In brief

Infections by △382 SARS-CoV-2, a variant with an impaired ORF8 protein, cause more robust immune responses compared to those by the original virus.

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How variants have loosened their grip

2 Dec 2022

A deletion in the genome of SARS-CoV-2 variants makes resulting infections milder and could also be a target for future COVID-19 treatments.

Another year into pandemic life and most of us have settled into a new normal. While masking and vaccinations continue to help keep COVID-19 case numbers down, the gradual de-escalation of the public health threat it poses may be partly thanks to a curious quirk of viral evolution—the ‘accidental birth’ of weaker variants.

Despite being more transmissible than the original virus, certain genetic variants of SARS-CoV-2 tend to cause milder disease symptoms with less inflammation throughout the body. Experts attribute this shift to a ‘mutational hotspot’ in a region of the virus’s genome called ORF8.

“The ORF8 region encodes one of SARS-CoV-2’s most rapidly mutating proteins,” said Siew‐Wai Fong, a Research Scientist at the A*STAR Infectious Diseases Labs (ID Labs). “Since the beginning of the pandemic, we’ve seen different ORF8 mutations in multiple variants of concern (VOCs), including Alpha, Gamma, Delta and Omicron.”

Fong explained that for viruses, random mutations are essential to adapt to host defences and keep replicating. While some mutations might boost a variant’s transmission speed, or lead it to induce more life-threatening symptoms, the luck of the genetic draw might also dull a variant’s infective edge.

Notably, some of the more benign SARS-CoV-2 variants carry genomes with sections deleted from ORF8. Fong and Lisa Ng, Executive Director at A*STAR’s ID Labs, co-led a pioneering study of how a local variant with a large 382-base deleted section in ORF8, known as △382 SARS-CoV-2, caused an altered immune system response versus the original (or wildtype) virus.

“Understanding the natural biology of host immune responses after infection with these SARS-CoV-2 variants will provide important insights into preventive and therapeutic strategies,” said Fong.

The researchers recruited a cohort of 66 patients with COVID-19 in Singapore, 19 of whom had been infected with the Δ382 variant. They then extracted genetic material from the participants’ blood samples and analysed them with RNA sequencing technology. This approach enabled the team to tease out molecular differences in the immune responses between wildtype SARS-CoV-2 and △382 infections.

The team found a potential explanation for the milder symptoms: with its ORF8 proteins disabled by the missing section of RNA, the Δ382 variant set off stronger and more immediate immune responses compared to the wildtype. The researchers’ data also revealed a surge in T cell activity and a decrease in inflammatory cytokine production, as well as faster antibody responses.

Fong said that these results put ORF8 in the spotlight as a previously unexplored target for future COVID-19 vaccines and antiviral treatments. However, ORF8 isn’t the only mutation hotspot in play for SARS-CoV-2; mutations affecting the virus’s spike protein may also influence infection severity and transmission speed.

“The asymptomatic or mild disease symptoms attributed to ORF8’s absence, in tandem with enhanced infectivity from spike mutations, may explain the high transmissibility of VOCs that became dominant over the pandemic’s course,” concluded Fong, adding that ORF8 mutation monitoring would be a focal point of the team’s ongoing studies.

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN) and A*STAR Infectious Diseases Lab (ID Labs).

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Fong, S.-W., Yeo, N.K.-W., Chan, Y.-H., Goh, Y.S., Amrun, S.N., et al . Robust Virus‐Specific Adaptive Immunity in COVID‐19 Patients with SARS‐CoV‐2 Δ382 Variant Infection. Journal of Clinical Immunology 42 , 214-229 (2021). | article

About the Researchers

Siew-Wai Fong obtained her PhD in human physiology from Universiti Sains Malaysia (USM). She joined A*STAR Infectious Diseases Labs to work on bridging the knowledge gap of vector-pathogen-host interactions in mosquito-borne virus transmission. Since 2020, she has conducted extensive research on the human immune response to SARS-CoV-2 infection. Key findings from her in-depth immunophenotyping of COVID-19 patients have aided Singapore’s efforts to tackle COVID-19. Her COVID-19 research works have been published in international scientific journals such as the Lancet, Nature and EMBO.
Lisa F.P. Ng obtained her PhD in molecular virology in coronaviruses from the National University of Singapore (NUS) in 2002. After joining A*STAR’s Genome Institute of Singapore (GIS) in 2002 as a Postdoctoral Fellow, she worked on viral diseases such as hepatitis, severe acute respiratory syndrome and influenza. Ng is currently the Executive Director at A*STAR Infectious Diseases Labs (ID Labs) where she focuses on the immune responses to arthritic arboviruses that are epidemic or highly endemic in the tropical region. Ng has won numerous accolades for her research, including the ASEAN ‘International Young Scientist and Technologist Award’ in 2008 and A*STAR’s ‘Most Inspiring Mentor Award’ in March 2013.

This article was made for A*STAR Research by Wildtype Media Group