Viral strategies to antagonize the host antiviral innate immunity: an indispensable research direction for emerging virus-host interactions

Abstract

The public's health is gravely at risk due to the current global outbreak of emerging viruses, specifically SARS-CoV-2 and MPXV. Recent studies have shown that SARS-CoV-2 mutants (such as Omicron) exhibit a higher capability to antagonize the host innate immunity, increasing their human adaptability and transmissibility. Furthermore, current studies on the strategies for MPXV to antagonize the host innate immunity are still in the initial stages. These multiple threats from emerging viruses make it urgent to study emerging virus-host interactions, especially the viral antagonism of host antiviral innate immunity. Given this, we selected several representative viruses that significantly threatened human public health and interpreted the multiple strategies for these viruses to antagonize the host antiviral innate immunity, hoping to provide ideas for molecular mechanism research that emerging viruses antagonize the host antiviral innate immunity and accelerate the research progress. The IAV, SARS-CoV-2, SARS-CoV, MERS-CoV, EBOV, DENV, ZIKV, and HIV are some of the typical viruses. Studies have shown that viruses could antagonize the host antiviral innate immunity by directly or indirectly blocking antiviral innate immune signaling pathways. Proviral host factors, host restriction factors, and ncRNAs (microRNAs, lncRNAs, circRNAs, and vtRNAs) are essential in indirectly blocking antiviral innate immune signaling pathways. Furthermore, via controlling apoptosis, ER stress, stress granule formation, and metabolic pathways, viruses may antagonize it. These regulatory mechanisms include transcriptional regulation, post-translational regulation, preventing complex formation, impeding nuclear translocation, cleavage, degradation, and epigenetic regulation.

Keywords: Emerging viruses; IAV; SARS-CoV-2; antagonism; host antiviral innate immunity; interferon production; interferon responses.

Figure 1.

Antiviral innate immune signaling pathways mediated by RIG-I, MDA5, TLR3/7, and cGAS/STING. After virus infection of cells, antiviral innate immune signaling pathways are activated to induce the phosphorylation of transcription factors and IFNα/β expression. Subsequently, IFNα/β binds to interferon receptors on target cells, thereby initiating antiviral interferon responses and, ultimately, ISGs expression.

Figure 2.

The viral strategies to indirectly block antiviral innate immune signaling pathways by hijacking ncRNAs and proviral host factors or antagonizing host restriction factors. Red, blue, purple, peacock blue, green, and light blue indicate viral proteins (viruses), microRNAs, lncRNAs, vtRNAs, proviral host factors, and host restriction factors, respectively.

Figure 3.

The viral strategies to block antiviral innate immune signaling pathways: inhibition of interferon induction. Viruses could block interferon production by targeting and regulating multiple steps of antiviral innate immune signaling pathways such as PRRs, signaling proteins, and transcription factors. Red, blue, purple, green, and light blue indicate viral proteins (viruses), microRNAs, lncRNAs, proviral host factors, and host restriction factors, respectively.

Figure 4.

The viral strategies to block antiviral innate immune signaling pathways: inhibition of interferon responses. Viruses could antagonize the host antiviral innate immunity by directly or indirectly blocking interferon responses. Red, purple, and peacock blue indicate viral proteins (viruses), lncRNAs, and vtRNAs, respectively.