Interferon-λ inhibits immunopathology and boosts T cell–mediated immunity in a mouse model of mucosal viral infection
Emily Feng, Alexa Mansour, Elizabeth Balint, Alyssa Mark, Sofia Tramonte, Jonathan K. Monteiro, Madison Read, Marie Joe Adaimy, Zhou Xing, Matthias Mack, Sergei V. Kotenko, Deanna M. Santer, Ali A. Ashkar
Emily Feng, Alexa Mansour, Elizabeth Balint, Alyssa Mark, Sofia Tramonte, Jonathan K. Monteiro, Madison Read, Marie Joe Adaimy, Zhou Xing, Matthias Mack, Sergei V. Kotenko, Deanna M. Santer, Ali A. Ashkar
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Research Article Immunology Infectious disease Inflammation

Interferon-λ inhibits immunopathology and boosts T cell–mediated immunity in a mouse model of mucosal viral infection

Abstract

Interferon lambda (IFN-λ) has emerged as a critical inducer of immune regulation in addition to its mucosal antiviral properties. However, the cellular and molecular mechanisms that govern its dual role during viral infections remain unclear. Here, we discovered that mucosal delivery of IFN-λ abrogates the herpes simplex virus type 2–induced (HSV-2-induced) vaginal tissue pathology observed in the absence of type I IFN signaling, through drastically inhibiting IL-6 production. At the same time, we demonstrated that IFN-λ rescued local production of CD4+ T cell–dependent IFN-γ, which is essential for protection against the development of toxic megacolon following genital HSV-2 infection. Mechanistically, we found that IFN-λ enhances the differentiation of CCR2+Ly6Chi cells into monocyte-derived antigen-presenting cells, thereby boosting T cell responses. In vivo depletion of CCR2+ cells abrogated this phenomenon. Together, these findings suggest that IFN-λ orchestrates a potent antiviral response, inhibiting hyperinflammatory responses while selectively augmenting effector T cell function. This study positions IFN-λ as a promising therapeutic candidate for enhancing local antiviral immunity and offers new insights into the regulation of immune responses in the context of mucosal viral infections.

Authors

Emily Feng, Alexa Mansour, Elizabeth Balint, Alyssa Mark, Sofia Tramonte, Jonathan K. Monteiro, Madison Read, Marie Joe Adaimy, Zhou Xing, Matthias Mack, Sergei V. Kotenko, Deanna M. Santer, Ali A. Ashkar

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Figure 1

IFN-λ treatment inhibits tissue pathology and viral dissemination and promotes viral clearance.

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IFN-λ treatment inhibits tissue pathology and viral dissemination and pr...
(A) Ifnar–/– mice were infected with 103 PFU HSV-2 333 and administered PBS or IFN-λ (n = 8, 11). Data representative of 2 pooled experiments. (B) Survival rates between PBS- and IFN-λ–treated mice. (C) Viral titers in vaginal washes. (D–J) Ifnar–/– mice were infected with 104 PFU HSV-2 strain 333 and administered PBS or IFN-λ. Data representative of 2 independent experiments. (D) Representative vaginal histology 3 DPI. Scale bars: 5 ×, 100 μm; 10 ×, 200 μm, respectively. (E) Percentage epithelial loss (n = 8, 9). (F) Pathology score. (G) Viral titers in vaginal washes 3 DPI. (H) IL-6 levels in vaginal washes (n = 10, 9). (I) IFN-γ levels in vaginal washes (n = 5, 5). mice. (J) Representative distal colon images and rates of toxic megacolon 5 DPI, pooled from 3 independent pooled experiments. (K–M) Ifnar–/– mice were infected with 103 PFU HSV-2 333 and administered PBS or IFN-λ (n = 5, 5). Data representative of 2 independent experiments. Viral titers in the (K) spine, (L) distal colon, and (M) vaginal tissue 6 DPI. (N) Primary cortical neurons from WT mice were stimulated with indicated concentrations of IFN-λ2 or IFN-β and infected with HSV-2. Infectious viral loads at the indicated time points in triplicate. (O) Ifnar–/– mice were infected with 104 PFU HSV-2 TK– and administered PBS or IFN-λ. Data shown are representative of 2 independent experiments. (P) Viral titers in vaginal washes (n = 5, 5). (Q) Rates of developing severe genital lesions. (R) Representative of genital lesion images. *P < 0.05, **P < 0.01, and ****P < 0.0001. Statistical significance determined by Kaplan-Meier survival analysis (B), repeated-measure 2-way ANOVA with Šídák’s multiple comparisons test (C, H, I, and P), ordinary 2-way ANOVA with Dunnett’s multiple comparisons test (N), and 2-tailed Student’s t test (E–G and K–M).