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.

The development of effective viroimmunotherapies for cancer relies on the ability of replicating viruses to infect the entire tumor tissue and induce comprehensive inflammation within the tumor microenvironment (TME). In this study, we investigate the impact of mutations in the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) on tumor cell infectivity, replication, and the immune response. Specifically, we focus on two key positions in GP1 (181 and 185) that significantly enhance tumor cell infectivity and improve CD8⁺ T cell function in the GP-mutated LCMV strain LCMV P52. Our findings demonstrate that LCMV strain LCMV P52 replicates preferentially in vivo in tumors, exhibits improved tumor penetration, attracts functional CD8⁺ T cells more effectively to the tumor, and reprograms the tumor toward a more immunogenic microenvironment to allow for effective checkpoint inhibitor combination.

Antiviral immunity profoundly impacts host metabolism, which can, in turn, modulate immune responses and influence disease pathology. The liver orchestrates systemic bile acid (BA) metabolism, a pathway disrupted in chronic liver diseases such as viral hepatitis. BAs are increasingly recognized for their immunomodulatory properties. Thus, improved understanding of the interplay between immunity and BA metabolism may reveal novel therapeutic avenues. Using lymphocytic choriomeningitis virus (LCMV) as a model, we investigated the interplay between chronic virus infection, BA metabolism, and immunity. Chronic LCMV infection increased BA levels and shifted circulating and liver BA composition toward host-derived, conjugated BAs. Hepatic BA transport and synthesis genes were broadly downregulated, in part depending on CD8 ⁺ T cells. Pharmacological inhibition of the main hepatic transporter of conjugated BAs, NTCP ( Slc10a1 ), increased hepatic damage, while combined genetic disruption of the BA transporters Slco1a1 , Slco1a4 , and Slco1b2 , responsible for the hepatic reuptake of unconjugated BA, reduced liver pathology and impaired antiviral CD8 ⁺ T cell responses. These findings reveal a reciprocal interplay between BA metabolism and CD8 ⁺ T cells, expanding our understanding of adaptive immunity in viral hepatitis. They also highlight how immunometabolic changes in liver disease may affect adaptive immune responses against infections.

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.

The lymphocytic choriomeningitis virus (LCMV) represents a strong T cell activating virus with anti-tumoral properties. In recent work, we developed an attenuated cancer cell-adapted reassortant LCMV strain carrying tumor-tropic mutations. The immunological mechanisms underlying these mutations remained unknown. Here, we passaged wild-type LCMV-WE in human lung cancer H1975 cells for 52 passages. After 29 passages, the virus acquired the GP1 mutations I181M and R185W, involved in viral receptor interactions, which remained stable throughout the subsequent 33 passages. Compared with wild-type LCMV-WE, LCMV-P52 showed increased infectivity, partly concomitant with enhanced propagation in human tumor cells. In vivo, LCMV-P52 induced reduced type I interferon (IFN-I) responses and showed accelerated expansion in CD169⁺ macrophages. Propagation within the splenic marginal zone correlated with accelerated priming of virus-specific CD8⁺ T cells and limited liver tissue damage. Mechanistic in vitro experiments showed that the I181M and R185W mutations were associated with substantially reduced infection of plasmacytoid dendritic cells (pDCs). Collectively, the I181M and R185W mutations limit systemic IFN-I induction and accelerate LCMV propagation in CD169⁺ macrophages, correlating with improved CD8⁺ T cell function and reduced liver damage. These findings provide mechanistic insight into how defined GP mutations can modulate viral tropism and antiviral immune responses.