Viruses use a variety of processes to evade the immune system and buy time to replicate. Some of these processes include inhibition of the humoral response, interfering, inhibiting, and modulating interferons, cytokines, chemokines, and apoptosis, as well as evading MHC. As viruses co-evolve with their hosts, they find new ways to evade detection.

When SARS-CoV-2 enters a cell, RIG-I-like receptors (RIG-I and MDA5) and endosomal TLR3, TLR7, and TLR8 sense the single-stranded RNA of the coronavirus and forward the signal downstream to MAVS, MyD88, and TRIF. This in turn activates IKK cascades leading to activation of IRF3 and NF-?B, which are required for IFN-I and pro-inflammatory cytokine expression. SARS-CoV-2 has found a way to interfere somewhere along these pathways, thereby evading the expected innate immune response.

Various SARS-CoV-2 accessory proteins affect the innate immune response pathways at different steps, but all leading to either antagonism of IFN-I production or suppression of IFN-I signaling. Early experiments show that IFN-I production is antagonized when SARS-CoV-2 ORF9b targets NEMO (IKK?), when nsp6 binds to TBK1 to suppress IRF3, when nsp13 binds to TBK1 to suppress its phosphorylation, and when ORF6 blocks IRF3 nuclear translocation. IFN-I signaling suppression appears to occur when viral proteins block STAT1 phosphorylation (M, nsp1, nsp6, nsp13, ORF3a, and ORF7b), when others suppress STAT2 phosphorylation (nsp6, nsp13, ORF7a, and ORF7b), and when ORF6 inhibits nuclear translocation of STAT1. ORF9c appears to reduce IFN signaling protein levels.

Additionally, ORF8 can downregulate MHC-I and ORF7a and ORF9c have other means of inhibiting antigen presentation. ORF3a induces apoptosis and also inhibits autophagy. And there is more to learn.

Research continues in understanding the exact mechanisms of SARS-CoV-2 immune evasion. ProSci does its part in supporting such research endeavors by supplying the life sciences community with antibodies and recombinant proteins to SARS-CoV-2 accessory proteins as well as the human proteins they interact with. Contact us to see how we can help your research.

The functional understanding of these proteins continues to expand.


Alcami, A., & Koszinowski, U. H. (2000). Viral mechanisms of immune evasion. Immunology Today, 21(9), 447–455.

Xia, H., Cao, Z., Xie, X., Zhang, X., Chen, J. Y.-C., Wang, H., Menachery, V. D., Rajsbaum, R., & Shi, P.-Y. (2020). Evasion of Type I Interferon by SARS-CoV-2. Cell Reports, 33(1), 108234.

Wu, J., Shi, Y., Pan, X., Wu, S., Hou, R., Zhang, Y., Zhong, T., Tang, H., Du, W., Wang, L., Wo, J., Mu, J., Qiu, Y., Yang, K., Zhang, L.-K., Ye, B.-C., & Qi, N. (2021). SARS-CoV-2 ORF9b inhibits RIG-I-MAVS antiviral signaling by interrupting K63-linked ubiquitination of NEMO. Cell Reports, 34(7), 108761.

Flower, T. G., Buffalo, C. Z., Hooy, R. M., Allaire, M., Ren, X., & Hurley, J. H. (2020). Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein. Proceedings of the National Academy of Sciences, 118(2), e2021785118.

Zhou, Z., Huang, C., Zhou, Z., Huang, Z., Su, L., Kang, S., Chen, X., Chen, Q., He, S., Rong, X., Xiao, F., Chen, J., & Chen, S. (2021). Structural insight reveals SARS-CoV-2 ORF7a as an immunomodulating factor for human CD14+ monocytes. IScience, 24(3), 102187.

Dominguez Andres, A., Feng, Y., Campos, A. R., Yin, J., Yang, C.-C., James, B., Murad, R., Kim, H., Deshpande, A. J., Gordon, D. E., Krogan, N., Pippa, R., & Ronai, Z. A. (2020). SARS-CoV-2 ORF9c Is a Membrane-Associated Protein that Suppresses Antiviral Responses in Cells. Cold Spring Harbor Laboratory.

Ren, Y., Shu, T., Wu, D., Mu, J., Wang, C., Huang, M., Han, Y., Zhang, X.-Y., Zhou, W., Qiu, Y., & Zhou, X. (2020). The ORF3a protein of SARS-CoV-2 induces apoptosis in cells. Cellular & Molecular Immunology, 17(8), 881–883.

Miao, G., Zhao, H., Li, Y., Ji, M., Chen, Y., Shi, Y., Bi, Y., Wang, P., & Zhang, H. (2021). ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation. Developmental Cell, 56(4), 427-442.e5.