Thursday, November 24, 2022

Nature: Enhanced Replication of SARS-CoV-2 Omicron BA.2 in Human Forebrain and Midbrain Organoids


In the opening months of the COVID pandemic, SARS-CoV-2 was billed as an influenza-like virus; mostly mild but capable of producing severe, and sometimes fatal, pneumonia in a small percentage of people.   

While many continue to cling to this view, over the past 34 months we've seen growing, and compelling, evidence that COVID can cause significant extrapulmonary impacts as well.

In April of 2020, we looked at the first major report (see JAMA: Neurologic Manifestations Of Patients With Severe Coronavirus Disease) on the neurological impact of COVID infection; one which found more than 1/3rd of a study group (n=214) hospitalized in Wuhan, China showing signs of neurological involvement.

Neurological manifestations ranged from relatively mild (headaches, dizziness, anosmia, mild confusion, etc.) to more profound (seizures, stupor, loss of consciousness, etc.) to potentially fatal (ischemic stroke, cerebral hemorrhage, muscle injury (rhabdomyolysis), etc.). 

Other studies around that that time found that COVID caused viremia (see Severe Acute Respiratory Syndrome Coronavirus 2 RNA Detected in Blood Donations), was linked to gastrointestinal issues (see NEJM Journal Watch Gastrointestinal Aspects of COVID-19), blot clots and strokes (see EID Journal: Two Reports On Thrombotic Events In COVID-19 Patients) and heart damage (see COVID-19 linked to cardiac injury).

Additionally, a growing number of `recovered' COVID cases have reported a wide spectrum of chronic, and often debilitating symptoms - often dubbed `Long COVID' (such as fatigue, recurrent fevers, `brain fog', myalgias, etc. ),  that are highly reminiscent of ME/CFS - which has disabled and traumatized well over a million Americans over the past 3 decades (see NIH About CFS/ME).

While most people survive the acute phase of SARS-COV-2 infection, there is growing evidence that even a mild course of illness can leave behind significant, and often long-lasting, sequelae.  Over the past year we've also seen evidence linking repeated infections to worse outcomes (see Nature: Acute and Postacute Sequelae Associated with SARS-CoV-2 Reinfection).

As early as the summer of 2020 we were seeing cautionary articles warning of the potential for post-COVID surge in neurological cases.

While some regarded these warnings as alarmist, there is historical precedence for post-pandemic neurological sequelae, something we discussed at length in The Lancet: COVID-19: Can We Learn From Encephalitis Lethargica?.

Fast forward a bit more than two years, and Long COVID or Post-COVID Conditions are well recognized by the CDC, and can be considered a disability under the Americans with Disabilities Act (ADA).  

While the symptoms of `Long COVID' can vary, neurological manifestations are common, including:

  • Difficulty thinking or concentrating (sometimes referred to as “brain fog”)
  • Headache
  • Sleep problems
  • Dizziness when you stand up (lightheadedness)
  • Pins-and-needles feelings
  • Change in smell or taste
  • Depression or anxiety

The mechanism behind these neurological manifestations remains poorly understood, but we have seen direct and indirect evidence that the SARS-CoV-2 virus can infect, and replicate, within brain tissues (see Nat. Comms: Neuropathology and Virus in Brain of SARS-CoV-2 Infected Non-human Primates).

All of which brings us to a research letter, published this past week in Nature, which describes laboratory infection of lab-grown brain organoids by various COVID variants, and finds that Omicron BA.2 variants - while less pathogenic in some regards - have a greater affinity for infecting brain tissue than older variants. 

They report that BA.2 replicated more efficiently and triggered substantially higher levels of apoptosis (the breakdown of cells) in the infected human forebrain and midbrain organoids.

I've only posted some excerpts from the letter, so follow the link to read it in its entirety. 

Signal Transduction and Targeted Therapy volume 7, Article number: 381 (2022) Cite this article

Dear Editor,

Coronavirus Disease 2019 (COVID-19) is associated with a variety of neurological complications, including encephalopathy, encephalitis, dementia, and others.1 The pathogenic mechanism of these neurological manifestations remains incompletely understood but may be due to factors such as coagulation problem, immune-mediated response, or direct viral invasion into the central nervous system (CNS).2 

We and others previously reported that ancestral SARS-CoV-2 could infect and replicate in human brain organoids.3,4 

More recently, SARS-CoV-2 Omicron BA.1 emerged in late 2021 and demonstrated altered virological features including increased immunoevasion and attenuated pathogenicity comparing to SARS-CoV-2 wildtype (WT) and previous variants.5 However, the neuroinvasiveness of Omicron sublineages remain unexplored. 

Here, we investigated the neuroinvasion and neurotoxicity of Omicron BA.1 and BA.2, and compared the findings with those of SARS-CoV-2 WT and Delta in human forebrain and midbrain organoids.
Our results demonstrated that BA.2 replicated more efficiently while triggered lower levels of type I interferon response than that of SARS-CoV-2 WT, Delta, and BA.1 in both human forebrain and midbrain organoids. In addition, BA.2 triggered substantially higher levels of apoptosis in the infected human forebrain and midbrain organoids. 

Together, these findings suggest that BA.2 may be different from SARS-CoV-2 WT and previous variants in its capacity in targeting and causing diseases in the human brain.


During the revision phase of the study, we additionally evaluated the more recently emerged BA.4.1 and BA.5.2 on their replication in forebrain and midbrain organoids. We found that while BA.4.1 did not replicate as efficiently as BA.2, BA.5.2 replicated to higher levels when compared with BA.2 (Supplementary Fig. 9). The gained virus replication of Omicron sublineages in brain organoids may be of critical medical and public health importance and warrants further investigation.

Together, our study revealed a number of interesting findings which will be important for follow-up studies. First, the reason behind the enhanced replication of BA.2 in brain organoids should be dissected. Second, the importance and mechanism behind the down-regulation of entry-related factors in SARS-CoV-2-infected brain organoids should be investigated. Third, the mechanism of why BA.2 triggered the lowest IFN response in brain organoid deserves further investigation. Forth, the cause and the physiological importance of BA.2-induced apoptosis in the brain organoids should be further dissected.

To date, over 620 million people have been infected by SARS-CoV-2 with a significant proportion of them infected during the Omicron wave. While most patients survived the infection, post-COVID-19 sequela including neurological manifestations are common.10 

The increased efficiency of BA.2 to replicate and causing apoptosis in the brain organoids is alarming, indicating that the long-term consequence of BA.2 infection in the CNS should be closely monitored.

         (Continue . . . )

Many people dismiss COVID infection as trivial since it is mostly mild, and point to the high survival rate - even among those hospitalized - as if that tells the whole story.
But as these studies continue to show - the long-term impacts of COVID infection can be serious and should not be underestimated - making this is an illness you really want to avoid if at all possible.