Virus-host interaction networks as new antiviral drug targets for IAV and SARS-CoV-2

Abstract

Currently, SARS-CoV-2, especially the Omicron strain, is ravaging the world and even co-infecting human beings with IAV, which is a serious threat to human public health. As of yet, no specific antiviral drug has been discovered for SARS-CoV-2. This requires deeper understandings of the molecular mechanisms of SARS-CoV-2-host interaction, to explore antiviral drug targets and provide theoretical basis for developing anti-SARS-CoV-2 drugs. This article discussed IAV, which has been comprehensively studied and is expected to provide the most important reference value for the SARS-CoV-2 study apart from members of the Coronaviridae family. We wish to establish a theoretical system for the studies on virus-host interaction. Previous studies have shown that host PRRs recognize RNAs of IAV or SARS-CoV-2 and then activate innate immune signaling pathways to induce the expression of host restriction factors, such as ISGs, to ultimately inhibit viral replication. Meanwhile, viruses have also evolved various regulatory mechanisms to antagonize host innate immunity at transcriptional, translational, post-translational modification, and epigenetic levels. Besides, viruses can hijack supportive host factors for their replication. Notably, the race between host antiviral innate immunity and viral antagonism of host innate immunity forms virus-host interaction networks. Additionally, the viral replication cycle is co-regulated by proteins, ncRNAs, sugars, lipids, hormones, and inorganic salts. Given this, we updated the mappings of antiviral drug targets based on virus-host interaction networks and proposed an innovative idea that virus-host interaction networks as new antiviral drug targets for IAV and SARS-CoV-2 from the perspectives of viral immunology and systems biology.

Keywords: IAV; Omicron; SARS-CoV-2; antiviral drug targets; host innate immunity; replication cycle; virus-host interactions.

Figure 1.

The mapping of antiviral drug targets focusing on IAV replication cycle. A complete IAV replication cycle consists of four stages: attachment, entry and uncoating, replication and transcription, assembly and release. Host restriction factors, supportive host factors, microRNAs, and lncRNAs can regulate IAV replication by directly acting on one or multiple steps of the IAV replication cycle. Theoretically, these host biomolecules, which regulate the viral replication cycle and each of these steps in the viral replication cycle, could be used as potential antiviral drug targets. Green lines indicate that supportive host factors target one or multiple steps of the IAV replication cycle. Red lines indicate that host restriction factors target one or multiple steps of the IAV replication cycle. Purple lines indicate that lncRNAs target one step of the IAV replication cycle. Blue lines indicate that microRNAs target IAV proteins.

Figure 2.

The mapping of antiviral drug targets focusing on host innate immune responses against IAV. The host PRRs can recognize dsRNA or ssRNA during IAV replication and quickly activate the innate immune signaling pathways to induce the expression of interferons and downstream ISGs, thereby inhibiting one or multiple steps of the IAV replication cycle. Meanwhile, IAV has evolved multiple strategies to directly or indirectly antagonize host innate immunity at transcriptional, translational, post-translational modification, and epigenetic levels. Notably, microRNAs, lncRNAs, and vtRNAs regulate innate immune signaling pathways. Theoretically, these host biomolecules, which regulate the host innate immune signaling pathways and the viral antagonism of host innate immune responses, could be used as potential antiviral drug targets. The red, blue, purple, peacock blue lines respectively indicate that IAV proteins, microRNAs, lncRNAs, vtRNAs target various steps of host innate immune signaling pathways.

Figure 3.

The mapping of antiviral drug targets focusing on SARS-CoV-2 antagonism of host innate immune signaling pathways. On the one hand, SARS-CoV-2 infection activates the host innate immune signaling pathways, thereby promoting the expression of type I/III interferons and downstream ISGs. On the other hand, SARS-CoV-2 can suppress the expression of interferons and downstream ISGs by targeting and inhibiting PRRs, signaling proteins, transcription factors, and interferon-activated JAK/STAT signal transduction. Theoretically, the viral antagonism of host innate immune signaling pathways could be used as potential antiviral drug targets. The red lines indicate that SARS-CoV-2 proteins target various steps of host innate immune signaling pathways.