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ORF8: A Complement evasion protein of SARS-CoV-2

Work done in the lab of Dr. Surajit Ganguly at Department of Molecular Medicine, Jamia Hamdard, New Delhi.

About author

Dr. Jitendra kumar pursued B.Sc Hons. and M.Sc in Zoology from University of Delhi. He joined School of Life Sciences, JNU New Delhi for M.Phil. Then he joined National Centre for Cell Science (NCCS) Pune for Ph.D. in Biotechnology and worked in the area of Virus-host interaction under the supervision of Dr. Arvind Sahu. During his PhD, Dr. Kumar was invited to present his research findings at 15th European Meeting for Complement and Human Diseases (EMCHD) 2015 in Uppsala, Sweden and won the best poster award. He went to UT Southwestern Medical Centre, Texas USA in 2018 for Postdoctoral Research on CAR-T therapy for solid tumors. During COVID-19 he returned back to India and resumed his Postdoctoral studies on SARS-CoV-2 in National Institute of Immunology and Jamia Hamdard, New Delhi. At present Dr. Jitendra is an Assistant Professor at Deshbandhu College, University of Delhi, and grooming undergraduate students in cutting-edge scientific areas.

Interview

How would you explain your research outcomes to the non-scientific community?

A novel Coronavirus spread worldwide in December 2019 causing 69 million infections and nearly 6.9 million deaths till May 2023. Recently the WHO declared the end of emergency but these types of viruses always remain a threat to humankind and there is a paramount possibility of the emergence and re-emergence of similar viruses in the future. The presence of complement activation markers (C3b, Bb, C4d, iC3b, C3a, Ba) in the vital organs of severely hospitalized patients is one of the prominent pathological features of COVID-19. Complement is the first line of defense and during infection, it plays a significant role in tagging and eliminating viruses, bacteria, and fungi. It appears that the complement system in COVID-19 has two opposite roles in the early and late phases of infection. In the early phase, all arms of innate immunity including the complement system tried to overcome the infection, as a response virus employed complement evasion strategies and succeeded to remain unnoticed which helps in viral replication. In the later phase, defective viral clearance induces the cytokine storm, immune cell infiltration, and inflammatory response as a result of excessive complement activation, which leads to lung damage. I was interested to know about the molecular mechanism and how SARS-CoV-2 circumvents Complement – one of the ancient enzyme cascade networks of plasma proteins and cell surface-bound receptors.

We have reported that ORF8 which is one of the 9 accessory proteins, screens the SARS-CoV-2 from immunological recognition and intervenes in its targeted elimination by complement. ORF8 is a binding partner of central complement component C3 and its metabolite (C3b, iC3b, C3 (H2O), C3d). C3b-ORF8 co-complex shield C3/C3b binding to Factor H (a cell surface/ soluble human complement regulator), serine proteases Factor B & Factor I, which eventually inhibits augmentation of complement amplification loop, a necessary step for killing SARS-CoV-2.

How do these findings contribute to your research area?

It is the first time we have assigned a novel function to this selectively evolved SARS-CoV-2 protein. Our findings open a completely new area of research for ORF8 protein-based complement inhibitors. Our research will be useful to better understand the pathogenesis of COVID-19 and to generate countermeasures.

“It is the first time we have assigned a novel function to this selectively evolved SARS-CoV-2 protein.”

What was the exciting moment during your research?

We have found around 30 % sequence similarity of ORF8 with part of the C-Terminal domain of human Factor I (FI). It was enthralling to observe that SARS-CoV-2 evolutionary adapted in such a short time and we could validate these in silico results with protein-protein interaction studies and complement specific wet lab assays.

What do you hope to do next?

We are looking into other Ig (Immunoglobulin) domain-containing host proteins, which could also be mimicked by SARS-CoV-2 and may help in immune evasion.

Where do you seek scientific inspiration from?

I am highly inspired by Dr. Arvind Sahu, my doctoral thesis supervisor, and internationally renowned Complement biologist.

How do you intend to help Indian science improve?

Being a College Professor, the implementation of the New Education Policy 2022 is one of the great steps toward igniting the research potential of Indian Science Graduates. I will use student’s subject knowledge to recognize the problem in animal sciences and focus them to develop an idea for solving the research-based questions of national importance.

Reference

Kumar J, Dhyani S, Kumar P, Sharma NR, Ganguly S. SARS-CoV-2-encoded ORF8 protein possesses complement inhibitory properties. J Biol Chem. 2023 Jan 19;299(3):102930. https://www.jbc.org/article/S0021-9258(23)00062-5/fulltext

Copy Editor: Nikita Nimbark

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