Innate immune sensing of coronavirus and viral evasion strategies

Abstract

The innate immune system is the first line of the host defense program against pathogens and harmful substances. Antiviral innate immune responses can be triggered by multiple cellular receptors sensing viral components. The activated innate immune system produces interferons (IFNs) and cytokines that perform antiviral functions to eliminate invading viruses. Coronaviruses are single-stranded, positive-sense RNA viruses that have a broad range of animal hosts. Coronaviruses have evolved multiple means to evade host antiviral immune responses. Successful immune evasion by coronaviruses may enable the viruses to adapt to multiple species of host organisms. Coronavirus transmission from zoonotic hosts to humans has caused serious illnesses, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease-2019 (COVID-19), resulting in global health and economic crises. In this review, we summarize the current knowledge of the mechanisms underlying host sensing of and innate immune responses against coronavirus invasion, as well as host immune evasion strategies of coronaviruses.

Fig. 1. Sensing of RNA virus invasion by RLRs and TLRs.

Invasion by RNA viruses is sensed by cytosolic and endosomal RNA sensors, RLRs and TLRs. Both RLRs and TLRs can detect viral RNA species such as viral genomic RNA and dsRNA produced during viral replication. While RIG-I and MDA5 are responsible for sensing cytoplasmic viral RNAs such as 5′-ppp RNA with a secondary structure (RIG-I) or dsRNA (short dsRNA; RIG-I and long dsRNA; MDA5), TLRs can detect endosomal ssRNA (TLR7/8) or dsRNA (TLR3). Activated RLRs undergo a conformational change that allows RLRs to expose CARDs and trigger the IFN signaling pathway through the CARD-CARD interaction between RLRs and MAVS. On the other hand, activated TLR3 and TLR7/8 initiate the antiviral IFN program by recruiting the signal adapter molecules TRIF and MyD88, respectively. Then, subsequent activation of the shared downstream kinases and transcription factors elicits the production of IFNs and proinflammatory cytokines.

Fig. 2. The host innate immune sensing pathway targeted by coronavirus.

The multiple host factors in the antiviral signaling cascade are targeted by coronavirus proteins. Innate antiviral sensors can recognize coronavirus invasion by sensing cytosolic or endosomal viral RNA. As discussed, activation of virus sensors triggers an antiviral signaling cascade to elicit the production of type I or type III IFN as well as proinflammatory cytokines. On the other hand, coronaviruses have evolved multiple strategies to avoid host recognition by impeding the function of antiviral proteins using various viral proteins.

Fig. 3. Antagonizing IFN-mediated immune responses by coronavirus.

Secreted type I IFNs, IFN-α, and IFN-β can activate IFNAR1/2 in bystander cells to provoke the host antiviral program. On the other hand, coronavirus suppresses host antiviral IFN responses by targeting multiple components of the IFN signaling pathway through the inhibitory functions of viral proteins.