Temporal lymphatic tissue destruction and impairment of de novo T cell responses after an acute virus infection

Abstract Post-acute infection sequelae (PAIS), which include diverse immunological alterations and clinical syndromes, represent a significant yet poorly understood phenomenon following acute viral infections. While the host typically resolves acute infections within weeks and develops virus-specific immunity, emerging evidence suggests that long-term symptoms can persist or arise after primary infection recovery. Using the acute lymphocytic choriomeningitis virus (LCMV) infection mouse model, we investigated potential mechanisms underlying immune-related PAIS. By combining mouse infections, different vaccine regimens, and immune monitoring with fluorescence microscopy and 3D image reconstruction of lymphatic tissues, we demonstrated that LCMV-recovered animals exhibit a prolonged immunocompromised state affecting dominantly de novo T cell responses. This is linked to the massive destruction of splenic lymphatic tissue, affecting the compartmentalization of the organ as well as crucial cell–cell contacts necessary for efficient T cell priming. Importantly, LCMV vaccination prevented LCMV-mediated lymphatic tissue destruction and the compromised immunological state. These findings underscore the importance of vaccination in preventing both acute virus infection-mediated pathology and potential PAIS. Our results highlight the complex interplay between virus infections, immune responses, and tissue integrity, challenging the common assumption that hosts fully recover their pre-infection homeostatic health state directly after an acute virus infection is controlled.