Non-coding RNA: a key regulator of the pathogenicity and immunity of Flaviviridae viruses infection

Flaviviridae is a family of viruses that mainly spread through arthropod vectors, such as mosquitoes. Major members of the Flaviviridae family include dengue virus (DENV), yellow fever virus, Zika virus (ZIKV), West Nile virus and hepatitis C virus (HCV). As Flaviviridae viruses remain a major global public health threat, elucidation of the exact mechanisms of pathogenesis during infection is required for the successful control of these deadly viruses.

Recent evidence has shown that non-coding RNAs induced by viral infection might play a critical role in regulating the virus−host interaction during Flaviviridae infection. We recently showed that severe human DENV infection induced the downregulation of microRNA (miRNA)-378 in peripheral blood mononuclear cells, which might suppress the expression of Granzyme B (GrzB) (Figure 1), suggesting that the DENV−miRNA−378−GrzB interaction axis is actively involved in the virus−host interaction during Flaviviridae infection.¹ However, whether and how miRNA-378 regulates pro-viral immunopathogenesis or anti-viral immunity during DENV infection require further study. The importance of host non-coding RNA in mediating the virus−host interaction is further solidified by recent findings suggesting that the liver-specific tumor suppressor miRNA-122 contributes to enhanced HCV replication; viral RNA appears to suppress the normal host targets of miRNA-122 and to enhance the long-term oncogenic potential of HCV infection² (Figure 1). Moreover, it is thought that miRNA-15b acts as a positive regulator of the production of virus-induced inflammatory cytokines, such as interleukin (IL)-1b, IL-6 and CCL2, in HeLa cells during Japanese encephalitis virus infection.³ Together, these findings suggest that miRNAs are a central mediator of immune networks or virus−host interaction processes during Flaviviridae virus infection.

Figure 1.

The importance and mechanisms of non-coding RNAs in mediating immunity and pathogenecity during flaviviridae viruses infection. circRNA, circular RNA; DENV, dengue virus; GrzB, granzyme B; HCV, hepatitis C virus; IFN, interferon; lncRNA, long non-coding RNA; miRNA, microRNA; ORF, open reading frame; piRNA, PIWI-interacting RNA; RIG-1, retinoic acid-inducible gene 1; sfRNA, subgenomic non-coding flavivirus RNA; UTR, untranslated region; WNV, West Nile virus; ZIKV, Zika virus.

In addition to miRNAs, other non-coding RNAs, such as long non-coding RNAs, circular RNAs and PIWI-interacting RNAs, may play critical roles in Flaviviridae virus infections.^{4, 5, 6, 7, 8, 9} Further studies are required to elucidate the expression profiles of non-coding RNAs and their roles (Figure 1). It is also worth mentioning that the expression levels of several miRNAs, including miRNA-378, are variable in severe cases of human DENV infection; it remains unclear how these miRNAs and other non-coding RNAs act to regulate T-cell, B-cell and monocyte function.

Flaviviridae viruses have genomic structures similar to positive-sense single-stranded RNA, containing one open reading frame flanked by 5′ and 3′ untranslated regions (UTRs). Recent evidence has shown, however, that 3′ UTRs of full-length genomic RNA contain subgenomic non-coding flavivirus RNA (sfRNA). Some human miRNAs are known to originate from viral genomes. Recent evidence suggests that the sfRNA of DENV is an important non-coding RNA, which is able to shape the epidemiological fitness of DENV by binding to TRIM25 (tripartite motif-containing protein 25), thereby inhibiting the anti-viral interferon response (Figure 1). It was recently reported that a complex fold structure, the multi-pseudoknot, is responsible for ZIKV sfRNA production (Figure 1), suggesting that sfRNA in the 3′ UTR may also participate in the pathogenicity of ZIKV.¹⁰ However, the exact role and mechanisms of action of ZIKV sfRNA require further study. Taken together, these data suggest that the non-coding RNA found in the genomes of Flaviviridae viruses is a key regulator of the balance between pro-viral pathogenicity and anti-viral immunity and is thereby a critical determinant of infection outcome.

Collectively, non-coding RNAs, either from the host or from the viral genome, are of great importance in modulating the balance between pro-viral pathogenicity and anti-viral immunity after infection by Flaviviridae viruses. Thanks to recent studies of non-coding RNAs and their function, we may expect to overcome the difficulty of developing vaccines against Dengue virus,¹¹ to establish new therapeutic approaches and to control deadly Flaviviridae virus infections in the near future.