Abstract
The immune system encounters a variety of viral infections and has to respond quickly to eliminate pathogens, while preventing overshooting of immune responses to preserve tissue integrity. Given that challenge, the immune system needs to find the balance between efficiently fighting viruses and preventing immunopathology. Despite the increased interest in coronavirus-induced diseases in the recent years, our understanding of the relevant tissue-specific, cellular and molecular mechanisms that govern immunity and pathophysiology during the different stages of coronavirus infection are still incomplete, especially at the very early and late stages. Coronaviruses, a family of single-stranded RNA viruses, have gained prominence due to their ability to cause a spectrum of respiratory symptoms, ranging from mild to severe disease. They have been responsible for several epidemics in the past, with the most recent being the coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2, which led to life-threatening infections in certain individuals. Severe disease is associated with increased viral loads, disturbed immune responses and tissue damage. While a number of dysregulated innate immune phenotypes have been reported in individuals with severe COVID-19, uncoupling the cause and consequence of insufficient early, immune-mediated restraint of viral replication in a heterogeneous population is challenging. In addition to the severe respiratory manifestations experienced during acute SARS-CoV-2 infection, the virus has been associated with long-term neurological and psychiatric symptoms. Usually, the central nervous system (CNS) is considered well-protected against external pathogens by multiple barriers. However, certain neurotropic viruses can overcome these barriers and replicate in the CNS. Accumulating evidence suggests that SARS-CoV-2 can infect the brain. The elucidation of neuroinflammatory processes following the resolution of acute infection in the patient population remains challenging given the inherent structure of this organ. In this respect, mouse models can be used to elaborate key inflammatory mechanisms in early and late coronavirus infection. Using a murine coronavirus model, the mouse hepatitis virus (MHV), we examined the early inflammatory responses orchestrating antiviral immunity against pulmonary coronavirus infection. We deliberately disrupted the cellular mechanisms related to type I interferon responsiveness, a critical signaling pathway that alerts the immune system to the presence of the virus, thereby enhancing subsequent antiviral defense mechanisms. By unleashing viral replication within that model we were able to delve into the cellular and molecular events occurring before the onset of severe coronavirus-induced disease. We identified that the ability of type I interferons to control early viral replication marks a crucial checkpoint determining the outcome of efficient antiviral immune responses or detrimental immunopathology. Although the ability of SARS-CoV-2 to actively replicate in the CNS remains debated, MHV is well known to establish a productive infection in this organ. To gain insight into the residual inflammatory state of the CNS following the resolution of acute neurotropic MHV infection, we assessed the quantity, phenotype and location of immune cells in the CNS. We identified that a substantial number of memory T cells persist in the CNS following viral clearance, situated at key perivascular sites in the meninges and parenchyma. Moreover, we demonstrate that immune-interacting fibroblasts underpinned lymphocytic clusters and interacted with memory T cells. Depopulation of these perivascular niches during viral recrudescence suggests that these structures support immune surveillance in the CNS. Through systematic histological evaluations, we identify regional patterns of perivascular lymphocytic clusters in proximity to known sites of acute viral replication. These findings imply fibroblastic cells as key directors of immune surveillance following viral infection, and also underscore the substantial post-acute neuroinflammation in the CNS following the resolution of coronavirus infection. Collectively, this thesis identifies two different aspects of the immune responses to coronavirus infections, providing valuable insights into both the immediate antiviral response and the long-term immune surveillance, all within distinct timeframes and spatial contexts.
Grabherr, Sarah