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Source: SARS-CoV-2 Variants  Aug 22, 2021  1 month ago
BREAKING! Australia’s COVID-19 Surge Caused By Second Generation Delta Variant With ORF7a Deletion! Malaysia Has Its Own Variants B.1.524 & AU.2!
BREAKING! Australia’s COVID-19 Surge Caused By Second Generation Delta Variant With ORF7a Deletion! Malaysia Has Its Own Variants B.1.524 & AU.2!
Source: SARS-CoV-2 Variants  Aug 22, 2021  1 month ago
Researchers from the University of New South Wales-Sydney and the Prince of Wales Hospital-Sydney have discovered that the current COVID-19 surge taking place in Australia is due to a new second generation Delta variant that has emerged that possess a frameshift deletion in the ORF7a protein.

 
The SARS-CoV-2 coronavirus encodes proteins that modulate antiviral responses (ORF3b, ORF6, ORF7a), including reducing type 1 interferon. The ORF7a of SARS-CoV-2 is an ortholog of the corresponding SARS-CoV antagonist of host restriction factor BST-2/CD317/Tetherin that induces apoptosis.
 
Most importantly cells with reduced BST2 enhance SARS-CoV-2 replication thereby releasing more virus and indirectly increases viral shedding loads, thus helping to spread the disease even more.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2021.08.18.21262089v1
 
Thailand Medical News has been constantly warning about the emergence of second, third and even fourth generation variants of the existing VOCs or variants of concern.
 
In fact Thailand Medical News hypothesizes that at least three different variants of the Delta variant has emerged in Thailand are each has its own unique pathogenesis and manifest different clinical conditions. Further detailed research is urgently needed to address this hypothesis.
 
In the case of Australia that is currently experiencing COVID-19 outbreaks from infection with SARS-CoV-2 Delta variants (B.1.617.2, AY.3), it is fortunate that alert researchers discovered the presence of such a unique second generation variant.
 
Detailed analysis of the index case reveals a sub-consensus level of sequencing reads (~25%) that support a 17-nucleotide deletion in ORF7a (ORF7aΔ17del). ORF7aΔ17del induces a frameshift mutation in ORF7a, which truncates the peptide and potentially leads to reduced suppression of host restriction factor BST-2/CD317/Tetherin. Despite this, the mutation has rapidly become represented at the consensus level in subsequent cases: approximately 72% of SARSCoV-2 genomes in the Australian outbreak possess ORF7aΔ17del, and 99.7% (1534/1538) of Delta genomes on GISAID with ORF7aΔ17del originate from the current Australian outbreak (5 August 2021).
 
Alarmingly the global abundance of this mutation might be underestimated given the difficulty of variant calling software correctly calling insertion/deletions (indels), the common inability of phylogenetics software to take indels into account, and the tendency of GISAID to not release submissions that contain a frameshift mutation (unless specifically requested).
 
On the whole,  the rapid increase of persistent ORF7aΔ17del variants is concerning, and suggests either a chance founder effect with a neutral mutation yet to be purged, or that the ORF7aΔ17del mutation provides a direct selective advantage.
 
Malaysia Surges Not Caused By Delta But Rather By Its Unique Variants Called B.1.524 and AU.2 Variants In Malaysia Which are More Transmissible Than Delta Variant And Alarmingly A New Mutation G1223C Is Appearing In Many Lineages! ng>
 
Malaysia is witnessing high COVID-19 infections rates in the last few months and despite an intensive vaccination programme, it has to date only managed to get about 36.8% of its population of about 32.83 million fully vaccinated.
 
However Malaysia’s COVID-19 crisis is slightly different from neighboring Thailand that is seriously inflicted with various VOCs (Variants of Concern) especially the Delta variant. The Alpha and Beta variants have also been found in the Thailand and God knows what else that the local authorities are not revealing. Thailand is already being bestowed the title of the “Hub of SARS-CoV-2 Variants!”
 
In the case of Malaysia, the surge is being driven by two unique variants called the B.1.524 and AU.2 variants.
 
Malaysian researchers from the Universiti Malaysia Pahang and the International Islamic University of Malaysia were the ones who identified the variants in Malaysia. It should also be noted that these variants have also been detected already in Thailand as well from spread via Malaysia.

The study team aimed to report new Malaysian lineages responsible for the sustained spikes in COVID-19 cases during the third wave of the pandemic.
 
Patients whose nasopharyngeal and oropharyngeal swabs were confirmed positive by real-time RT-PCR with Ct-value < 25 were chosen for WGS(Whole Genome Sequencing). The 10 SARS-CoV-2 isolates obtained were then sequenced, characterized and analyzed, including 1356 sequences of the dominant lineages of D614G variant currently circulating throughout Malaysia.
 
Interestingly the prevalence of clade GH and G formed strong ground of the discovery of two Malaysian lineages that caused sustained spikes of cases locally ie the B.1.524 and AU.2 variants.
 
Statistical analysis on the association of gender and age group with Malaysian lineages revealed a significant association (p < 0.05). Phylogenetic analysis revealed dispersion of 41 lineages, for which 22 lineages are still active.
 
Importantly detailed mutational analysis revealed a unique G1223C missense mutation in Transmembrane Domain of Spike protein. Thus, calls for the large-scale WGS analysis of strains found around the world for greater understanding of viral evolution and genetic diversity especially in addressing the question of the effect of deleterious substitution mutation in transmembrane region of Spike protein.
 
The study findings were also published on a preprint server and are currently also being peer-reviewed. https://www.medrxiv.org/content/10.1101/2021.08.11.21261902v1
 
Interesting observations from the study were that these two variants possibly are even more transmissible than the Delta variant.
 
The most important finding from the study was the discovery of the present of an emerging mutation found on all the new variants in Malaysia ie the G1223C mutation.
 
While the significance of G1223C mutation is still unknown, it is well known that Spike protein mediates entry of SARS-CoV-2 into target cells through two steps. First, it involves binding of RBD to its receptor human ACE2 and is proteolytically activated by human proteases at the S1/S2 boundary. Second, it follows by S2 of which include TM domain will undergo structural change to mediate viral membrane fusion with targeted cells.
 
To date, very little attention was put on the TM domain in the requirements for SARS-CoV cell entry. Although sequence analysis on TM domain among all coronaviruses Spike protein conducted previously revealed a high conservation rate, extensive mutation in TM domain of SARS-CoV however caused incapability of the virus to establish complete membrane fusion process.
 
Highly conserved small amino acids in TM domain of SARS-CoV-2 Spike protein (G1219, A1222, G1223, A1226) which initially thought to be important for TM domain oligomerization, but latest finding showed neither glycine nor alanine in the trimer structure appear to be important for hydrophobic core formation. Thus, suggesting a possible role of the glycine motif is in a later step of fusion.
 
The study team believes the effect of G1223C mutation in TM domain deserves to further analyze in future functional experiments for addressing above question.
 
If the G1223C mutation does promote fusion, it could alarmingly imply that variants with these mutations could cause more severe conditions in those infected!
 
For the latest on SARS-CoV-2 variants, keep on logging to Thailand Medical News.
 
 
 
 
 

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