Pathogenesis and outcome of VA1 astrovirus infection in the human brain are defined by disruption of neural functions and imbalanced host immune responses Journal Article
| Authors: | Maximova, O. A.; Weller, M. L.; Krogmann, T.; Sturdevant, D. E.; Ricklefs, S.; Virtaneva, K.; Martens, C.; Wollenberg, K.; Minai, M.; Moore, I. N.; Sauter, C. S.; Barker, J. N.; Lipkin, W. I.; Seilhean, D.; Nath, A.; Cohen, J. I. |
| Article Title: | 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. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. |
| Keywords: | immunohistochemistry; adolescent; adult; clinical article; controlled study; human tissue; protein expression; human cell; fludarabine; prednisone; pathogenesis; case report; cisplatin; doxorubicin; cytarabine; rituximab; nuclear magnetic resonance imaging; cytology; cerebellum; purkinje cell; gene expression; image analysis; transcription initiation; astrocyte; brain cortex; aciclovir; cyclophosphamide; dexamethasone; vincristine; genetic transcription; neurons; immunofluorescence; immunoreactivity; central nervous system; b lymphocyte; whole body radiation; immune response; brain; cerebrospinal fluid; sequence alignment; microarray analysis; graft versus host reaction; nerve injury; innate immunity; methylprednisolone; real time polymerase chain reaction; leukocyte count; immunity; immune deficiency; adaptive immunity; macrophage; phagocytosis; encephalitis; bioinformatics; neurologic disease; nerve cell; ataxia; electrophysiology; follicular lymphoma; brain stem; electroencephalogram; foscarnet; cyclosporine; leukoencephalopathy; phagocyte; dendrite; motor neuropathy; immunocompromised patient; phylogeny; cerebellum nucleus; fatality; neurophysiology; synapse; molecular pathology; central nervous system infection; budesonide; microglia; gray matter; rna isolation; thalamus; phylogenetic tree; brain tissue; synaptic transmission; guillain barre syndrome; false discovery rate; gene ontology; autofluorescence; diffuse large b cell lymphoma; pleocytosis; methylprednisolone sodium succinate; mycophenolate mofetil; astrocytosis; disease burden; humans; human; male; article; agammaglobulinemia; differential expression analysis; nerve biopsy; astroviridae infections; astrovirus infection; human astrovirus; pontine nucleus |
| Journal Title: | PLoS Pathogens |
| Volume: | 19 |
| Issue: | 8 |
| ISSN: | 1553-7366 |
| Publisher: | Public Library of Science |
| Date Published: | 2023-08-01 |
| Start Page: | e1011544 |
| Language: | English |
| DOI: | 10.1371/journal.ppat.1011544 |
| PUBMED: | 37595007 |
| PROVIDER: | scopus |
| PMCID: | PMC10438012 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
