Platelet Immune Responses in Aging and Influenza

描述（由申请人提供）：血小板是一种动态和多功能的免疫效应细胞，介导宿主对呼吸道病毒感染（包括流感）的反应。在老年人中，流感感染很常见，并导致大量发病率和死亡率。我们的拨款题为“衰老和流感中的血小板免疫反应”，将研究新发现的血小板免疫蛋白的年龄相关变化，以及受损的反应如何导致不良的临床结果。这个蛋白家族，干扰素诱导的跨膜蛋白（IFITMs），可以阻止流感病毒的复制和传染性。IFITM家族成员以前未在人类血小板中被描述。我们的具体目标和假设是基于丰富的初步数据，这些数据表明，在流感感染期间和流感疫苗接种后，老年人的血小板中ifitm的表达减少。我们还发现，无法上调IFITM蛋白表达与流感相关死亡风险增加相关。在我们的初步研究中，有证据表明IFITM的表达发生在血小板的转录和转录后检查点

DESCRIPTION (provided by applicant): 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.