# Host Determinants of Human Metapneumovirus Immunity and Pathogenesis

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $466,434

## Abstract

HMPV is a major cause of lower respiratory infection (LRI) in children worldwide, second only to respiratory
syncytial virus (RSV). Although nearly all people are infected with HMPV during childhood, immunity to HMPV
is incomplete and re-infections occur throughout life. Hospitalization with HMPV is more likely in persons with
underlying conditions such as asthma, chronic obstructive pulmonary disease, HIV, or prematurity. There are
no approved antiviral therapies or vaccines. Host or viral determinants of virulence are not known for HMPV.
One limitation of many prior studies is that most HMPV research uses one of a few lab-adapted strains that
cause minimal disease in mice. We have identified clinical isolates of HMPV that cause severe and fatal
disease in mice, providing tools to elucidate mechanisms of pathogenesis. Our preliminary data show that
virulent HMPV potently induces types I and III interferon (IFN), and that these cytokines exhibit discordant
roles. IFN is critical to initiate and shape adaptive immune responses but can contribute to disease; we aim to
define the contribution of types I and III IFN in HMPV. HMPV inhibits type I IFN responses including STAT1
and STAT2 phosphorylation by an unknown mechanism, and HMPV lacks the paramyxovirus V protein or
NS1/NS2 of RSV. Several HMPV proteins have been implicated, including G, M2-1, P, and SH. Published data
from our group and others suggest SH mediates immune inhibition but a mechanism or specific SH-host
protein interaction is unknown. The contribution of other HMPV proteins to virulence has not been defined.
We propose to use in vitro and in vivo approaches to address these knowledge gaps. In Aim 1, we will define
the contributions of type III IFN (IFN-λ) to HMPV immunity and pathogenesis using global and conditional
knockout mice. Aim 2 proposes to identify the cellular target(s) of SH, define interacting domains, and discover
the molecular mechanisms of innate immune inhibition by HMPV. We will use transient transfection of tagged
mutant SH proteins and viruses with SH mutations in cell and mouse experiments. In Aim 3, will use reverse
genetics developed in the lab to generate chimeric viruses and identify viral protein determinants of virulence
using established mouse models. Our preliminary data suggest an important role for IFN-λ in HMPV immunity,
confirm innate immune inhibition by HMPV SH, and demonstrate the strength of the avirulent and virulent
strains to identify viral determinants of virulence. The results of the proposed research will clarify mechanisms
of HMPV pathogenesis and provide a blueprint for potential therapeutic avenues and strategies for viral
attenuation for vaccines. The findings are likely to be relevant to other respiratory viruses.

## Key facts

- **NIH application ID:** 10893507
- **Project number:** 5R01AI085062-13
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** John V. Williams
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $466,434
- **Award type:** 5
- **Project period:** 2010-06-05 → 2024-10-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893507

## Citation

> US National Institutes of Health, RePORTER application 10893507, Host Determinants of Human Metapneumovirus Immunity and Pathogenesis (5R01AI085062-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10893507. Licensed CC0.

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