Identification of heterologous Torque Teno Viruses in humans and swine

Torque teno viruses are small DNA viruses which were discovered as a possible cause of post-transfusion hepatitis in humans1. Since then, TTVs have been detected in many mammalian hosts; including dogs, cats, chimpanzees and swine2. While the prevalence of TTVs in other species has not been studied extensively, they are reported to range from 5–90% in humans3,4, and about 55–100% in swine5,6. The virus is detected in all major organs, secretions, excretions, blood and blood cells. The tissue distribution and localization of TTVs are similar in humans and swine3,7. Generally, TTVs establish chronic infections without causing overt pathology. Hence their role as primary pathogens is a subject of scientific debate. Several epidemiological studies have associated TTVs with a spectrum human diseases such as hepatitis B or C, multiple sclerosis, hepatocellular carcinomas, respiratory infections, blood disorders and autoimmune diseases8,9. In swine, experimental infection of gnotobiotic pigs with swine Torque Teno virus 1 or 2 (TTSuV1 or 2) causes mild to moderate respiratory, hepatic and nephritic lesions, indicating that TTSuVs can act as a primary pathogens in swine. In experimental coinfections, TTSuV’s potentiated other swine viral diseases10,11. Therefore, the question of whether TTVs can establish cross-species infections is of considerable importance. The lack of a reliable cell culture system has limited the exploration of the molecular biology and pathogenesis of TTVs. However, recent studies show that TTV proteins encode auto-reactive epitopes which are also detected in multiple sclerosis and lupus patients12, and that a TTV encoded miRNA depresses host interferon signaling13. Viremia in TTV-infected individuals is inversely correlated with immune status. Indeed, it has been suggested that TTV DNA loads can be used as an indicator of immuno-suppression14,15. Therefore, in immuno-compromised individuals, the possibility that TTVs could replicate to high levels and facilitate pathology cannot be ruled out. Widespread environmental contamination, based on the detection of human TTV (huTTV) DNA, is extremely common in water sources16,17,18, sewage19 and in air or on surfaces, especially in hospitals20. Contamination of swine-derived laboratory enzymes such as trypsin and some veterinary vaccines with TTSuVs is also reported21. Current screening protocols for blood donors do not include detection of TTVs. However, given their ubiquitous nature, TTVs are also potential contaminants of the blood supply22. Humans are likely to frequently ingest TTSuVs in food and water. Both pork products and human feces contain TTSuV DNA23,24. Moreover, with the availability of improved technology, there is an increased interest and potential for the use of swine-based xenotransplantation products25. Therefore, from a public health perspective, it is especially critical to determine whether TTSuVs can establish infections in humans. In this study, we examined sera from humans and swine for the presence of TTSuV and human TTVs (huTTV) DNA by PCR. Interestingly, both TTSuV and huTTV DNA were detected at high levels in both species. We also determined that TTSuV1 can serially infect human PBMCs and reduce their ability to proliferate in response to mitogens. Antibody responses to TTSuV1 were detected in some human samples, indicating that TTSuVs can potentially establish infections in humans. Our data provides key, primary evidence for the possible transmission of TTVs between mammalian species and is significant in understanding the ecology and pathogenesis of this highly-prevalent virus.