Neurotropic Astroviruses in Animals

Abstract

Astrovirus infections are among the main causes of diarrhea in children, but their significance for animal health has remained underestimated and largely unknown. This is changing due to the increasing amount of newly identified neurotropic astroviruses in cases of nonsuppurative encephalitis and neurological disease in humans, pigs, ruminant species and minks. Neurological cases in ruminants and humans usually occur sporadically and as isolated cases. This contrasts with the situation in pigs and minks, in which diseases associated with neurotropic astroviruses are endemic and occur on the herd level. Affected animals show neurological signs such as mild ataxia to tetraplegia, loss of orientation or trembling, and the outcome is often fatal. Non-suppurative inflammation with perivascular cuffing, gliosis and neuronal necrosis are typical histological lesions of astrovirus encephalitis. Since astroviruses primarily target the gastrointestinal tract, it is assumed that they infect the brain through the circulatory system or retrograde following the nerves. The phylogenetic analysis of neurotropic astroviruses has revealed that they are genetically closely related, suggesting the presence of viral determinants for tissue tropism and neuroinvasion. In this review, we summarize the current knowledge on neurotropic astrovirus infections in animals and propose future research activities.

Keywords: astrovirus; neurological disease; non-suppurative encephalitis.

Figure 3

Phylogenetic analysis of available full-length genomes of neurotropic astroviruses. Officially recognized Mamastrovirus (MAstV) genotype species are indicated in italics, whereas the provisional MAstV genotype species are in parentheses. Strains detected in brain tissues in association with encephalitis are highlighted for humans (orange and green) and animals (red). Strains included in the analysis were selected based on the former classification with the available full-length reference genomes [61] and the available full-length NT-AstV strains. Sequences were aligned with MUSCLE [62], and the tree was constructed with MEGA X [63] using the Maximum Likelihood method and General Time Reversible model [64] with 1000 bootstrap replications. The bar indicates nucleotide sequence p-distances. The BoAstV CH13/NeuroS1 clade includes strains with GenBank accession numbers KF233994, KM03579, KX266901–KX266908, KT956903, LC341267 and LN879482. The PoAstV-3 clade includes strains with GenBank accession numbers KY940545, KY073229, KY073231, KY073232 and JX556691.

Figure 1

Schematic representation of the astrovirus genome. The ribosomal frameshift signal between ORF 1a and ORF 1b (RFS) is located downstream of a slippery sequence A(6)C, resulting in an incomplete −1 frameshift and the translation of the nonstructural proteins nsp1a and nsp1ab, respectively. A conserved subgenomic promoter sequence (*) leads to the translation of the ORF2 during viral replication from a subgenomic RNA. Additionally, the translation of ORFX encoded in the +1 frame or of ORF Y encoded in the −1 frame with reference to the ORF2 is proposed being translated by a ribosomal leaky scanning mechanism.

Figure 2

Neuropathology of astrovirus-associated encephalitis in the mesencephalon of a cattle (female, 1 ¼ years, strain bovine astrovirus CH13/NeuroS1 (BoAstV CH13/NeuroS1)). (A) HE-staining, showing mild hypercellularity (gliosis) and perivascular cuffs involving mononuclear leukocytes. (B) Demonstration of viral antigen in neurons by immunohistochemistry (IHC) with a polyclonal antibody against the capsid protein of BoAstV-CH13/NeuoS1 [32] (red labeling). (C) Demonstration of viral RNA in neurons by in situ hybridization (ISH) with a probe targeting the ORF2 of BoAstV-CH13/NeuroS1 (brown labeling). The arrows point to perivascular cuffs, and scale bars are presented at the bottom right.