This is the twelfth article in a series called “How SARS-CoV-2 Evades And Suppresses The Immune System,” which will explore an underappreciated but highly significant aspect of SARS-CoV-2 replication. The ability of SARS-CoV-2 to delay, evade, and suppress the immune system has myriad implications for drugs, vaccines, and other aspects of our pandemic response. The first set of pieces in this series are intended for a general audience; the second set, for the medical community; and the third and final set, for biomedical researchers looking for a deeper understanding of variants, how they’re generated, and what we might do to control them. Read parts 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11.
Ganging up to knock out the key players
Interferon is a key player in the innate immune response. But interferon doesn’t operate in isolation. Its broad effectiveness is contingent on the recruitment of other genes. Once activated, many of these interferon-stimulated genes inhibit virus replication directly, whereas others rally the immune system’s second line of defense, the adaptive immune response, into action.
In Part 11, I examined the left half of the diagram below, which illustrates how SARS-CoV-2 blocks the induction of interferon (see Figure 1). We saw how SARS-CoV-2 blockade prevents synthesis of type-I interferons, limiting its action within the cell. Should any interferon escape suppression, other factors restrict its exit from the infected cell to alert nearby cells of impending danger.
Now we will turn to the latter half of the signaling pathway, more specifically how SARS-CoV-2 blocks induction of the interferon type-I induced genes and proteins.
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When type-I interferons are secreted, they bind to interferon receptors that trigger a cascade of downstream factors culminating in the expression of many interferon-stimulated genes. Two of these are the kinases Janus kinase 1 (JAK1) and Tyrosine kinase 2 (TYK2). Kinases are responsible for phosphorylation of target proteins. In this case, JAK1 and TYK2 add phosphate groups to STAT1 and STAT2, or signal transducer and activator of transcription proteins. Once phosphorylated, STAT1 and STAT2 assemble into a heterodimer. The STAT 1/STAT2 heterodimer then activates interferon regulatory factor 9 (IRF9). It is this interaction that produces interferon-stimulated gene factor 3 (ISGF3). The complex then migrates to the nucleus, where it stimulates interferon-sensitive response elements.
The phosphorylation of STAT1 and STAT2 makes a key point of interference for SARS-CoV-2, which dispatches several proteins to apprehend STAT1/STAT2 before they produce ISGF3. According to a study of SARS-Cov-2 obstruction of interferon signaling pathways published in October 2020, inhibition of STAT1 phosphorylation involves the nonstructural proteins Nsp1, Nsp6, and Nsp13; the open reading frames Orf3a and Orf7b; and the M protein. The inhibition of STAT2 phosphorylation also involves Nsp6, Nsp13, and Orf7b, but Orf7a as well. The exact mechanisms of suppression are unknown, but without either phosphorylation, the STAT1/STAT2 heterodimer cannot form and therefore interferon-stimulated genes cannot be produced.
The last leg of the interferon signaling pathway that SARS-CoV-2 inhibits is the translocation of ISGF3, or the STAT1/STAT2/IRF9 complex, to the nucleus. Once there, ISGF3 can bind to interferon-stimulated response elements and thus activate the transcription of many hundreds of interferon-stimulated genes that engage in antiviral activity. Recall that in the first half of the pathway, which I described at length in my most recent article, Orf6 blocks translocation of IRF3 to the nucleus by binding to the transport receptor KPNA2. It appears that Orf6 also blocks translocation of STAT1 to the nucleus, effectively preventing the expression of interferon-stimulated genes.
Mutations that disrupt the function of any of these genes and protein pathways dramatically decrease the replication and pathogenesis of the mutant virus, as studies of new and emergent variants have shown. This will be the focus of a later article in this series. Next up, I will discuss how SARS-CoV-2 interferes with the germinal centers of infected cells.