# Host Factors Required by Human Parainfluenza Virus 3: Determinants of entry and viral spread

> **NIH NIH F31** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $48,974

## Abstract

Project Summary
Human parainfluenza viruses (HPIV) cause significant lower respiratory diseases, including croup, bronchiolitis,
and pneumonia, that lead to illness or death in millions of infants and young children worldwide. Viral infection is
initiated when the viral fusion complex, comprised of the surface glycoproteins HN (receptor-binding protein;
hemagglutinin-neuraminidase) and F (fusion protein), mediates fusion upon HN engaging sialic acid receptor.
Bound-HN triggers F to undergo conformational rearrangements that promote viral entry when F is sufficiently
close to insert into the host membrane. To mediate fusion, the fusion protein precursor (F0) must first be cleaved
by host proteases into its active form. F0 cleavage has been thought to be executed intracellularly by the
ubiquitously expressed furin, because F0 contains a dibasic cleavage site. However, the sponsor’s laboratory
found that the dibasic cleavage site underlying the assumption is an artifact of laboratory adaptation, whereas
circulating strains of HPIV3 have a monobasic cleavage site that is cut by an unidentified extracellular protease
in the lung. F0 cleavage by extracellular proteases opens the possibility that catalytic activation of F may be
delayed until a target cell is reached, thereby enabling the fusion protein to remain in a more stable uncleaved
state until reaching specific protease expressing target cells. The goal of this proposal is to identify the
proteases required for HPIV3 spread in the human lung and novel mechanisms by which the virus exploits these
proteases to selectively target cells, proliferate in the respiratory system, and survive host-to-host transmission.
Aim 1 will identify host proteases that are necessary for circulating HPIV3 F0 cleavage and assess the impact
of their expression on viral tropism in authentic lung models.
Aim 2 will determine how the timing of F cleavage affects fusion efficiency, and how a delay in F cleavage until
the time of infection may enable virions to evade inactivation of the viral fusion machinery by host factors during
traversal of the human respiratory tract.
The proposed project employs an array of cell biological, biochemical, and imaging techniques to apply
complementary, yet independent approaches for understanding critical host protease determinants of HPIV3
infectivity and novel viral mechanisms for maintaining fusion protein functionality. The breadth of approaches will
contribute to the project’s scientific rigor, since each question will be answered in several different ways, and
provide technical and theoretical learning opportunities. By the time of completion, this project will have identified
F cleaving proteases, characterized the role of cleavage in regulating F activity, and explored the broader
implications of F0 for viral evasion of virucidal host factors, like mucins. Data gleaned from these studies will
clarify an essential step of HPIV life cycles and our overall understanding of the HN-F...

## Key facts

- **NIH application ID:** 10824958
- **Project number:** 1F31AI176760-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Kyle Stearns
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-03-06 → 2026-03-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824958

## Citation

> US National Institutes of Health, RePORTER application 10824958, Host Factors Required by Human Parainfluenza Virus 3: Determinants of entry and viral spread (1F31AI176760-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10824958. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*