Limited nasal IFN production contributes to delayed respiratory virus clearance and suboptimal vaccine responses
Jorna Sojati, … , Monika Johnson, John V. Williams
Jorna Sojati, … , Monika Johnson, John V. Williams
Published September 16, 2025
Citation Information: JCI Insight. 2025;10(20):e182836. https://doi.org/10.1172/jci.insight.182836.
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Research Article Immunology Infectious disease Virology

Limited nasal IFN production contributes to delayed respiratory virus clearance and suboptimal vaccine responses

Abstract

Acute lower respiratory infections are the primary cause of global mortality in postneonatal children. Most respiratory viruses primarily involve upper airway infection and inflammation, yet nasal responses are poorly characterized. Using a mouse model of human metapneumovirus (HMPV), we found viral burden was higher in nasal airways and exhibited delayed clearance. Despite high burden, there was low nasal expression of type I and III interferon (IFN). Single-cell RNA-sequencing (scRNA-Seq) from HMPV-infected mice showed lower nasal IFN-stimulated gene (ISG) expression and nasal enrichment of genes negatively regulating IFN. scRNA-Seq of patients with COVID-19 verified lower ISG expression in upper airways. HMPV infection downregulated nasal expression of IFN regulatory factor 3, suggesting a mechanism for limited response. To rescue the quiescent environment, we administered type I or III IFN to upper airways early postinfection, leading to lower nasal HMPV titer and virus-specific CD8+ T cell upregulation. Intranasal immunization adjuvanted with type I or III IFN improved immune response, reduced clinical disease, and enhanced viral clearance in HMPV and influenza infection. IFN adjuvant increased recruitment of dendritic cells, recruitment of resident memory T cells, and neutralizing antibodies. These findings reveal locally suppressed IFN production contributes to a quiescent nasal immune landscape that delays viral clearance and impairs mucosal vaccine responses.

Authors

Jorna Sojati, Olivia B. Parks, Taylor Eddens, Jie Lan, Monika Johnson, John V. Williams

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Figure 5

Type III IFN treatment of upper airway increases HMPV-specific CD8+ T cell recruitment and enhances viral clearance.

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Type III IFN treatment of upper airway increases HMPV-specific CD8+ T ce...
Mice were first infected with 5 × 105 PFU C2-202 HMPV intratracheally, followed by an intranasal treatment with recombinant mouse IFN-λ (1 μg in 10 μL) on day 1 postinfection (or mock treatment with same volume 0.1% BSA) as shown by schematic (A). Disease was assessed by measuring weight (B) to day 10 postinfection, represented as % of day 0. HMPV titer (PFU/g) was measured in nasal turbinates of mock- or IFN-λ–treated mice on day 7 (C) and 10 (D) postinfection. Limit of detection noted by dashed black line. (D–G) HMPV-infected mice receiving either mock or IFN-λ treatment were euthanized day 7 postinfection, and immune responses were assessed. (D) Frequency of total nasal (left), virus-specific (M94+) (middle), and inhibitory receptor–expressing HMPV-specific CD8+ T cells (right). (E) Frequency of nasal CD8+ T cells expressing CD107a (left) or IFN-γ (right) after 5-hour ex vivo stimulation with HMPV M94 peptide. (F) Frequency of total nasal CD4+ T cells (left) and CD4+ subsets (right) Th1 (% Tbet+ of CD4), Th2 (% GATA3+ of CD4), Th17 (% RORγT+ of CD4), and Treg (% FoxP3+ of CD4). (G) Frequency of EOMES expression (of total CD4, of total CD8, and of total M94-specific CD8). For this experiment 5 mock-treated and 5 mouse IFN-λ-treated mice were used. Analyses by Student’s t test (C–E) or 2-way ANOVA (F and G). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Tim3, T cell immunoglobulin mucin receptor 3; Lag3, lymphocyte activation gene 3.