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Circulation of 3 Lineages of a Novel Saffold Cardiovirus in Humans

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Circulation of 3 Lineages of a Novel Saffold Cardiovirus in Humans RESEARCH Circulation of 3 Lineages of a Novel Saffold Cardiovirus in Humans Jan Felix Drexler, Luciano Kleber de Souza Luna, Andreas Stöcker, Patrícia Silva Almeida, Tereza Cristina Medrado Ribeiro, Nadine Petersen, Petra Herzog, Célia Pedroso, Hans Iko Huppertz, Hugo da Costa Ribeiro Jr., Sigrid Baumgarte, and Christian Drosten Cardioviruses cause serious disease, mainly in ro- rodents and swine. The type species is Encephalomyocardi- dents, including diabetes, myocarditis, encephalomyelitis, tis virus, which includes strains of murine encephalomyo- and multiple sclerosis–like disseminated encephalomyeli- carditis virus (EMCV), Mengo virus, and Maus Eberfeld tis. Recently, a human virus isolate obtained 25 years ago, virus. The species Theilovirus is represented by Theiler’s termed Saffold virus, was sequenced and classifi ed as a murine encephalomyelitis virus (TMEV, also known as cardiovirus. We conducted systematic molecular screen- mouse poliovirus) and rat encephalomyelitis virus. Both ing for Saffold-like viruses in 844 fecal samples from pa- tients with gastroenteritis from Germany and Brazil, across species show clinical association with encephalomyelitis all age groups. Six cardioviruses were identifi ed in patients in mice, and EMCV shows an additional association with <6 years of age. Viral loads were 283,305–5,044,412,175 myocarditis (1). EMCV is used in laboratory mice to model copies/g of stool. Co-infections occurred in 4 of 6 children. the symptoms and pathogenesis of human type I diabetes No evidence for outbreak-like epidemic patterns was found. and viral myocarditis (2,3). TMEV comprises strains of Phylogenetic analysis identifi ed 3 distinct genetic lineages. differing neuropathogenicity, which constitute accepted Viral protein 1 amino acids were 67.9%–77.7% identical mouse models of either human acute poliomyelitis or dis- and had a distance of at least 39.4% from known cardio- seminated encephalomyelitis. The latter is indistinguish- viruses. Because closely related strains were found on 2 able from multiple sclerosis in humans (4,5). continents, global distribution in humans is suspected. Saf- No human-pathogenic cardiovirus is recognized today. fold-like viruses may be the fi rst human cardiovirus species Isolation of EMCV-like viruses from mammals other than to be identifi ed. rodents and pigs has been reported in the past (6–9), but the clinical relevance of these sporadic fi ndings has been he family Picornaviridae comprises 9 genera with doubted, especially fi ndings involving humans. TMEV- T>142 species and 200 serotypes, many of which are like cardiovirus may have been involved in an apparently highly pathogenic for humans and animals. The genus Car- infectious neurodegenerative disease in persons living in diovirus contains 2 animal-pathogenic species— Encepha- Vilyuisk, Siberia (10). A virus related to TMEV, named Vi- lomyocarditis virus and Theilovirus—that occur mainly in lyuisk virus, was isolated from a laboratory mouse that had been injected intracerebrally with blood and cerebrospinal Author affi liations: Federal University of Bahia, Salvador, Brazil fl uid (CSF) of a symptomatic patient (11,12). However, se- (J.F. Drexler, A. Stöcker, P. Silva Almeida, T.C. Medrado Ribeiro, rum antibodies to Vilyuisk virus were found only in some C. Pedroso, H. da Costa Ribeiro Jr.); Bernhard Nocht Institute for but not all Vilyuisk encephalitis patients by a mouse neu- Tropical Medicine, Hamburg, Germany (J.F. Drexler, L.K. de Souza tralization assay (13–15). Therefore, controversy remains Luna, N. Petersen, P. Herzog); Professor Hess Paediatric Hospital, on whether the virus really circulates in humans or whether Bremen, Germany (H.I. Huppertz); Institute of Hygiene and the En- the isolate may have resulted from mouse passage. vironment, Hamburg (S. Baumgarte); and University of Bonn Medi- Recently, the genome of another cardiovirus, the Saf- cal Centre, Bonn, Germany (C. Drosten) fold virus, was characterized (16). This virus was isolated DOI: 10.3201/eid1409.080570 in 1982 from a stool sample of a child with fever of un- 1398 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 14, No. 9, September 2008 Human Saffold Virus Circulation known origin. No mouse passage was involved, but the Cohort 2 original stool sample had been passaged several times in Archived stool samples from 118 patients with acute Wistar Institute–38, human fetal diploid lung–645, and enteritis were obtained from the routine diagnostic labora- human fetal diploid kidney cells. No associated study has tory of a municipal health service in Hamburg, Germany. been conducted to determine whether this singular cell cul- This cohort contained 3 subcohorts classifi ed with regard ture isolate had any clinical meaning. Most recently, Abed to patient age and context of sampling: 1) children sampled and Boivin reported that a cardiovirus similar to Saffold during childcare center outbreaks (n = 51); 2) adults sam- virus was identifi ed from a cell culture showing cytopathic pled in the context of outbreaks of gastroenteritis mainly in effects but reacting only weakly with antienterovirus se- association with catering and canteen food (n = 35); and 3) rum pools (17). Specifi c screening identifi ed the same or senior citizens sampled because of outbreaks of enteritis in a closely related virus from >2 cell cultures. All cultures retirement homes (n = 32). had been injected with respiratory secretions from children with respiratory disease. The report summarized 3 clinical Cohort 3 cases but did not address prevalence, disease association, This cohort contained 188 samples from infants and or molecular–epidemiologic aspects of the virus. children in Brazil with acute diarrhea, defi ned as >3 wa- In this study, we used broad-range nested reverse tran- tery stools in the previous 24 hours and within 13 days be- scription–PCR (RT-PCR) targeted at domains conserved fore admission. Patients were seen as outpatients or were between the Saffold prototype virus, various TMEV strains, hospitalized because of severe dehydration from February and EMCV. We screened 844 patients from all age groups through December 2006 at the University Hospital Profes- with acute enteritis, including 39 controls, in 3 independent sor Edgar Santos in Salvador de Bahia, Brazil. Informed cohorts from 2 countries (Germany and Brazil) on 2 con- consent was obtained from the mothers of all patients en- tinents. Viral loads were determined by specifi c real-time rolled in the study. The study was approved by the institu- RT-PCR. Phylogenetic analysis showed 3 independent tional ethics committee. All analyses were performed at the lineages of circulating Saffold-like viruses (SafVs). Analy- Infectious Disease Research Laboratory, University Hospi- sis of amino acid identities and considerations regarding tal Professor Edgar Santos. transmission patterns suggest that SafV most likely con- Co-infection in the Brazil cohort was assessed by us- stitutes a new cardiovirus that is associated with humans ing recently published methods of real-time RT-PCR for worldwide. norovirus, rotavirus, enterovirus, parechovirus, adenovirus, and astrovirus (18–23). For the Germany cohorts, testing Materials and Methods was done with the IDEIA rotavirus, adenovirus, and astro- virus antigen enzyme immunoassays (DakoCytomation, Patients and Samples Ely, UK) and nested RT-PCRs as described before (23). All samples had been stored at –20°C and thawed a few Cohort 1 times before this study. From January through December 2004, 538 stool sam- ples were collected from patients in urban areas in north- Preparation of Stool Samples for RT-PCR ern Germany in a prospective study on acute, community- Stool samples stored at –20°C were extracted by us- acquired diarrhea. All patients were outpatients who had ing the QIAamp DNA Mini Stool Kit or the QIAamp Viral been examined by general practitioners; 96 (17.8%) were RNA Mini Kit (QIAGEN, Hilden, Germany). Both proto- <6 years old. Diarrhea in these patients was defi ned as ex- cols used an input of ≈200 mg of stool prediluted 1:10 in cretion of at least 2 loose and malodorous stools during 24 phosphate-buffered saline. Suspensions were vortexed and hours for breastfed infants and of at least 2 loose stools centrifuged, and 200 or 140 μL of supernatant, respective- in a 24-hour period for all other patients. Patients were ly, was extracted according to the manufacturer’s instruc- excluded if they had infl ammatory bowel disease, celiac tions. disease, cystic fi brosis, food intolerance, or a known ma- lignant disease. The cohort included stool samples from 39 Nested RT-PCR for Cardiovirus Screening control patients of compatible ages with conditions other Primers (Table 1) were designed upon aligning the than enteritis. Written informed consent was obtained from Saffold virus (GenBank accession no. EF165067) (16) all patients or their parents. The study protocol and data with genomes of EMCV and TMEV strains. Saffold vi- handling were approved by the local ethics committee. In rus served as the template sequence. Formulations of both both groups, patients with norovirus, adenovirus, enterovi- rounds of amplifi cation are shown in Table 1. Although the rus, astrovirus, or rotavirus infection were excluded. fi rst round alone was suffi cient for amplifi cation of an 800- bp fragment in samples with an apparently high viral load, Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 14, No. 9, September 2008 1399 RESEARCH Table 1. PCR oligonucleotides and formulations for cardiovirus
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