Mechanisms of severe acute respiratory syndrome pathogenesis and innate immunomodulation

Abstract

The modulation of the immune response is a common practice of many highly pathogenic viruses. The emergence of the highly pathogenic coronavirus severe acute respiratory virus (SARS-CoV) serves as a robust model system to elucidate the virus-host interactions that mediate severe end-stage lung disease in humans and animals. Coronaviruses encode the largest positive-sense RNA genome of approximately 30 kb, encode a variety of replicase and accessory open reading frames that are structurally unique, and encode novel enzymatic functions among RNA viruses. These viruses have broad or specific host ranges, suggesting the possibility of novel strategies for targeting and regulating host innate immune responses following virus infection. Using SARS-CoV as a model, we review the current literature on the ability of coronaviruses to interact with and modify the host intracellular environment during infection. These studies are revealing a rich set of novel viral proteins that engage, modify, and/or disrupt host cell signaling and nuclear import machinery for the benefit of virus replication.

Figures

FIG. 1.

SARS-CoV and MHV genome structure. The genome structure of coronaviruses is very conserved among all known coronaviruses. In each coronavirus, the N-terminal two-thirds of the genome encodes the nonstructural proteins, also called the replicase proteins (orange box). The C-terminal one-third of the genome encodes the structural (red boxes) and accessory (gray boxes) ORFs. The structural ORFs encode the spike, envelope (E), membrane (M), and nucleocapsid (N) proteins. Each coronavirus has similar structural ORFs in their genomes. The accessory ORFs, in gray, are unique to each coronavirus. There is no sequence or structural similarities between the MHV and SARS-CoV accessory proteins.

FIG. 2.

The innate immune induction pathway and SARS-CoV. The major proteins in the innate induction pathway are shown as they signal from sensing a pathogen to induction of IFN-β. Initially, RIG-I and MDA5 sense dsRNA in the cytoplasm, produced as a by-product of RNA virus replication. They signal to the mitochondrial membrane protein MAVS, which in turn activates the kinases TBK1 and IKKɛ. These kinases then phosphorylate IRF3, causing it to dimerize and traffic to the nucleus, where it, along with NF-κB, induces the transcription of IFN-β. SARS-CoV proteins actively modulate this pathway. ORF3b, N, and NSP1 affect the signal transduction pathway that activates IRF3 by an unknown mechanism. NSP1 also affects the mRNA stability of IFN-β transcript. The PLP of SARS-CoV also affects IRF3 and NF-κB. PLP blocks the phosphorylation of IRF3 and its activation while also blocking the activation of NF-κB. This results in a block in IFN-β induction.

FIG. 3.

The JAK/STAT signaling pathway and SARS-CoV. The JAK/STAT pathway responds to type I IFN secreted from neighboring cells. The IFN-α/β receptor binds to either IFN-α or -β and signals to the Jak1 or TYK1 kinase. These kinases phosphorylate both STAT1 and STAT2. This phosphorylation induces the complex formation of STAT1/STAT2/IRF9 (the ISGF3 complex) and targets the complex to the nucleus with the help of the import factors KPNA1 (Kα1) and KPNB1 (Kβ1). Once in the nucleus, the complex turns on genes containing an ISRE in their promoter. SARS-CoV proteins have been shown to affect this pathway. NSP1 reduces the levels of Jak1 in the cytoplasm and affects it kinase activity. ORF6 blocks the nuclear import of ISGF3 by reducing the free Kβ1 in the cytoplasm and retaining it on the ER/Golgi membrane.