Neuropathogenicity of Two Saffold Virus Type 3 Isolates in Mouse Models

Abstract

ObjectiveSaffold virus (SAFV), a picornavirus, is occasionally detected in children with acute flaccid paralysis, meningitis, and cerebellitis; however, the neuropathogenicity of SAFV remains undetermined.MethodsThe virulence of two clinical isolates of SAFV type 3 (SAFV-3) obtained from a patient with aseptic meningitis (AM strain) and acute upper respiratory inflammation (UR strain) was analyzed in neonatal and young mice utilizing virological, pathological, and immunological methods.ResultsThe polyproteins of the strains differed in eight amino acids. Both clinical isolates were infective, exhibited neurotropism, and were mildly neurovirulent in neonatal ddY mice. Both strains pathologically infected neural progenitor cells and glial cells, but not large neurons, with the UR strain also infecting epithelial cells. UR infection resulted in longer inflammation in the brain and spinal cord because of demyelination, while the AM strain showed more infectivity in the cerebellum in neonatal ddY mice. Additionally, young BALB/c mice seroconverted following mucosal inoculation with the UR, but not the AM, strain.ConclusionsBoth SAFV-3 isolates had neurotropism and mild neurovirulence but showed different cell tropisms in both neonatal and young mouse models. This animal model has the potential to recapitulate the potential neuropathogenicity of SAFV-3.

Neurotropism of Saffold virus in a mouse model

“…In addition SAFV can infect the heart and the CNS, as expected for a member of the genus Cardiovirus. These observations are congruent with those of Kotani et al (2016), which were published while this paper was in revision. These authors report the neuropathogenicity in mice, of two SAFV-3 clinical isolates.…”

Immunohistochemical insights into Saffold virus infection of the brain of juvenile AG129 mice

“…1 & Additional file 1: Figure S1), indicating that the virus infects both neuronal and glial cells, but neither exclusively. Our results agree with Sorgeloos et al [16] who showed infection of both neuronal and glial cells, but not with Kotani et al [17] who showed infection of glial cells, but not neuronal cells, in both early adult (6 week-old) and neonatal brains of ddY and BALB/c mice. However it should be noted that Sorgeloos et al [16] showed a preference to glial cells over neuronal cells.…”

Saffold virus, an emerging human cardiovirus

“…They further showed demyelination in the spinal cord of infected neonatal ddY mice spine in one of their strains, but not in adult mice. It should be noted that while Kotani et al showed demyelination, they attributed it to a TMEV infection rather than an effect of SAFV. Both our laboratory and Sorgeloos et al have also shown that it is highly unlikely that SAFV causes demyelination, and similarly in humans, Galama et al suggested that an association between SAFV and MS is highly improbable.…”

“…This was later supported by Sorgeloos et al when they demonstrated that infection of interferon receptor deficient (IFNAR‐KO) 129/sv mice permitted infection of the brain, spinal cord, heart, pancreas, and spleen. At the same time, Kotani et al showed that ic inoculation of SAFV causes non‐fatal infection of neonatal and 6‐week‐old ddY and BALB/c mice. They further showed demyelination in the spinal cord of infected neonatal ddY mice spine in one of their strains, but not in adult mice.…”

“…While the study above had started to uncover the pathogenesis of SAFV, hinting at invasive CNS infection, little progress was made thereafter. In 2016, however, 3 separate groups published work done on various mouse models, directly showing SAFV CNS infection . The first accepted paper was from our laboratory, which used SAFV‐3 on BALB/c mice and AG129 mice (mice with an intact immune system, but lacking alpha/beta interferon (IFN‐α/β) and IFN‐γ receptors).…”