Non-Coding RNAs and Their Role in Respiratory Syncytial Virus (RSV) and Human Metapneumovirus (hMPV) Infections

Abstract

Recent high-throughput sequencing revealed that only 2% of the transcribed human genome codes for proteins, while the majority of transcriptional products are non-coding RNAs (ncRNAs). Herein, we review the current knowledge regarding ncRNAs, both host- and virus-derived, and their role in respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) infections. RSV is known as the most common cause of lower respiratory tract infection (LRTI) in children, while hMPV is also a significant contributor to LRTI in the pediatrics population. Although RSV and hMPV are close members, belonging to the Pneumoviridae family, they induce distinct changes in the ncRNA profile. Several types of host ncRNAs, including long ncRNA (lncRNA), microRNAs (miRNAs), and transfer RNA (tRNA)-derived RNA fragments (tRFs), are involved as playing roles in RSV and/or hMPV infection. Given the importance of ncRNAs in regulating the expression and functions of genes and proteins, comprehensively understanding the roles of ncRNAs in RSV/hMPV infection could shed light upon the disease mechanisms of RSV and hMPV, potentially providing insights into the development of prevention strategies and antiviral therapy. The presence of viral-derived RNAs and the potential of using ncRNAs as diagnostic biomarkers are also discussed in this review.

Keywords: RSV; hMPV; ncRNAs.

Figure 1

Schematic diagram of the respiratory syncytial virus (RSV)-mediated microRNAs (miRNAs)-messenger RNA (mRNA) interaction networks involved in inflammatory responses. The RSV-increased miRNAs are indicated in red, the decreased miRNAs by RSV are shown in green. Arrows mark the positive effects between elements, whereas stop bars denote inhibitory effects.

Figure 2

Schematic diagram of the effect of RSV-regulated miRNAs on cell survival. RSV-induced and -decreased miRNAs are indicated in red and green, respectively. Arrows mark and stop bars respectively denote the positive and negative effects on the downstream molecules.

Figure 3

Biogenesis and classification of transfer RNA (tRNA)-derived RNA fragments (tRFs). The tRFs are generally classified into tRF-1 series, tRF-3 series, and tRF-5 series. tRF-1 series are usually those from the 3′-trailer sequences of pre-tRNA. tRF-3 and tRF-5 series are those whose sequences aligned to the 3′- and 5′- end of the mature tRNAs respectively; The length of tRFs ranges from 18 to 40 nt.

Figure 4

Model on the molecular mechanism used by tRF5-GluCTC to promote RSV replication. RSV infection induces tRF5-GluCTC, which targets APOER2 and suppresses its expression. APOER2 is an antiviral protein carrying out its antiviral role via its sequestration of the P protein of RSV. Therefore, the decreased expression of APOER2 frees more P proteins and makes them more available to form RdRp with other viral proteins.