Pathogenesis and outcome of VA1 astrovirus infection in the human brain are defined by disruption of neural functions and imbalanced host immune responses

Abstract

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.

Structure and antigenicity of the divergent human astrovirus VA1 capsid spike

“…In 2010, HAstV-VA1 was first identified by metagenomic sequencing as the causative agent of encephalitis in an immunocompromised patient with X-linked agammaglobulinemia who ultimately died after 71 days of hospitalization [6]. To date, 15 cases of neuronal HAstV infections have been reported in immunocompromised individuals, causing encephalitis or meningitis and resulting in high mortality rates [22][23][24][25][26][27][28][29][30][31][32][33][34]. Of these cases, a majority (9/15) were caused by HAstV-VA1.…”

Brainstem Encephalitis as a Cause of Sudden Infant Death Syndrome

“…Other enteroviruses such as EV-71 and astrovirus are also known to cause brainstem encephalitis. 6,7 This phenomenon has also been implicated in sudden death associated with SARS-CoV-2 infection. 8 Viruses are not the only microbial pathogen to travel retrogradely along the vagus nerve.…”

“…One other possibility is that because the vagus nerve innervates the respiratory and gastrointestinal tracts, the virus may travel along the vagus nerve into the brainstem. Other enteroviruses such as EV-71 and astrovirus are also known to cause brainstem encephalitis . This phenomenon has also been implicated in sudden death associated with SARS-CoV-2 infection .…”