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 8

T cell–mediated and humoral immunity are both required for improved nasal HMPV vaccine response with IFN adjuvant.

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T cell–mediated and humoral immunity are both required for improved nasa...
Mice were immunized as described in Figure 6A with low-dose HMPV (UR-HMPV) in either a B cell–deficient model of muMt- (muMT) mice (A) or a T cell–deficient model with neutralizing CD4+ and CD8+ antibody depletion (B). IgG isotype control antibody was used as a negative control. HMPV titer (PFU/g) was measured in lungs (C) and nasal turbinates (D) of immunized mice day 5 postinfection. Limit of detection noted by dashed black line. (E) Disease was assessed by measuring body weight to day 5 postinfection, represented as % of day 0. ***P < 0.001, ****P < 0.0001 for T cell–deficient immunized mice versus other groups. ###P < 0.001, ####P < 0.0001 for B cell–deficient immunized mice versus other groups. (F–H) Mice received HMPV immunization adjuvanted with IFN-λ or IFN-β as previously described, in a T cell–deficient model (orange), or in a B cell–deficient model (blue). HMPV titer (PFU/g) was measured in lungs (F) and nasal turbinates (G) of IFN-adjuvanted immunized mice day 5 postinfection. Limit of detection noted by dashed black line. (H) Disease was assessed by measuring body weight to day 5 postinfection, represented as % of day 0. **P < 0.01, ****P < 0.0001 for B cell–deficient groups versus other groups. #P < 0.05, ##P < 0.01, ####P < 0.0001 for IFN-λ–adjuvanted T cell–deficient mice versus other IFN-adjuvanted immunized mice groups. Analyses by 1-way or 2-way ANOVA. **P < 0.01, ***P < 0.001, ****P < 0.0001.