SARS-CoV-2 can invade the central nervous system and impair synapsis morphology and activity
The revolution in infectious diseases has just started
Countless studies have now demonstrated the post-acute outcomes of SARS-CoV-2 infection, including a massive neurocognitive impact characterized by brain fog, memory issues, changes in mood and habits, decline in several neurocognitive skills, and so on. Patients and family associations are being noticing and highlighting this impact since years now. In a recent post, I summarized a few of the recent major findings on neurocognitive decline in people after SARS-CoV-2 infection, highlighting that a similar impact can also happen - hopefully and luckily less frequently - also in children.
Nevertheless, the public, people, even parents of patients suffering from these problems, and researchers, clinicians, academics, around the world, are still debating if these problems are real and caused by the virus, or are a consequence of other social interventions (including lockdowns, economic consequences, etc).
“Luckily”, a new study is further reinforcing the potential role of SARS-CoV-2 in causing a direct damage in the central nervous system (CNS). To be short, if you don’t have much time to read, the study provides molecular insights into SARS-CoV-2–brain interactions, which may contribute to COVID-19-related neurological disorders.
However, I do suggest you to continue reading this post where I summarize the main findings of this study. This study is going to be a milestone of the history of medicine and is going to revolutionize the way we see viral infections. Do you remember when I predicted the “Long Covid Revolution?”
More in details, using cerebral organoids - organotypic culture of human brain explants from individuals without COVID-19 and post-mortem brain samples from individuals with COVID-19 - they found that neural cells are permissive to SARS-CoV-2 to a low extent. SARS-CoV-2 induces aberrant presynaptic morphology and increases expression of the synaptic components Bassoon, latrophilin-3 (LPHN3) and fbronectin leucine-rich transmembrane protein-3 (FLRT3). Furthermore, they found that LPHN3-agonist treatment with Stachel partially restored organoid electrical activity and reverted SARS-CoV-2-induced aberrant presynaptic morphology. Finally, they observed accumulation of relatively static virions at LPHN3–FLRT3 synapses, suggesting that local hindrance can contribute to synaptic perturbations.
WHAT ARE THE IMPLICATIONS OF THIS STUDY? WHAT EXACTLY THESE FINDINGS MEAN?
Although hypoxia and neuroinflammation may be important processes involved in severe neuroCOVID, it cannot fully explain subtle neurological and/or psychiatric disorders in patients with mild COVID-19 in the acute and post-acute phases. The virus has been shown to persist at low levels in the brain of patients with COVID-19 for long periods of time, but the dynamics and impact of SARS-CoV-2 particles in the CNS remain unknown. The groundbreaking findings of the study show that exposure to SARS-CoV-2 can perturb neuronal synapse morphology, modulate the synaptosome landscape and interfere with local electrical field potential. Basically, in some people SARS-CoV-2 can completely change the why your neurons communicate eachother. This means that if you don’t feel the same as before covid from a cognitive perspective, here are the reasons, or the evidence, of what is probably going on in your head.
The primary neural target of SARS-CoV-2 is mostly found to be neuronal, although other neural cell types have been reported to show some degree of permissiveness. Interestingly, the sustained viral load the authors measured in organoids and brain slices suggests that some basal levels of active replication occurs, despite that no virus release in the supernatant could be detected by plaque assay. Neural cells express low levels of ACE-2, a main SARS-CoV-2 receptor, which could explain low permissiveness but also point toward a potential mechanism for the establishment of a CNS reservoir for the virus. I have discussed already about the evidence of SARS-CoV-2 persistence, and this new paper on nature closes the debate. Do not forget that viral persistence has also been demonstrated in children.
Another important finding of the study is that the authors failed to spot a single leukocyte in these infected regions or anywhere else in the examined tissue samples, suggesting that low levels of viral replication in the cortex may not be sufficient to elicit potent neuroinflammation. A previous report indicated that microglial activation, T-cell infiltration and astrogliosis were observed in the cortex of SARS-COV-2-infected patients with COVID-19. They also could not identify SARS-CoV-2 RNA in any of the samples. A recent study reported little to no neuroinflammation in patients during acute and convalescent stages in their autopsy cohort, although they clearly showed SARS-CoV-2-infected cells in the brain16. All togheter, these studies suggest that other mechanisms, rather than local neuroinflammation, can mediate the neurocognitive problems. reinforce these observations, including the absence of leukocyte and T-cell infiltration and microglial activation. Emma Partiot et al most probably found the explanation.
The amazing and groundbreaking finding was that SARS-CoV-2 infection was associated to elongated presynaptic morphology. This observation is reminiscent of the homeostatic synaptic scaling concept, which postulates that the strength of neuronal synapses scales up in response to decreased presynaptic activity, resulting in enlarged synapse morphology (FOR NON EXPERTS, SYNAPSES ARE THE CONNECTION BETWEEN NEURONAL CELLS, basically the area all complex neurologic connections happen and allows you to do whatever physical or mental tasks). So basically, most probably if you have cognitive problems your synapsis are different compared to how they were before covid.
This finding is in line with another major one. Mutations in LPHN3 are a well-established risk factor for attention deficit hyperactivity disorder, and LPHN3 defects are also correlated to increased reward motivation and addiction, and spatial and egocentric cognitive impairments. At the molecular level, LPHN3 is involved in the formation of both excitatory and dopaminergic synapses. Emma Partiot et al highlighted that LPHN3 was one of the most up-regulated proteins in cerebral organoids infected by SARS-CoV-2 and confirmed its up-regulation at the protein level in OPAB and mRNA level in non-neurologic patients with COVID-19. LPHN3 is involved in synapse formation and maintenance through its direct interaction with the presynaptic protein FLRT341. These findings allowed the authors to hypothesize that the physical hindrance of the virion at the LPHN3–FLRT3 interface can block the normal LPHN3 activation through FLRT3 interaction and that Stachel treatment could bypass this block by activating LPHN3 independently of FLRT3 and thus restore, at least in part, synaptic function. In fact their models confirmed that SARS-CoV-2 virions are retained at synaptic sites containing FLRT3. The physical retention of a virion at neuronal synapses offers a paradigm to explain potential viro-induced CNS perturbations (SUCH A MAJOR REVOLUTION!). This observation could explain that transient and diverse neurological manifestations occur in patients with asymptomatic/mild COVID-19. The authors themsevles state “Indeed, one could envision a scenario in which low level of SARS-CoV-2 replication in neurons induces local perturbation of the neural network through physical hindrance at the synapse, and because of the low immune response, microglial cells would take time to clear this local perturbance, leading to transient neurological symptoms”. My addition: unfortunately, for many people these neurological symptoms are lasting years and are not transient!
Even more “amazingly”, all these morphological data have a functional correlate. IN fact, the authors showed that SARS-CoV-2 exposure to the brain impacts electrical activity of whole organoids using 3D MEAs. Remember that everything we do (when we thin, when we see or talk, when we move our body) is the consequence of electrical connections between our neuronal cells (at level of synapses). So basically, this neuro-electrical dysfunction can easily explain your post-covid neurocognitive problems!
So what now?
Please stop arguing if SARS-CoV-2 can cause neurocognitive problems or not! Stop arguing if post infectious neurocognitive are real or not! Stop arguing if viral infections can cause central nervous system problems, most probably all viruses have the potential and similar mechanisms are simply under investigated with other viruses, and not simply exclusive of SARS-CoV-2.
Stop that, and start with
1- recognize the problems that thousands or millions people are complaining, including children
2- spare funds not for survey or observational studies, but invest in discovering molecules that can change these problems, or in trials with existing molecules, including natruceuticals
3- advocate for more funding in post acute sequelae of viral infections.
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