BREAKING! COVID-19 News: University Of Queensland Study Shockingly Finds That BA.5 Sub-lineages Are More Neurovirulent That Earlier Omicron Variants!

COVID-19: A new study led by Australian scientist from the University of Queensland along with researchers from QIMR Berghofer Medical Research Institute and the Australian Infectious Disease Research Centre-Queensland has shockingly found that the BA.5 subvariant and its sub-lineages to be more neurovirulent than previous Omicron variants and sub-lineages!


 
The study findings dispel the common fallacy that the SARS-CoV-2 virus is evolving to be less pathogenic and is mild.
 
The finding also raises alarms about the kind of damage that even asymptomatic and mild to moderate symptomatic infections with the BA.5 variant and its various sub-lineages can do to the brain and nervous system over time.
 
It should also be noted that although the increased level of immunity in human populations makes it difficult to distinguish between reduced intrinsic pathogenicity and increasing protective immunity. The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described and appears to be due to reduced utilization of TMPRRS2.
 
The fallacy that this reduced pathogenicity remains true for omicron BA.5 was recently propagated by lots of so called ‘experts’, many that can be found on twitter and also in various other garbage COVID-19 News coverages in the West.
 
The study team in sharp contrast show that a BA.5 isolate was significantly more pathogenic in K18-hACE2 mice than a BA.1 isolate, with BA.5 infection showing increased neurovirulence, encephalitis and mortality, similar to that seen for an original strain isolate. The infected mice also exhibited rapid weight loss and various neurological issues.
 
Alarmingly, it was also found BA.5 also infected human cortical brain organoids to a greater extent than a BA.1 and original strain isolate. Neurons were the target of infection, with increasing evidence of neuron infection in COVID-19 patients.
 
The study findings argue that while omicron virus may be associated with reduced respiratory symptoms, BA.5 shows increased neurovirulence compared to earlier omicron sub-variants.
 
Importantly, the study suggest that the omicron lineage is not evolving towards reduced pathogenicity, with BA.5 showing increased neuropathology over BA.1.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2022.12.22.521696v1
 
The study findings contrast with a previous study, but is consistent with recent hamster studies.
https://www.nature.com/articles/s41586-022-05482-7
 
https://www.biorxiv.org/content/10.1101/2022.08.05.502758v1
 
https://onlinelibrary.wiley.com/doi/10.1002/jmv.28326
 
The COR-22 isolate used in the study that claims BA.5 had reduced pathogenicity had two substitutions from the original ancestral not seen in the QIMR03 isolate used herein (Spike T76I, NSP5 P252L).
https://www.nature.com/articles/s41586-022-05482-7
 
The QIMR03 isolate used in this current Australian study (BE.1 sub-lineage) also has seven substitutions from the original ancestral not seen in COR-22; NS3 (Orf3a) G49C and V48F, NSP3 A386T, NSP2 Q376K and I273V, NSP13 M233I, N E136D.
 
According to the study team, to the best of their knowledge no pertinent activities have been ascribed to these substitutions, although N, NSP3 and NSP13 are involved in suppression of type I IFN responses, which may provide an explanation for differences between COR-22 and QIMR03.
 
An increase in pathogenicity of BA.5 over BA.1 in K18-hACE2 mice may be associated with an increased reliance on TMPRSS2.
 
It was found that the early omicron variants tended to be less dependent on TMPRSS2 than original ancestral isolates, and showed an increased propensity to use the endocytic route of entry; a shift associated with lower pathogenicity and changes in spike.
https://pubmed.ncbi.nlm.nih.gov/35104837/
 
https://pubmed.ncbi.nlm.nih.gov/34951565/
 
Both the BA.1 and BA.5 isolates used in this current study have 14 amino acid differences in the spike protein.
 
Pathogenicity has been shown to be dependent on TMPRSS2 utilization, with TMPRSS2 utilization reported to be a virulence determinant, even for omicron variants.
https://pubmed.ncbi.nlm.nih.gov/33638460/
 
https://pubmed.ncbi.nlm.nih.gov/36243815/
 
Interestingly, treatment with a TMPRSS2 inhibitor also prevented brain infection in K18-hACE2 mice.
https://pubmed.ncbi.nlm.nih.gov/34340553/
 
An increased ability to infect, even TMPRSS2-low, cells in the olfactory epithelium may thus promote entry of BA.5 into the brains of K18-hACE2 mice.
 
However, what remains perplexing is how the TMPRSS2-dependent original ancestral isolate can produce such a fulminant brain infection, despite the low-level expression (mean of only 3.6 reads) of TMPRSS2.
 
Viral reads in K18-hACE2 267 mice infected with the original ancestral isolate illustrate a loss of the QTQTN sequence adjacent to the furin cleavage site, which impairs furin cleavage, in virus populations in the brain in half of the animals, but not the lung.
 
A furin cleavage site deletion is seen in virus sequences in brains of SARS-CoV-2 infected hamsters.
https://pubmed.ncbi.nlm.nih.gov/35857629/
 
Hence, during brain infection, the original ancestral isolate acquires a reduced dependence on TMPRSS2.
 
BA.5 would thus appear to have both TMPRSS2-dependent and TMPRSS2-independent capabilities, the first perhaps promoting neurotropism and the second neurovirulence.
 
RNA-Seq of organoids illustrated zero or very low TMPRSS2 mRNA expression (PRJNA813692), explaining the very poor infection by the original ancestral isolate.
 
However, the more efficient infection by BA.5 was thus likely due to TMPRSS2-independent infection.
 
Surprising was the lack of induction of type I IFN response by BA.5 in these organoids.
 
A study using an original ancestral isolate however also showed no IFN induction, whereas as an early, and a BA.2, omicron isolate induced clear type I IFN responses in slightly different organoid systems.
https://pubmed.ncbi.nlm.nih.gov/33433624/
 
https://pubmed.ncbi.nlm.nih.gov/36314791/
 
https://pubmed.ncbi.nlm.nih.gov/36411276/
 
Organoids in the study are capable of generating type I IFN responses when infected with other viruses, suggesting BA.5 can effectively suppress anti-viral response in this glia-free, neural organoid system.
 
Suppression of type I IFN responses by SARS-CoV-2 involves multiple non-structural proteins, with a trend towards better suppression capabilities emerging with each new variant.
 
A widely repeated contention is that viruses tend to evolve towards lower virulence, even though there are good examples where this is clearly not the case.
 
The contention also does not appear to hold for SARS-CoV-2; for example, a higher proportion of patients infected with BA.5 develop anosmia, when compared with BA.1.
https://pubmed.ncbi.nlm.nih.gov/36270311/
 
Also, it was noted that anosmia was recently closely linked to long-lasting cognitive problems in COVID-19 patients, with infection of the olfactory epithelium potentially proving access to the brain.
https://aaic.alz.org/downloads2022/AAIC-2022-Overview-Release.pdf
 
https://pubmed.ncbi.nlm.nih.gov/36395835/
 
https://pubmed.ncbi.nlm.nih.gov/33251489/
 
The study findings would support the view that BA.5 has developed an increased propensity for neuroinvasiveness over earlier omicron variants. The detection of spike in infected brain cortical structures demonstrate that the SARS-CoV-2 can not only access these regions via an unknown mechanism but also selectively affect groups of neurons within these regions. It is worth noting that the detection of the S-protein in vesicular structures in the soma of pyramidal neurons suggest a possible transport mechanism that likely involve endocytosis and is potentially influenced by co-receptor neuropilin.
 
More detailed studies are warranted to better understand this neuroinvasive mechanism as this likely contribute to neurological symptoms of COVID. Thus, even if respiratory disease is less severe for omicron variants as a whole, BA.5 may show increased risk of acute and long-term neurological complications over earlier omicron variants.
 
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