Saffold Virus, a Human Theiler's-Like Cardiovirus, Is Ubiquitous and Causes Infection Early in Life

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Abstract
The family Picornaviridae contains well-known human pathogens (e.g., poliovirus, coxsackievirus, rhinovirus, and parechovirus). In addition, this family contains a number of viruses that infect animals, including members of the genus Cardiovirus such as Encephalomyocarditis virus (EMCV) and Theiler's murine encephalomyelits virus (TMEV). The latter are important murine pathogens that cause myocarditis, type 1 diabetes and chronic inflammation in the brains, mimicking multiple sclerosis. Recently, a new picornavirus was isolated from humans, named Saffold virus (SAFV). The virus is genetically related to Theiler's virus and classified as a new species in the genus Cardiovirus, which until the discovery of SAFV did not contain human viruses. By analogy with the rodent cardioviruses, SAFV may be a relevant new human pathogen. Thus far, SAFVs have sporadically been detected by molecular techniques in respiratory and fecal specimens, but the epidemiology and clinical significance remained unclear. Here we describe the first cultivated SAFV type 3 (SAFV-3) isolate, its growth characteristics, full-length sequence, and epidemiology. Unlike the previously isolated SAFV-1 and -2 viruses, SAFV-3 showed efficient growth in several cell lines with a clear cytopathic effect. The latter allowed us to conduct a large-scale serological survey by a virus-neutralization assay. This survey showed that infection by SAFV-3 occurs early in life (>75% positive at 24 months) and that the seroprevalence reaches >90% in older children and adults. Neutralizing antibodies were found in serum samples collected in several countries in Europe, Africa, and Asia. In conclusion, this study describes the first cultivated SAFV-3 isolate, its full-length sequence, and epidemiology. SAFV-3 is a highly common and widespread human virus causing infection in early childhood. This finding has important implications for understanding the impact of these ubiquitous viruses and their possible role in acute and/or chronic disease. Recently, a new picornavirus was isolated from humans, named Saffold virus (SAFV). Picornaviruses are small RNA viruses with poliovirus as prototype. Saffold virus is genetically related to Theiler's virus, a member of the Cardiovirus genus, which until this recent discovery did not contain human viruses. Theiler's virus is an important mouse pathogen that causes chronic inflammation in the brains, closely resembling multiple sclerosis in humans. By analogy, SAFV may be a relevant human pathogen. Thus far, SAFVs have been sporadically detected by molecular techniques in respiratory and fecal specimens, but the epidemiology and clinical significance have remained unclear. Here we describe the first SAFV type 3 (SAFV-3) isolate, its growth characteristics in cell lines, full-length RNA-sequence, and epidemiology. Unlike the previously isolated SAFV-1 and SAFV-2, SAFV-3 grows well in cell lines, resulting in cell damage. This feature enabled us to conduct a large-scale serological survey for virus-neutralizing antibodies. This survey showed that SAFV-3 infection occurs early in life and that >90% of children >2 years and adults had antibodies. Neutralizing antibodies were found in serum samples collected in several countries in three continents. Hence, we concluded that SAFV-3 is a genuine and widespread human virus causing infection early in life.