COVID-19 News: Study Finds That Two Cholesterol-Lowering Drugs, Gemfibrozil And Lovastatin, Reduces SARS-CoV-2 Propagation In Brain Cells!

COVID-19 News: A new study by South Korean researchers from Chonnam National University, Korea Research Institute of Chemical Technology along with scientist from University of North Carolina at Chapel Hill-USA has found that SARS-CoV-2 neuroinvasiveness and neuroinfection is governed by cholesterol homeostasis and translational machinery-associated genes! The study team found that brain corticogenesis and cholesterol homeostasis promotes SARS-CoV-2 infection and replication.


 
The study findings also showed that two cholesterol-lowering drugs, Gemfibrozil and Lovastatin, reduces SARS-CoV-2 propagation in brain cells.
 
Though the neuroinvasiveness of SARS-CoV-2 has been extensively studied, the correlation between virus infectivity and brain maturation remained unclear.
 
It has been found that among the reported Long COVID conditions that has been covered in many past COVID-19 News coverages, neurological and psychiatric complications appear frequent and diverse. Also, cognitive dysfunction or memory loss issues are common across all age groups, persisting up to 7 months from recovery.
 
Considering the range of COVID-19 complications to human brain, extensive investigations have attempted to clarify the mechanism governing virus neurotropism.
 
However, as pathogenesis of SARS-CoV-2 in human brain is intricated that cannot be fully explained by one single mechanism, a comprehensive understanding of this aspect is still lacking.
 
In this study, the researchers demonstrated the susceptibility of human brain cells to COVID-19 and reported the periodic decreases and increases in viral genome copy number within CBOs (Cerebral organoids) over time.
 
The study team utilzing human-induced pluripotent stem cells-derived three-dimensional cerebral organoids (CBOs), presented the first quantitative data for long-term kinetics of SARS-CoV-2 propagation in brain for 20 days post-infection.
 
The study findings showed that mature brains are more susceptible to SARS-CoV-2 than immature counterparts, evident from increased viral replication rate and higher TUNEL + cells proportion.
 
Transcriptome profiling identified enhancement of corticogenesis and gliogenesis and indicated enrichments in translation machinery- and lipid metabolism-associated genes in mature brain, suggesting the major factors conferring the robust infectivity of SARS-CoV-2.
 
Also, the role of cholesterol in promoting viral replication was confirmed by the reduced number of infected cells in lipid lowering-drugs condition.
 
The study findings highlight that permissiveness of the brains to SARS-CoV-2 is greatly enhanced with their maturation and suggests cholesterol as a new target for suppressing viral replication.
 
The findings validate a strong correlation existing between SARS-CoV-2 replication efficiency and brain maturity, which is governed by cholesterol homeostasis and translational machinery-associated genes.
 
The study findings provide a novel insight into neurotropism of SARS-CoV-2 and suggests a potential target for suppressing viral replication, thereby, alleviating the sequelae and optimizing recovery.
 
The study findings were published on a preprint server and are currently being peer reviewed for publication into the journal: Nature
https://www.researchsquare.com/article/rs-2481841/v1
 
Till now, evidences for neurotropism potential of SARS-CoV-2 are contradictory, when some studies showed the absence of virus from the brain, and cerebrospinal fluid, but others demonstrated their tropism.
 
The study findings here confirmed the neurotropism of SARS-CoV-2 to human brain which was proved through CBOs platform.
 
SARS-CoV-2 replication kinetics have been reported in somatic cell lines and CBOs but only for a short period (3–6 days), generally showing limited neurotropism with decelerating multiplication rate. As the acute phase is far beyond that period, this short-time investigation is not sufficient to reflect dynamic nature of CBOs post-infection.
 
Hence, this new study is the pioneering quantitative report for long-term kinetics of SARS-CoV-2 propagation in brain for 20 days, where corticogenesis and gliogenesis dynamically involve upregulation of ACE2 expression level, ribosomal and translational enhancement, and cholesterol metabolism.
 
Also, by showing SARS-CoV-2 infectivity in monolayer of neuronal and glial cells, the findings exclude any possibilities that unknown factors associated with organoid structure can affect viral entry to CBOs, hence, demonstrating that mature neurons and astrocytes can modulate the susceptibility to SARS-CoV-2 infection.
 
Importantly, from single cell transcriptome profiling, the study team showed that as brain maturation progresses, corticogenesis is orchestrated that thickens the upper and deeper neurons layers, hence, enhancing the complexity of cortical plate.
 
Furthermore, the study findings suggest migration of progenitor cells and their divergence to glial cells, proving the occurrence of gliogenesis. Thus, corticogenesis and gliogensis, which enrich the populations of neurons, astrocytes, and oligodendrocytes in the brain, are the hallmarks differentiating mature from immature brain.
 
Interestingly, gene expression profiling of EB60 and EB120 found that most translational machinery-associated genes were upregulated in EB120, such that viral proteins can be more efficiently translated in the matured CBOs. Besides, GSEA analysis showed upregulations of cholesterol homeostasis associated genes in mature CBOs.
 
Considering that lipid metabolism is crucial for neuro- and oligo-genesis, the expansion of cortical plate as well as myelinated areas during late-stage development requires high lipid synthesis within short time, thus, swiftly enhance lipid composition within mature CBOs.
 
Proceeding research has proved the essential role of host lipid species in viral cycle of positive-strand RNA viruses, and particularly, of SARS-CoV-2.
 
The study team demonstrated that lipid-rich brain cells generate a favorable environment for SARS-CoV-2 to propagate. This finding, however, is contrary to previous studies which showed minimal infection of SARS-CoV-2 on neurons and astrocytes monolayer coculture.
 
However, this could be explained by the much lower virus titers for cells exposure associated with the shorter treatment time. In addition, different virus infection rates to the cells could be resultant from different cell lines used.
 
Supporting the current study findings on the relationship between cholesterol level and virus neuroinvasiveness, a past study proved the effect of SR-B1, an HDL receptor on astrocytes and neurons, in enhancing SARS-CoV-2 entry,
thereby, increasing viral infection to brain cells.
https://pubmed.ncbi.nlm.nih.gov/33244168/
 
Hence the study finding about the accelerated rate of SARS-CoV-2 infection in CBOs with developed brain cellular networks is consolidated.
 
With regards to ACE2 and TMPRSS2, the study team respectively found the linear increase and stability in their expression, which is highly correlated with our previous observation, in which cellular differentiation promotes ACE2 level, but not TMPRSS232. We also found that its expression pattern is strongly associated with mature neurons (MAP2+) and astrocytes (GFAP+), suggesting the link between ACE2 receptor and cholesterol level.
 
Importantly, this is consistent with previous finding which found ACE2 protein distributes mainly in cholesterol-rich membrane domains.
https://pubmed.ncbi.nlm.nih.gov/14647384/
 
It has also been shown that cholesterol can affect ACE2 conformation and antigenic epitopes presentation, and depletion of this steroid compound within the lipid raft drastically changes the spatial localization of ACE2 receptor.
https://pubmed.ncbi.nlm.nih.gov/18814896/
 
https://pubmed.ncbi.nlm.nih.gov/33890572/
 
These study findings strengthen the hypothesis that brain maturation affects viral infectivity through cholesterol homeostasis.
 
Importantly, the role of cholesterol in brain maturation - SARS-CoV-2 infection rate correlation suggests it as a potential target for virus suppression.
 
The study team confirmed the considerable effect of two cholesterol-lowering drugs, Gemfibrozil and Lovastatin, respectively belonging to Fibrate and Statin group, on reducing SARS-CoV-2 propagation in brain cells.
 
Though these agents target different molecules, they both act to reduce total cholesterol level, especially in cholesterol-rich lipid raft, hence, reducing the interaction between SARS-CoV-2 spike protein and ACE-2 receptor, thereby, significantly repress SARS-CoV-2’s infection and replication rate.
 
A noteworthy issue must be concerned in dealing with SARS-CoV-2 infection to brain is neuroinflammation, a hallmark of neurodegenerative diseases.
 
Though inflammation is indispensable for defending pathological events, it entails the risk of causing neuronal death and brain injury due to excessive production of neurotoxic reactive astrocytes and proinflammatory molecules triggered by microglia activation.
 
Interestingly, Lovastatin and Gemfibrozil showed their potentials in mitigating SARS-CoV-2 induced inflammatory responses and inhibiting microglia activation.
 
These study findings suggest a prominent feature for novel antiviral candidates that targets cholesterol to block the virus, reduce inflammation and thus, complications, on the hosts.
 
The study team concluded that neurotropism ability of SARS-CoV-2 in the human brain and proved that its propagation crucially depends upon brain maturity, reflected by the enriched translational machinery and ribosome associated genes, and the enhanced cholesterol composition in developed neurons and glia network.
 
The research is a pioneering study in extending the evaluation time post-infection for examining the replication efficiency of SARS-CoV-2 upon brain maturation. The CBOs used closely resemble the corticogensis and gliogenesis during maturation process of the brain, providing a model that clearly reflects changes for the validation of brain maturation-viral replication correlation.
 
By determining cellular factors participating in controlling brain permissiveness to SARS-CoV-2, the study team suggests cholesterol homeostasis as a potential target for effectively suppressing viral spread in host and mitigating complications caused by inflammatory effects.
 
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