Why A Milder Variant of Coronavirus (Δ382) Just Disappeared

Shin

Decreased virulence but no boost in transmissibility might have led to its demise.

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What is biological fitness? It is the organism’s ability to adapt to and reproduce in different environments. How might a microbe improve its fitness then? It is by being more transmissible and not too virulent because a dead host is a dead end after all.

That is why we have been hearing news or viewpoints that SARS-CoV-2, the causative agent of Covid-19, is becoming more transmissible and less virulent. While the former is true with the infamous D614G mutation (with >70% worldwide prevalence), no robust evidence has supported the latter. A few cohort studies have observed no difference in death rates between patients infected with the D614G-mutated and -unmutated SARS-CoV-2.

What the D614G Mutation Means for Covid-19 Spread, Fatality, Treatment, and Vaccine

New evidence for a milder SARS-CoV-2 variant

But a published study in The Lancet this week, titled “Effects of a major deletion in the SARS-CoV-2 genome on the severity of infection and the inflammatory response: an observational cohort study,” provides the first evidence for a milder variant of SARS-CoV-2.

Researchers from institutions across Singapore screened Covid-19 patients for a SARS-CoV-2 variant called Δ382, which has a 382-nucleotide deletion in the genes that code for open reading frames (ORF) 7B and 8. This means that 382 genetic letters disappeared in the SARS-CoV-2 genome, resulting in truncated ORF7B and removed ORF8 genes.

Their sample size was 131, of which 70% were infected with the normal (wild-type) SARS-CoV-2 and 30% with the Δ382 variant. All groups had similar baseline characteristics, in terms of age, sex, and ethnicity. Results revealed that:

  • Patients infected with the ∆382 variant had better clinical outcomes than the wild-type virus. All groups had similar rates of pneumonia diagnosis. But none of those infected with the Δ382 variant developed hypoxia requiring supplemental oxygen or need intensive care unit (ICU) level of care. In contrast, 28% and 10% of the wild type group developed hypoxia and were admitted to ICU, respectively.
  • Patients infected with the Δ382 variant had lower circulating levels of pro-inflammatory chemokines and growth factors associated with lung injury, and higher levels of antiviral and anti-inflammatory cytokines, than those infected with the wild-type SARS-CoV-2.

“The ∆382 variant causes clinically significant illness, including pneumonia, but infections tended to be milder compared with those caused by the wild-type virus, with less pronounced cytokine release during the acute phase of infection,” the study authors wrote. “The observed attenuated clinical features further suggest that ORF8 is a possible target for therapeutic intervention.”

Significance of the ORF8 protein

As mentioned, the ∆382 variant has a 382-nucleotide deletion that removed the gene that codes for the ORF8 protein. What does the ORF8 protein do?

A published study in Nature in late April used modern bioinformatics and molecular techniques to craft over 300 protein interactions pathways that happen when SARS-CoV-2 infects a human cell. In one of the pathways, the ORF8 protein inhibits the MHC class I molecules that are required for activating cytotoxic T-cells that kill infected cells. Basically, the ORF8 protein helps SARS-CoV-2 to avoid detection and killing by T-cells.

Reduced virulence without increased transmissibility does not improve reproductive fitness.

This function of the ORF8 protein of SARS-CoV-2 was further verified by a pre-print study, titled “The ORF8 protein of SARS-CoV-2 mediates immune evasion through potently downregulating MHC-I,” which was also featured by the reputable Nature Reviews Immunology journal.

The Δ382 variant disappeared: Why?

It should be noted that this study in The Lancet did their research between January 22 and March 21, 2020. Other epidemiologists have observed that the ∆382 variant arose in Singapore in late January, accounting for about 23% of screened samples at that time. The ∆382 variant was also detected in Taiwan, but only in one sample or person. However, the Δ382 variant seems to have gone extinct. Why?

One reason might be the stringent policies Singapore has employed to control the pandemic. “The most recent Δ382 viruses were detected in Singapore on 6 March 2020, suggesting that these viruses are no longer circulating in Singapore, likely due to the aggressive contact tracing and isolation or quarantine that had been enacted in the country,” wrote authors of a separate study published in the American Society for Microbiology in July.

Another reason might be that the ORF8 gene deletion brought more harm than good. To reiterate, the ORF8 protein helps SARS-CoV-2 to avoid being killed by T-cells. As follows, being easily killable might have contributed to its extinction. “∆382 variants might also be less effective at establishing infection in a new host because of the loss of the immune evasion functions of ORF8,” researchers explained.

“The ∆382 variant causes clinically significant illness, including pneumonia, but infections tended to be milder compared with those caused by the wild-type virus, with less pronounced cytokine release during the acute phase of infection.”

And reduced virulence without increased transmissibility does not improve reproductive fitness. Genomics analysis has shown that the ∆382 variant belongs to a different evolutionary clade than the G614 variant (brought about by the D614G mutation). The G614 variant exhibited 10-fold increased infectivity in cultured cells in the lab, although it is unclear if this translates to human-to-human spread. Anyways, the point is that the ∆382 variant might not have evolved increased transmissibility as the G614 variant did. Moreover, a prior study showed that patients infected with the ∆382 variant had similar viral loads compared to those with the wild-type virus, which further indicates no change in virus replication rates or reproductive fitness.

Short Abstract

Scientists finally discovered a ∆382 variant of SARS-CoV-2 with reduced virulence compared to the wild-type virus. Patients infected with the ∆382 variant had better clinical outcomes than those with the original virus. The ∆382 variant has a 382-nucleotide deletion in gene regions that code for part of ORF7B and full ORF8 proteins. The ORF8 protein helps SARS-CoV-2 to avoid being killed by the host T-cell immune responses. However, the ∆382 variant has gone extinct, which might be due to the strict pandemic control measures and weakened virulence yet no boost in transmissibility.

(Note on variant vs. strain. Variants mean any genetic mutation that makes a virus’s genome different than others. However, mutations do not necessarily result in a change in biological properties. To qualify as a strain, the new variant has to exhibit a distinct biological function(s). Thus, the G614 or ∆382 variants could count as strains of SARS-CoV-2.)

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