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  • The following are the supplementary data related to this art


    The following are the supplementary data related to this article.
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    Introduction MicroRNAs (miRNAs) are non-coding RNAs of ~22nucleotides (nt) in length, which influence development, cell differentiation, and apoptosis through post-transcriptional regulation [1], [2], [3], [4], [5], [6], [7]. MicroRNAs are also important regulators of virus–host interactions [8]. Viruses can reportedly regulate host cell microRNAs, or encode virus-like small RNAs, to support viral replication, persistent infection, and host immune escape [9], [10], [11]. Viral miRNAs (vmiRNAs) were first discovered in 2004, with the identification of a vmiRNA encoded by the Epstein-Barr virus (EBV) [12]. Since then, sequencing identification and bioinformatics prediction have led to the identification of miRNAs or miRNA-like molecules encoded by many viral families [13], [14], [15], [16], [17], [18], [19], [20], [21], and some vmiRNAs have been sequenced and functionally analyzed. Most vmiRNAs are encoded by large-genome DNA viruses (e.g., herpes viruses). It remains controversial whether RNA viruses also encode miRNAs, and the role of virus-like small RNAs in RNA virus infection is unclear. Rotavirus (RV) infection is an important cause of severe gastroenteritis among infants and children under 5years old worldwide [22]. RV belongs to the family Reoviridae, members of which have a double-stranded RNA genome comprising 11 dsRNA segments that encode six structural proteins (VP1–VP4, VP6, and VP7) and six non-structural proteins (NSP1–NSP6) [23]. The mechanism of interaction between RV and host LOXO-101 remains largely unknown, and the role of virus-like small RNA in RV infection is unclear. In general, viruses successfully replicate in host cells by adapting to the host cell environment, and utilizing the cell's nutrients, energy, and signaling pathways. Viral invasion causes the host cell to enter the stress state, prompting a series of survival reactions and defensive measures, including initiation of autophagy. Autophagy mediates the degradation of cytoplasmic material, such as misfolded proteins and exogenous pathogens. It occurs at basal levels in eukaryotic cells to maintain cellular homeostasis, and can be activated and strengthened by nutrient deprivation; growth factor depletion; or cellular stress, such as hypoxia, energy depletion, endoplasmic reticulum (ER) stress, and high temperature [24]. Autophagy can also be repressed by the class I PI3K/Akt/mTOR pathway. Autophagy plays important roles in initiating the innate and adaptive immune response to pathogens, including viral infection [25]. Viral replication in a host cell is a complex process that relies on structural and non-structural proteins working together to adapt to the host cell environment. Over the course of adaptation, viruses execute more strategies to co-opt host cell pathways, and pathogenic viruses, especially RNA viruses, rapidly evolve in response to host cell immunological processes [26]. Some pathogens take advantage of host cell autophagy to benefit their own replication; however, the mechanisms by which pathogens initiate the autophagy process have not been elucidated. Moreover, viruses can also inhibit autophagy processes to avoid being degraded. The mammalian target of rapamycin (mTOR), is reportedly involved in negative modulation of autophagy [27]. However, the mechanism of autophagy induction by RV is unknown. We previously investigated differential miRNA expression based on the infection of sensitive host cells with the wild-type RV strain ZTR-68, which was isolated in our lab [28]. Deep sequencing revealed five new small RNA sequences of 20–24nt in length, including one that we called RV-vsRNA1755. In our present study, we found that RV-vsRNA1755 is encoded by the NSP4 RV gene, and targets the host IGF1R in the PI3K/Akt pathway. RV-vsRNA1755 blockades the PI3K/Akt pathway and triggering autophagy in the early infection, but it ultimately inhibits autophagy to promote viral replication. Rotavirus adapts to manipulate PI3K/Akt signaling at different phases of infection.