Besides its robust antiviral activity, type I interferon (IFN-I) also exerts immunomodulatory effects and can even drive pathology during chronic viral infections. Mechanisms that regulate IFN-I induction during virus infection, thus strongly affecting the outcome of disease, remain to be defined. Here, using the lymphocytic choriomeningitis virus (LCMV) Docile strain, we identified acid ceramidase (aCDase, Asah1 ) as a critical lipid-metabolic regulator of endosomal, nucleic acid-driven IFN-I responses and disease outcome during chronic virus infection. aCDase is highly expressed in plasmacytoid dendritic cells (pDCs) and required for robust early IFN-I production. aCDase deficiency resulted in ceramide accumulation, blunting IFN-α/β induction, impairing IFN-I-dependent upregulation of programmed death-ligand 1 (PD-L1) on antigen-presenting cells and preventing the exhaustion of virus-specific CD8 ⁺ T cells, leading to severe immunopathology. This pathology is abrogated by CD8 ⁺ T-cell depletion or by adoptive transfer of IFN-I-induced PD-L1-expressing macrophages. Conversely, limiting ceramide production in acid sphingomyelinase (Asm)-deficient mice prevented ceramide accumulation, and pDCs showed accelerated IFN-I induction. Mechanistically, ceramide abundance regulated IFN-I production by altering endosomal signaling microdomains. Collectively, our findings reveal ceramide homeostasis as a key determinant of IFN-I-driven CD8 ⁺ T-cell exhaustion and immunopathology during chronic viral infection and highlight aCDase as a potential therapeutic target.

Anaphylaxis is a life-threatening hypersensitivity reaction. Clinical observations suggest heightened susceptibility during viral infections, yet the mechanisms remain poorly defined. Here, we show that both active and passive IgG-mediated anaphylaxis were exacerbated in the setting of acute viral infection. In mice, this enhancement was driven predominantly by FcγRIV, the homolog of human FcγRIIIa. FcγRIV crosslinking induced anaphylactic symptoms selectively in infected animals, with no effect in naive conditions. Among leukocytes, inflammatory monocytes emerged as the principal drivers of this lethal reaction. Viral infection triggered a strong upregulation of FcγRIV on inflammatory monocytes, an effect absent in type I IFN receptor–deficient ( Ifnar1 -deficient) mice. Extending these findings, we observed increased frequencies of CD16-expressing classical monocytes in patients with acute COVID-19, and murine SARS-CoV-2 infection recapitulated this phenotype. Mechanistically, FcγRIV crosslinking during infection promoted the production of platelet-activating factor, the key mediator of mortality, in a type I IFN–dependent (IFN-I–dependent) manner. Together, these findings indicate that viral infection creates an immune milieu that heightens monocyte sensitivity to Fcγ receptor engagement, positioning these cells as major effectors of IgG-mediated hypersensitivity in the infected host. They further suggest that Fc receptor pathway modulation merits further investigation in contexts with heightened IFN-I responses, such as in systemic lupus erythematosus.

Ubiquitin-specific peptidase 22 (Usp22) cleaves ubiquitin moieties from numerous proteins, including histone H2B and transcription factors. Recently, it was reported that Usp22 acts as a negative regulator of interferon-dependent responses. In the current study, we investigated the role of Usp22 deficiency in acute viral infection with lymphocytic choriomeningitis virus (LCMV). We found that the lack of Usp22 on bone marrow-derived cells (Usp22^fl/fl Vav1-Cre mice) reduced the induction of type I and II interferons. A limited type I interferon response did not influence virus replication. However, restricted expression of PD-L1 led to increased frequencies of functional virus-specific CD8⁺ T cells and rapid death of Usp22-deficient mice. CD8⁺ T cell depletion experiments revealed that accelerated CD8⁺ T cells were responsible for enhanced lethality in Usp22 deficient mice. In conclusion, we found that the lack of Usp22 generated a pathological CD8⁺ T cell response, which gave rise to severe disease in mice.

Ubiquitin-Specific-peptidase 22 (Usp22) cleaves ubiquitin moieties from numerous proteins, in particular transcription factors. Recently, it was reported that Usp22 acts as negative regulator of interferon-dependent responses. In the current study, we investigated the role of Usp22 deficiency upon acute viral infection with lymphocytic choriomeningitis (LCMV) virus. We found that lack of Usp22 on bone marrow derived cells (Usp22 fl/fl Vav1-Cre mice) reduced induction of type I and II interferons. Limited type I interferon response did not influence virus replication. However, restricted expression of PD-L1 led to increased frequencies of functional virus-specific CD8+ T cells and rapid death of Usp22 deficient mice. CD8+ T cell depletion experiments revealed that accelerated CD8+ T cells were responsible for enhanced lethality in Usp22 deficient mice. In conclusion, we found that the lack of Usp22 generated a pathological CD8+ T cell response, which gave rise to severe disease in mice.