#世卫警告 "Disease X" is 20 times deadlier than the coronavirus#
As the Chinese New Year approaches, the country will usher in a large-scale population movement, and the spread of respiratory diseases may increase. According to experts' judgment, the mainland will continue to show a variety of respiratory pathogens alternately or co-epidemic this winter and next spring, and influenza viruses will still be the main epidemic in the short term, but the new coronavirus infection epidemic may also rebound at the beginning of this month.
According to a press conference held by the National Health Commission on January 14, Wang Dayan, director of the National Influenza Center of the Institute of Viral Diseases of the Chinese Center for Disease Control and Prevention, said that after the New Year's Day holiday, the proportion of the JN.1 variant of the new coronavirus has shown an upward trend. Affected by multiple factors such as the continuous importation of the JN.1 variant, the gradual decline in domestic influenza activity and the decline in population immunity, it is urgent to guard against the "comeback" of the new coronavirus.
If it were just a single cough and fever, the coronavirus would not be enough to cause such a high level of concern. Other health hazards caused by "repeated infections" have become "nightmares" for people, such as neurological abnormalities.
Most intuitively, many people experience abnormal or loss of taste/smell after being infected with "yang", or neurological diseases such as headaches, seizures, strokes, and acute inflammatory polyneuropathy. In addition, a large retrospective cohort study of more than 230,000 people showed an increased risk of multiple neurological and psychiatric disorders within six months of COVID diagnosis.
Recently, a joint study by Professor Chen Shuibing from Cornell Medical College and other universities has revealed the reason behind the "new crown causes neurological problems" - the new crown virus can directly infect dopaminergic (DA) neurons in the midbrain, triggering inflammation and cellular aging responses, thereby inducing a series of neurological symptoms.
However, don't worry too much. At present, three drugs have been found to protect DA neurons, rescue the cell senescence phenotype, and prevent new crown infection: riluzole, metformin, and imatinib.
https://doi.org/10.1016/j.stem.2023.12.012
DA neurons are one of the main targets of neurodegenerative processes in Parkinson's disease. In order to explore the effect of the novel coronavirus on DA neurons, researchers developed an organoid/cell platform derived from human pluripotent stem cells (hPSCs) to differentiate DA neurons from hPSCs, which were verified in vivo and in vitro experiments, respectively.
In the in vivo model, immunofluorescence staining showed that 24 hours after intraocular injection of the novel coronavirus, the detected luciferase was mainly concentrated in Nurr1:GFP+ DA neurons. This suggests that the novel coronavirus is capable of directly infecting DA neurons in the body.
A similar situation occurs in in vitro experiments. A large number of viral replications were detected at the RNA level at 48 hours after infection, and immunostaining of SARS-N proteins also confirmed that the novel coronavirus was highly infectious to DA neurons.
In summary, both in vivo and in vitro experiments show that DA neurons are susceptible to new coronavirus infection. Data shows that about 5% of DA neurons exposed to the coronavirus will be infected.
The novel coronavirus is capable of directly infecting DA neurons
Surprisingly, after being infected by the new coronavirus, the researchers further observed strong induction of chemokines and cytokine transcripts in DA neurons, including BMP2, CCL2, CCL20, CCL25, CXCL1, etc. At the same time, inflammation-related genes were also significantly upregulated.
In addition, pathway analysis software (IPA) revealed that the most changed pathway in DA neurons after COVID infection is the aging pathway.
Specifically, the biomarker of cellular senescence, β-galactosidase (β-Gal), was significantly up-regulated in DA neurons, while the genes IGFBP7 and LAMIN B1, which are related to the aging pathway, were significantly up-regulated and down-regulated, respectively.
The researchers concluded that given the activation of the aging pathway and the increased vulnerability, the infection of the new coronavirus is likely to be a potential trigger for the degeneration of DA neurons.
Interestingly, the team also tested lung cells, heart cells, pancreatic islet β cells, but the senescence pathway was only activated in DA neurons, which was very unexpected.
COVID infection induces neuronal senescence in DA
But the research doesn't stop there.
Now that the coronavirus can induce aging of DA neurons, the team explored drug candidates that could prevent this from happening—three FDA-approved drugs — riluzole, metformin, and imatinib.
All three drugs have been shown to reduce the β-Gal activity of DA neurons in a dose-dependent manner, but do not cause cytotoxicity. In addition, DA neurons treated with 10 μM riluzole, 50 μM metformin, or 10 μM imatinib had a significantly reduced number of β-Gal+ cells compared to the control group.
In addition, qRT-PCR analysis showed that all three drugs led to the reduction of IGFBP7, a gene related to the aging pathway, and the upregulation of LAMIN B1.
It can be seen that under the action of riluzole, metformin and imatinib, the senescence of DA neurons induced by the new coronavirus has been significantly improved. Further RT-qPCR analysis confirmed that all three drugs could significantly reduce the RNA of the new coronavirus, preventing the aging of DA neurons by blocking viral infection.
Three drugs restored COVID-induced aging
The lean research team also demonstrated the findings in autopsy samples from COVID-infected patients: features of inflammation and cellular senescence were observed in the substantia nigra tissue of three COVID-19 patients, as well as low levels of COVID-19 RNA.
The coronavirus was detected in an autopsy substantia nigra sample
In summary, the new coronavirus can infect DA neurons in the human body and further trigger the aging pathway, and the aging of DA neurons is very likely to induce neurological diseases such as Parkinson's disease, and DA neuron dysfunction is also related to drowsiness and mind wandering.
However, this adverse health effect can be mitigated – the FDA-approved drugs riluzole, metformin and imatinib can block COVID-mediated neuronal aging in DA, or become one of the treatments for COVID-19.
The Chinese New Year is approaching, and the Spring Festival is about to begin. While returning home happily, remember to take good precautions, and feel at ease for yourself and your family, so as not to let the new coronavirus and other respiratory diseases take advantage of it!
参考资料:[1] Yang L, Kim TW, Han Y, Nair MS, Harschnitz O, Zhu J, Wang P, Koo SY, Lacko LA, Chandar V, Bram Y, Zhang