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Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, Lu P, Weizman OE, Liu F, Dai Y, Szigeti-Buck K, Yasumoto Y, Wang G, Castaldi C, Heltke J, Ng E, Wheeler J, Alfajaro MM, Levavasseur E, Fontes B, Ravindra NG, Van Dijk D, Mane S, Gunel M, Ring A, Kazmi SA, Zhang K, Wilen CB, Horvath TL, Plu I, Haik S, Thomas JL, Louvi A, Farhadian SF, Huttner A, Seilhean D, Renier N, Bilguvar K, Iwasaki A. Neuroinvasion of SARS-CoV-2 in human and mouse brain. J Exp Med. 2021 Mar 1;218(3) PubMed.
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Our findings show that the SARS-CoV-2 viral spike protein S1, which is required for cellular uptake of virus, can enter the mouse brain following intravenous or intranasal administration. This might relate to the fact that people with COVID-19 are often suffering cognitive effects, such as brain fog, and fatigue.
This finding is also important because binding proteins such as S1 can detach from the virus and themselves cause toxicity in patients following COVID-19 infection. The S1 protein in SARS-CoV-2 and the gp 120 protein in HIV-1 might function similarly. They are glycoproteins—proteins that have a lot of sugars on them, hallmarks of proteins that bind to other receptors. Both proteins function as the arms and hands for their viruses by grabbing onto other glycoproteins on the cell surface. Both cross the blood-brain barrier and S1, like gp120, is likely toxic to brain tissues. We (Bill Banks and myself) worked with recombinant gp 120 as part of previous mouse studies.
The breathing problems seen following COVID-19 infection might not only relate to infection in the lungs but also to respiratory centers of the brain following viral uptake in the brain. We find that transport of S1 is faster in the olfactory bulb and kidney of males than females. This observation might relate to the increased susceptibility of men to more severe COVID-19 outcomes. Our findings that wild-type mice, which do not express the human ACE2 receptor, can be used in kinetics studies of the S1 protein and probably SARS-CoV-2 suggest that the assumption that human ACE2 must be used for these kind of studies in mice, is incorrect. These results also support the use of recombinant proteins or virus-like proteins to increase our knowledge about the effects of SARS-CoV-2 proteins on the brain, rather than active replicating viruses, which require additional biosafety precautions and animal facilities.
References:
Raber J, Toggas SM, Lee S, Bloom FE, Epstein CJ, Mucke L. Central nervous system expression of HIV-1 Gp120 activates the hypothalamic-pituitary-adrenal axis: evidence for involvement of NMDA receptors and nitric oxide synthase. Virology. 1996 Dec 15;226(2):362-73. PubMed.
Banks WA, Kastin AJ, Akerstrom V. HIV-1 protein gp120 crosses the blood-brain barrier: role of adsorptive endocytosis. Life Sci. 1997;61(9):PL119-25. PubMed.
View all comments by Jacob RaberThese findings are quite consistent with reports, espoused by many eminent researchers, and central to our stance on www.ALZgerm.org, that many viruses, bacteria, and parasites can enter the brain, either temporarily or long-term. They may live quietly, trigger inflammation, or directly damage brain cells. And so, COVID joins herpes simplex, spirochetes, toxoplasma, chlamydia, mycobacteria, and prions as a possible future trigger of AD.
We also recall that after chickenpox, the neurotropic herpes zoster virus becomes latent for decades until emerging as shingles. The neurotrophic spirochetes of syphilis, and perhaps borrelia, may damage the brain years after initial infection and then latency. As I warned in comments on Alzforum April 1, 2020, COVID infections may disturb, visibly or not, future neurologic findings and outcomes in cohorts of seniors being followed longitudinally in dementia studies.
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