Changes of Small Non-coding RNAs by Severe Acute Respiratory Syndrome Coronavirus 2 Infection

Abstract

The ongoing pandemic of coronavirus disease 2019 (COVID-19), which results from the rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a significant global public health threat, with molecular mechanisms underlying its pathogenesis largely unknown. In the context of viral infections, small non-coding RNAs (sncRNAs) are known to play important roles in regulating the host responses, viral replication, and host-virus interaction. Compared with other subfamilies of sncRNAs, including microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs), tRNA-derived RNA fragments (tRFs) are relatively new and emerge as a significant regulator of host-virus interactions. Using T4 PNK‐RNA‐seq, a modified next-generation sequencing (NGS), we found that sncRNA profiles in human nasopharyngeal swabs (NPS) samples are significantly impacted by SARS-CoV-2. Among impacted sncRNAs, tRFs are the most significantly affected and most of them are derived from the 5′-end of tRNAs (tRF5). Such a change was also observed in SARS-CoV-2-infected airway epithelial cells. In addition to host-derived ncRNAs, we also identified several small virus-derived ncRNAs (svRNAs), among which a svRNA derived from CoV2 genomic site 346 to 382 (sv-CoV2-346) has the highest expression. The induction of both tRFs and sv-CoV2-346 has not been reported previously, as the lack of the 3′-OH ends of these sncRNAs prevents them to be detected by routine NGS. In summary, our studies demonstrated the involvement of tRFs in COVID-19 and revealed new CoV2 svRNAs.

Host tRNA-Derived RNAs Target the 3′Untranslated Region of SARS-CoV-2

“…The 5 -tDRs 5008c, 5013c, 5027c and 5028c were decreased in COVID-19 patients, and 5020a was increased. As previously reported, the 5 tDRs, were significantly changed in response to SARS-CoV-2 infection [17]. In addition, an assessment of patients above 60 years old that were diagnosed with COVID-19 compared to patients below 60 years old with COVID-19 revealed that 5013c was increased and 5019a was decreased (File S1).…”

“…Viruses are also known to produce sncRNAs from their own genomes [16]. Viral encoded small RNAs have recently been identified in SARS-CoV-2-infected cells [17,18].…”

“…Furthermore, a host tDR has been shown to contribute to the anti-viral response in respiratory syncytial virus [21,22]. Many publicly available next generation sequencing (NGS) studies, focus on the miRNAs altered in response to SARS-CoV-2 infection; however, the tDRs, have been characterized in only a few of those studies [17,23,24].…”

tatDB: a database of Ago1-mediated targets of transfer RNA fragments

“…As an additional illustration of the utility of tatDB, we provide here an example of a possible hypothesis generation for interpreting of the results of the current active research in coronavirus. We have noted earlier various factors linking the features of the SARS-CoV-2 genome with short RNAs ( 45 ), and were also intrigued by an observation of a significant increase in tRF levels in patient samples ( 46 ). Although the tRF IDs in that paper do not match ours, we performed a sequence search of a highly upregulated (∼35 fold) tRF5-Leu-AAG in tatDB and identified RPL18A as a potential target.…”

Parent tRNA Modification Status Determines the Induction of Functional tRNA-Derived RNA by Respiratory Syncytial Virus Infection

“…Noncoding RNAs (ncRNAs) comprise most of the human genome (as compared with protein-coding RNAs) [ 4 , 5 ], and their functions in physiological and pathological settings are increasingly recognized. tRNA-derived RNA fragments (tRFs) are a recently discovered category of ncRNAs whose importance in viral infectious diseases is becoming more evident [ 6 , 7 , 8 , 9 , 10 ]. We have recently shown that RSV infection induces a significant increase in tRFs.…”