# Cell-specific restriction of influenza A virus assembly

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $227,440

## Abstract

Project Summary/Abstract
The influenza A virus continues to be a major cause of morbidity and mortality worldwide despite
implementation of vaccines and a few antiviral drugs. Our long-term goal is to determine the molecular
mechanisms regulating assembly and spread of influenza A virus, which potentially serve as new targets for
antivirals. In the current proposal, our objective is to determine the mechanism that gives rise to the cell type-
specific differences in infectious virus assembly. The Influenza A virus can infect macrophages, but
macrophages are much less permissive than airway epithelial cells. Our preliminary studies showed that
infectious titer release from human primary monocyte-derived macrophages (MDMs) is severely impaired
relative to differentiated THP-1, a human monocytic cell line. Using correlative fluorescence and scanning
microscopy further revealed that efficient assembly of virus particles at the plasma membrane is detectable in
differentiated THP-1 but not in MDMs even though both differentiated THP-1 and primary MDM express viral
structural proteins at the cell surface to the same extent. The expression levels of total viral RNA and proteins
are also similar. These results indicate that assembly of progeny virus particles is highly inefficient in human
primary macrophages. Interestingly, we observed that influenza transmembrane proteins HA and M2, both of
which plays key roles in virus assembly and release, fail to come in close proximity of each other in MDMs but
not in differentiated THP-1 or epithelial cells and that this restriction in MDMs is reversed upon disruption of
actin cytoskeleton. Based on these and other preliminary results, in this proposal we plan to test our central
hypothesis that actin cytoskeletons restrict influenza A virus assembly via modulation of viral protein
distribution at the plasma membrane in a cell-dependent manner. We will first identify viral structural proteins
that render the virus susceptible to this inhibition of HA-M2 association (Aim 1). Then, we will determine the
cellular mechanism that contributes to this inhibition (Aim 2). The rationale behind focusing on cell-specific
differences in influenza virus assembly and release is to facilitate identification of cellular mechanisms that
support or inhibit influenza virus propagation. Once identified, such mechanisms may serve as potential targets
for therapeutic modulation designed to block virus spread in the respiratory epithelial cells.

## Key facts

- **NIH application ID:** 9833492
- **Project number:** 5R21AI143276-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Akira Ono
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $227,440
- **Award type:** 5
- **Project period:** 2018-12-07 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9833492

## Citation

> US National Institutes of Health, RePORTER application 9833492, Cell-specific restriction of influenza A virus assembly (5R21AI143276-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9833492. Licensed CC0.

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