# Influenza D Virus Entry and Tissue Tropism

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2021 · $518,267

## Abstract

PROJECT SUMMARY
 Novel influenza D virus (IDV) utilizes bovines as a primary reservoir with periodical spillover to
other mammalian hosts including pigs and horses. Of greater public health importance, serological
evidence of IDV infections in humans has been demonstrated. Preliminary investigations have revealed
that IDV binds to human 9-O-acetylated N-acetylneuraminic acid (Neu5,9Ac2), the receptor of human
influenza C virus (ICV), and non-human N-glycolylneuraminic acid (Neu5Gc9Ac) and likely utilizes
them for viral entry. Further functional studies indicate that IDV is more efficient in recognizing both
human Neu5,9Ac2- and non-human Neu5Gc9Ac-containing glycans than ICV, and ICV seems to
preferentially bind to human Neu5,9Ac2 over non-human Neu5Gc9Ac. In agreement with this, ICV has
a limited host range with humans as a reservoir. These results suggest that IDV and ICV diverge in
communicating with sialic acids (SA) for infection. The hypothesis is that subtle differences in the
sequence and structure of the receptor-binding pocket residing in the hemagglutinin-esterase-fusion
(HEF) protein between IDV and ICV cause substantial differences in the virus-receptor interaction,
which can expand or reduce, or change tissue and species tropisms. Furthermore, the recent
observation on the extracellular resistance of IDV to low pH inactivation versus the intracellular
requirement of low pH for viral entry suggests a novel entry/fusion mechanism by which IDV employs
to deliver its genome into the target cell. Three aims are proposed to address these hypotheses in this
R01 application, which involve a comparative study of IDV and ICV. Aim 1 will elucidate the entry
mechanism of IDV, while Aim 2 will define the molecular basis of the HEF receptor binding affinity and
specificity and its impact on IDV tropism. Aim 3 is deigned to address how two IDV lineages, swine and
bovine, read the glycan receptors differentially and how this information is transduced to different
tissue and species tropisms between these two groups of IDVs. In summary, this proposal leverages the
team's expertise in IDV research and novel aspects of IDV-receptor interaction and entry to elucidate
the cross-species transmission mechanism of IDVs. Understanding molecular details of virus-receptor
interaction may lead to development of novel strategies for the control and prevention of IDV and ICV
infections in humans.

## Key facts

- **NIH application ID:** 10240750
- **Project number:** 5R01AI141889-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** FENG LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $518,267
- **Award type:** 5
- **Project period:** 2018-09-21 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240750

## Citation

> US National Institutes of Health, RePORTER application 10240750, Influenza D Virus Entry and Tissue Tropism (5R01AI141889-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10240750. Licensed CC0.

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