Severe Cases of COVID-19 Are Associated with Changes in Circulating Small RNA

RNA-interference is described as an evolutionary conserved host defense mechanism against viral infection. Up to now, the relevance of this mechanism for SARS-CoV-2-directed immune responses remains elusive. Here, we used high throughput sequencing to profile the plasma of active and convalescent COVID-19 patients for the presence of small circulating RNAs. The presence of SARS-CoV-2 derived small RNAs in plasma samples of mild and severe COVID-19 cases is described. Clusters of high siRNA abundance were discovered, homologous to the nsp2 3´-end and nsp4 virus sequence. Four virus derived small RNA sequences have the size of human miRNAs and target search revealed candidate genes associated with ageusia and long COVID symptoms. These virus-derived small RNAs are detectable also after recovery from the disease. The additional analysis of circulating human miRNAs revealed differentially abundant miRNAs discriminating mild from severe cases. 29 miRNAs are reduced or absent in severe cases. Several of these are associated with the Interferon JAK-STAT response (e.g. hsa-miRNA4516, hsa-miR-320 b, c and d, hsa-miR-126-3p).Funding Statement: This project was partially funded by the German Research Foundation (CRC 841, to MB) as well as by the Martin-Luther-University Halle (Saale) and Leibniz Institute of Plant Genetics and Crop Plant Research, Gatersleben, Germany.Declaration of Interests: The authors have no conflict of interests.Ethics Approval Statement: Blood collection was performed under institutional review board approvals numbers 2020- 039 and 11/17.