settings of influenza infection and following influenza vaccination, whether aging alters the induction of IFITM proteins in human platelets. We will also establish whether age-related impairments in IFITM induction contribute to influenza-related illness severity and mortality. Moreover, we will dissect the mechanisms and patterns of IFITM expression in human platelets and model megakaryocytes derived from young and older human subjects. While we will investigate IFITM family members in detail, we will also use deep RNA-sequencing (RNA-seq) to identify other candidate immunomodulatory genes in platelets and megakaryocytes that are altered in older adults. Candidates identified by RNA-seq will be examined in-depth at the message, protein, and/or activity level. These investigations are the first studies to characterize IFITMs in megakaryocytes and platelets. As our investigations will be accomplished using human subjects and primary human cells, our findings will have immediate clinical relevance. Our multi-disciplinary team unites young and senior investigators, clinicians, and basic scientists. All techniques and tools are established and in place and we have proven track records of paradigm-shifting, bench-to-bedside discovery research. Thus, we are poised to determine how aging alters immune sensing by platelets and megakaryocytes and define new mechanisms regulating influenza-induced platelet immune responses in the elderly.

Public Health Relevance

Older adults are at the highest risk of influenza infection and related complications. Age-related changes in platelets, underappreciated immune cells, contribute to this risk but remain largely unexamined. Our investigations will identify new mechanisms and pathways of age-related impairments in platelet immune responses. Our findings will contribute to the improved prevention and treatment of influenza in the elderly.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZAI1-LAR-I (S1))
Program Officer
Fuldner, Rebecca A
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University of Utah
Internal Medicine/Medicine
Schools of Medicine
Salt Lake City
United States
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Yost, Christian C; Schwertz, Hansjörg; Cody, Mark J et al. (2016) Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation. J Clin Invest 126:3783-3798
Brown, Samuel M; Sorensen, Jeffrey; Lanspa, Michael J et al. (2016) Multi-complexity measures of heart rate variability and the effect of vasopressor titration: a prospective cohort study of patients with septic shock. BMC Infect Dis 16:551
Koliopoulou, Antigone; McKellar, Stephen H; Rondina, Matthew et al. (2016) Bleeding and thrombosis in chronic ventricular assist device therapy: focus on platelets. Curr Opin Cardiol 31:299-307
Rondina, Matthew T; Weyrich, Andrew S (2016) Arf6 arbitrates fibrinogen endocytosis. Blood 127:1383-4
Stubblefield, William B; Alves, Nathan J; Rondina, Matthew T et al. (2016) Variable Resistance to Plasminogen Activator Initiated Fibrinolysis for Intermediate-Risk Pulmonary Embolism. PLoS One 11:e0148747
Shih, Lauren; Kaplan, David; Kraiss, Larry W et al. (2016) Platelet-Monocyte Aggregates and C-Reactive Protein are Associated with VTE in Older Surgical Patients. Sci Rep 6:27478
Kaplan, David; Rondina, Matthew T (2016) Response. Chest 149:1107-8
Rondina, Matthew T; Tatsumi, Kohei; Bastarache, Julie A et al. (2016) Microvesicle Tissue Factor Activity and Interleukin-8 Levels are Associated with Mortality in Patients with Influenza A/H1N1 Infection. Crit Care Med 44:e574-8
Rondina, M T; Weyrich, A S (2015) Regulation of the genetic code in megakaryocytes and platelets. J Thromb Haemost 13 Suppl 1:S26-32
Buitrago, Lorena; Rendon, Augusto; Liang, Yupu et al. (2015) αIIbβ3 variants defined by next-generation sequencing: predicting variants likely to cause Glanzmann thrombasthenia. Proc Natl Acad Sci U S A 112:E1898-907

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