부산대학교 도서관

Astroviruses (AstVs) can cause of severe infection of the central nervous system (CNS) in immunocompromised individuals. Here, we identified a human AstV of the VA1 genotype, HAstV-NIH, as the cause of fatal encephalitis in an immunocompromised adult. We investigated the cells targeted by AstV, neurophysiological changes, and host responses by analyzing gene expression, protein expression, and cellular morphology in brain tissue from three cases of AstV neurologic disease (AstV-ND). We demonstrate that neurons are the principal cells targeted by AstV in the brain and that the cerebellum and brainstem have the highest burden of infection. Detection of VA1 AstV in interconnected brain structures such as thalamus, deep cerebellar nuclei, Purkinje cells, and pontine nuclei indicates that AstV may spread between connected neurons transsynaptically. We found transcriptional dysregulation of neural functions and disruption of both excitatory and inhibitory synaptic innervation of infected neurons. Importantly, transcriptional dysregulation of neural functions occurred in fatal cases, but not in a patient that survived AstV-ND. We show that the innate, but not adaptive immune response was transcriptionally driving host defense in the brain of immunocompromised patients with AstV-ND. Both transcriptome and molecular pathology studies showed that most of the cellular changes were associated with CNS-intrinsic cells involved in phagocytosis and injury repair (microglia, perivascular/parenchymal border macrophages, and astrocytes), but not CNS-extrinsic cells (T and B cells), suggesting an imbalance of innate and adaptive immune responses to AstV infection in the brain as a result of the underlying immunodeficiencies. These results show that VA1 AstV infection of the brain in immunocompromised humans is associated with imbalanced host defense responses, disruption of neuronal somatodendritic compartments and synapses and increased phagocytic cellular activity. Improved understanding of the response to viral infections of the human CNS may provide clues for how to manipulate these processes to improve outcomes. Author summary: Immunocompromised individuals are at increased risk of severe viral infection of the central nervous system (CNS) due to a failure to contain infection before it reaches the brain. Here, we identified the VA1-clade astrovirus infection as the cause of fatal encephalitis in an immunocompromised patient and show that it targeted neurons in the brain. Study of brain tissues from three cases of astrovirus encephalitis in immunocompromised patients showed that the disease was associated with impairment of many functions of neurons and disruption of both excitatory and inhibitory synapses that form neuronal connections. Further analyses showed that the early innate, but not later adaptive immune response was driving antiviral host defense response in the brain. Activation of the CNS-resident cells important for phagocytosis, homeostasis, and repair (microglia, macrophages, and astrocytes) was evident, with little activity of the adaptive peripheral immune cells (T cells and B cells). These results demonstrate that the pathogenesis and outcome of astrovirus infection in the brain of patients with underlying immunodeficiencies is defined by an imbalance of different arms of the antiviral host defense system and disruption of functions of infected neurons. These findings suggest pathways that can be targeted to improve outcome of viral CNS infections. [ABSTRACT FROM AUTHOR]