# Mechanisms of platelet reprogramming during influenza infection

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $418,750

## Abstract

PROJECT SUMMARY
 Influenza infection increases the incidence of acute MI (AMI) within the first 7 days after detection and
the therapeutic benefit of vaccination is comparable to current therapies for secondary prevention of AMI.
Platelets are the blood component central to thrombosis and uncontrolled platelet activation is a major contributor
to unstable coronary syndromes and AMI. Although thrombotic events have been associated with some viral
infections, the molecular mechanisms underlining platelet mediated thrombosis during progression of global viral
infection such as influenza have not been established. The major objective of this proposal is to examine the
role of a previously undescribed molecular mechanism in platelets that leads to sensing of influenza and
ultimately increased thrombosis. The mechanism of reference involves a cytoplasmic receptor known as the
retinoic acid-inducible gene-I (RIG-I) receptor and its downstream signaling cascade. Preliminary results show
that RIG-I and proteins related to RIG-I molecular signaling become specifically upregulated in platelets from
influenza infected patients. Since platelets are anucleated the upregulated expression of RIG-I suggests direct
involvement of their precursors the megakaryocytes (MKs) during infection. For that purpose, we will also study
the contribution of RIG-I in MKs to platelet reprogramming toward more efficient viral response that may lead to
thrombosis. Considering that the RIG-I-signaling axis is present in platelets and specifically upregulated, we
hypothesize that during infection, platelets sense influenza through the RIG-I signaling axis leading to their
activation and MKs reprogram platelets toward an increased antiviral and thrombotic response. Thus, we
propose two specific aims of research: Aim 1. To determine the expression and activity of the RIG-I axis in
platelets with respect to their antiviral and/or thrombotic responses; and Aim 2. To characterize how MKs sense
influenza and how this sensing subsequently reprograms the RIG-I/MAVS pathway, leading to enhanced
expression of antiviral and prothrombotic genes. Building upon novel observations obtained in preliminary
studies, our proposed research plan will determine the role of a previously unknown signaling pathway in
platelets, RIG-I/MAVS, in mediating influenza antiviral and thrombotic responses. The outcome of this proposal
will define the fundamental mechanisms of platelet viral cytosolic signaling, MK response to infection, how this
synergistic response contributes to immunity and thrombosis, and how targeting this pathway could ameliorate
thrombotic and infectious disease pathologies.

## Key facts

- **NIH application ID:** 10451515
- **Project number:** 5R01HL153235-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Milka Koupenova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451515

## Citation

> US National Institutes of Health, RePORTER application 10451515, Mechanisms of platelet reprogramming during influenza infection (5R01HL153235-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10451515. Licensed CC0.

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