Human Astrovirus VA1 Encephalitis in Pediatric Patients With Cancer: Report of 2 Cases and Review of the Literature

Bami, Sakshi; Hidinger, Jennifer; Madni, Arshia; Hargest, Virginia; Schultz‐Cherry, Stacey; Cortez, Valerie; Cross, Shane J; Ward, Deborah; Hayden, Randall T.; Rubnitz, Jeffrey E.; Pui, Ching-Hon; Khan, Raja B.; Hijano, Diego R.

doi:10.1093/jpids/piac045

Cited by 11 publications

(8 citation statements)

References 19 publications

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“…Our phylogenetic results agree with those previously published and suggest that different BAstV genotypes could be responsible for encephalitis and diarrhea. The dual enteric and neurotropic tropism observed in cattle was also described in other species, including minks ( 46 , 47 ), swine ( 48 , 49 ), sheep ( 50 , 51 ), and humans ( 52 – 54 ). In cats and dogs, AstV infection has been linked only to gastroenteric disease so far ( 55 – 58 ).…”

Section: Discussionmentioning

confidence: 62%

Identification of Astrovirus in the virome of the upper and lower respiratory tracts of calves with acute signs of bronchopneumonia

Gaudino,

Salem,

Ducatez

et al. 2023

Microbiol Spectr

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Bovine Astroviruses (BAstV) are small single-stranded, positive-sense RNA viruses that have been historically associated with the infection of the enteric tract in cattle, causing outbreaks of diarrhea, especially in young immunologically naive calves. Long neglected, BAstV have recently regained interest as they have been associated with several nonsuppurative encephalitis cases in cattle as well as in other species. Yet, the difficulty in isolating the virus in conventional cell cultures prevents a full understanding of BAstV tropism and pathogenesis in this species. Here, we describe the metagenomic identification of BAstV in the respiratory tract of calves affected by respiratory distress in French farms. BastV were prevalently detected in the lower respiratory tract of sick calves; however, molecular testing of further cohorts of respiratory samples highlighted their presence also in nasal swabs. Phylogenetic analyses revealed two divergent clades for neurotropic and enteric BAstV, suggesting that their tropism is likely to be strain-specific. BAstV detected in the respiratory tract of calves with respiratory disease were genetically related to enteric strains already described in cattle in Asia, displaying between 85% and 95% nucleotide identity. In addition, the sequences from France belonged to the clade of BAstV identified in yaks, roe deer, and camelids, underlining the interspecies transmission potential of the virus. More studies are warranted to understand if BAstV have a potential role in the onset of bovine respiratory disease. IMPORTANCE Astroviruses (AstV) are known suspects of enteric disease in humans and livestock. Recently, AstV have been linked to encephalitis in immunocompromised patients and other animals, such as cattle, minks, and swine. In our study, we also identified AstV in the respiratory samples of calves with signs of bronchopneumonia, suggesting that their tropism could be even broader. We obtained one bovine AstV (BAstV) complete genome sequence by next-generation sequencing and showed that respiratory and enteric AstV from different species formed a divergent genetic cluster with AstV isolated from encephalitis cases, indicating that tropism might be strain-specific. These data provide further insight into understanding the biology of these understudied pathogens and suggest BAstV as a potential new candidate for bovine respiratory disease.

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Section: Discussionmentioning

confidence: 62%

Identification of Astrovirus in the virome of the upper and lower respiratory tracts of calves with acute signs of bronchopneumonia

Gaudino,

Salem,

Ducatez

et al. 2023

Microbiol Spectr

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“…To date, only 9 cases of HAstV-VA1 associated encephalitis are reported, of which six of those HAstV-VA1 capsid sequences are reported [22,23,[27][28][29][30][31]33]. To understand if sequence and/ or structural changes might be driving some strains of HAstV-VA1 to be able to infect the CNS, we first evaluated the capsid spike sequence differences in five representative sequences of HAstV-VA1 associated with gastroenteritis (HAstV-VA1 gastro ) and all six of the publicly available sequences of HAstV-VA1 associated with neurological disease (HAstV-VA1 neuro ) (Fig 5A) [60,61].…”

Section: Sequence and Structural Comparison Of Hastv-va1 Gastro And H...mentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

Structure and antigenicity of the divergent human astrovirus VA1 capsid spike

Ghosh,

Delgado-Cunningham,

López

et al. 2024

PLoS Pathog

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Human astrovirus (HAstV) is a known cause of viral gastroenteritis in children worldwide, but HAstV can cause also severe and systemic infections in immunocompromised patients. There are three clades of HAstV: classical, MLB, and VA/HMO. While all three clades are found in gastrointestinal samples, HAstV-VA/HMO is the main clade associated with meningitis and encephalitis in immunocompromised patients. To understand how the HAstV-VA/HMO can infect the central nervous system, we investigated its sequence-divergent capsid spike, which functions in cell attachment and may influence viral tropism. Here we report the high-resolution crystal structures of the HAstV-VA1 capsid spike from strains isolated from patients with gastrointestinal and neuronal disease. The HAstV-VA1 spike forms a dimer and shares a core beta-barrel structure with other astrovirus capsid spikes but is otherwise strikingly different, suggesting that HAstV-VA1 may utilize a different cell receptor, and an infection competition assay supports this hypothesis. Furthermore, by mapping the capsid protease cleavage site onto the structure, the maturation and assembly of the HAstV-VA1 capsid is revealed. Finally, comparison of gastrointestinal and neuronal HAstV-VA1 sequences, structures, and antigenicity suggests that neuronal HAstV-VA1 strains may have acquired immune escape mutations. Overall, our studies on the HAstV-VA1 capsid spike lay a foundation to further investigate the biology of HAstV-VA/HMO and to develop vaccines and therapeutics targeting it.

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“…To date, twelve publications describe 14 human cases of AstV neurological disease (AstV-ND) [13][14][15][16][17][18][19][20][21][22][23][24] with the neuropathological findings reported only for 7 cases (postmortem findings from 5 cases [13,14,16,17,19] and biopsy findings from 2 cases [15,22]). We reviewed these publications and summarized the reported underlying premorbid conditions, types of infected cells, and pathology within the CNS (S1 Table ).…”

Section: Introductionmentioning

confidence: 99%

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

Maximova,

Weller,

Krogmann

et al. 2023

PLoS Pathog

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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.

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Human Astrovirus VA1 Encephalitis in Pediatric Patients With Cancer: Report of 2 Cases and Review of the Literature

Cited by 11 publications

References 19 publications

Identification of Astrovirus in the virome of the upper and lower respiratory tracts of calves with acute signs of bronchopneumonia

Identification of Astrovirus in the virome of the upper and lower respiratory tracts of calves with acute signs of bronchopneumonia

Structure and antigenicity of the divergent human astrovirus VA1 capsid spike

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

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