Interferon and cytokine responses to SARS-coronavirus infection

Abstract

The sudden emergence of severe acute respiratory syndrome (SARS) has boosted research on innate immune responses to coronaviruses. It is now well established that the causative agent, a newly identified coronavirus termed SARS-CoV, employs multiple passive and active mechanisms to avoid induction of the antiviral type I interferons in tissue cells. By contrast, chemokines such as IP-10 or IL-8 are strongly upregulated. The imbalance in the IFN response is thought to contribute to the establishment of viremia early in infection, whereas the production of chemokines by infected organs may be responsible for (i) massive immune cell infiltrations found in the lungs of SARS victims, and (ii) the dysregulation of adaptive immunity. Here, we will review the most recent findings on the interaction of SARS-CoV and related Coronaviridae members with the type I interferon and cytokine responses and discuss implications for pathogenesis and therapy.

Fig. 1

Parallel pathways of type I IFN induction by RNA viruses. (A) Intracellular pathway. Characteristic by-products of virus replication such as dsRNA or 5′triphosphorylated ssRNA lead to activation of the transcription factor IRF-3. Cooperative action with NF-κB and AP-1 is required for full activation of the IFN-β promoter. IRF-3 is phosphorylated by the kinases TBK-1 and IKKɛ (not shown) which in turn are activated by the RNA-sensing molecules RIG-I (recognizing 5′ triphosphorylated ssRNA) and MDA-5 (recognizing dsRNA). PKR, which also recognizes dsRNA, is important for activating NF-κB. AP-1 is activated by the stress-responsive kinase Jun. (B) Endosomal pathway. TLR7/8 and TLR3 recognize viral ssRNA and dsRNA, respectively, and activate IFNα/β transcription via the transcription factors IRF-7, IRF-3, and NF-κB. Only those parts of the pathways are depicted which are relevant for the discussion of coronaviral interactions (see main text). For comprehensive representations see recent reviews , , .

Fig. 2

Coronavirus life cycle and RNA-specific pathogen recognition receptors. The coronavirus life cycle is illustrated together with PRRs with the potential to sense viral RNA. Coronaviruses enter their host cells either on the plasma membrane or via endosomes where they could be recognized by TLR 3, 7, or 8. Note that MHV is shown to be recognized by TLR7 in pDCs . Upon uncoating the capped viral ssRNA is released into the host cell cytoplasm and could be sensed by MDA-5 or PKR due to secondary structures containing dsRNA domains. Viral RNA synthesis takes place in or at double membrane vesicles (DMVs) and involves the appearance of dsRNA , again potentially recognized by MDA-5 and PKR. The negative-sense RNAs arising as an intermediate of DMV-associated genome replication and transcription are possibly 5′-triphosphorylated and thus could be recognized by RIG-I. Finally, a nested set of viral mRNAs are released into the cytoplasm (putative sensors: MDA-5 or PKR) where they are translated. The full-length genomic RNA can also be translated and is eventually packaged into progeny virus particles which are released from the host cell via the exocytosis pathway.