The loss of smell (anosmia) and disruption or loss of taste (dysguesia or ageusia) are unique symptoms of COVID-19. The sensations of hot peppers and mint can also be lost, but these are transmitted by different neurons, those for pain. The former 2 lack ACE2 viral receptors but some of the pain sensor neurons have them. Most recover smell and taste within 6 months, but some require 2 years or fail to recover the senses at all. During recovery, parosmia may occur, which is the sensing of irrelevant smells unrelated to the objects’ odors. Irrelevant tastes, often unpleasant ones, may also develop. These effects are postulated to be from errors in re-established neuronal connections, which can be corrected, in time, due to the plasticity of the nervous system. Influenza has produced anosmia in the past, and provides some understanding of the symptomology and prognosis. The primary mechanism for the loss of smell and taste with COVID is not infection of neurons but supporting cells that help maintain neuronal function. For smell, these are sustentacular cells, and different supporting cells for taste. The neurons per se are spared, but in the case of the attack on sustentacular cells, the finger-like cilia on the neurons, which contain the smell receptors, are lost because of the loss of the supporting sustentacular cells. Since the neurons are not attacked directly, the loss of smell and taste are not usually irreversible. The pain sensation associated with sensing aromatics like mint and plant capsaicinoids like capsaicin (8-methyl-N-vanillyl-6-none amid) is another matter since these neurons have ACE2 viral receptors https://www.scientificamerican.com/article/mysteries-of-covid-smell-loss-finally-yield-some-answers1/.
A more ominous effect on the Central Nervous System (CNS) of some virus infections and chronic neurodegenerative diseases, that resemble the response to a virus but have no known virus such as Multiple Sclerosis (MS) associated with them, is demyelination. It, like the effects of SARS-CoV-2 on the sustentacular cells, involves supporting cells of neurons, the oligodendrocytes. In MS, the demyelination occurs in the Central Nervous System (CNS), the white matter of the brain and spinal cord, leading to pain, tremors, speech difficulties, loss of balance, vision difficulties, sensation loss and paralysis to various degrees, with multiple isolated episodes of recurrence. The myelin is a fatty coating of the nerve processes that resembles insulation on an electrical wire, strip it away and nerve conduction fails. It has been associated with viral infections, Epstein-Barr virus most recently (https://www.science.org/doi/10.1126/science.abj8222), and genetic pre-disposition leading to this autoimmune disease. Previously, measles, and even closely related canine distemper viruses, were suspected of causing MS. The latter because it commonly causes CNS demyelination in dogs, especially adult dogs. In puppies it starts as a respiratory virus with skin lesions, causing footpads to thicken and harden, leading to its nickname, “hard pad disease” (measles also causes hypersensitivity in the skin causing damage to small blood vessels and a rash, Koplik’s spots). Measles can also attack the CNS directly or secondarily, probably by triggering autoimmunity. CNS involvement, even in uncomplicated measles, is common. Transient EEG abnormalities are detected in 50% of patients. Measles virus is rarely isolated in acute measles panencephalitis. Therefore, it is considered the result of autoimmunity. Distemper does not kill the oligodendrocytes, which make myelin, but inhibits its synthesis. Sterile demyelination can be induced in animals (in guinea pigs, experimental allergic encephalomyelitis (EAE) induced by guinea pig myelin basic protein) by immunization against their own basic protein, a component of myelin. Other viruses like alphaviruses, encephalitis viruses, do not use this mechanism, but open the CNS blood vessels (blood brain barrier) to penetration by lymphocytes and other inflammatory cells causing collateral damage to the brain. SARS-CoV-2 has the potential of following all these neurological pathogenic pathways: damaging blood vessels in the brain to let in inflammatory cells; damaging or altering cells that support neurons (glia); and causing autoimmune responses in the CNS. With as many people as have been infected, all of these are likely to be seen, at one time or another, no matter how rare. Oddly enough, the CNS may provide a way to truncate the disease so mild COVID-19 does not turn into severe to lethal or chronic disease. The answer may be in a class of drugs, Selective Serotonin Re-uptake Inhibitor (SSRI), for anti-depression and anti-anxiety. New data shows fluvoxamine (FLV; Luvox), one such drug, could keep mild COVID-19 from worsening. In a preliminary study, 65 patients who received fluvoxamine (50 mg twice daily) and 48 who did not, the results were the incidence of hospitalization being 0% (0/65) with fluvoxamine and 12.5% (6/48) with no treatment. At 14 days, residual symptoms persisted in 0% (0/65) with fluvoxamine and 60% (29/48) with no treatment, (David Seftel and David R Boulware, Prospective cohort of fluvoxamine for early treatment of COVID-19, published by Oxford University Press on behalf of Infectious Diseases Society of America, 2021, and https://jamanetwork.com/journals/jama/articlepdf/2773108/jama_lenze_2020_pc_200006_1607119471.77989.pdf). Fluvoxamine has a well-established mechanism of action as an anti-inflammatory (Dorian A. Rosen et al, Modulation of the sigma-1 receptor−IRE1 pathway is beneficial in preclinical models of inflammation and sepsis, Sci Transl Med 11, eaau5266. DOI: 10.1126/scitranslmed.aau5266, 2019; https://stm.sciencemag.org/content/scitransmed/11/478/eaau5266.full.pdf). The related SSRI drug Fluoxetine (Prozac) has a long history of anti-inflammatory action against stress-induced oxidative cell damage; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876141/pdf/PRP2-4-e00231.pdf.
The ER stress sensing protein IRE1alpha, and the closely related protein IRE1beta, are able to powerfully affect the inflammatory behavior of both immune and non-immune cells. A major ER stress sensor, inositol-requiring enzyme (IRE1) is selectively activated by the Toll-like receptor 4 (TLR4) for the ligand lipopolysaccharide (LPS), bacterial endotoxins. IRE1 regulates inflammatory cytokine production via both its endonuclease activity and transcriptional regulation. IRE1 activity is required for cytokine production, likely via XBP1-mediated transactivation of interleukin-6 (IL-6) and tumor necrosis factor–alpha (TNF-alpha). FLV, an antidepressant drug, has low-nanomolar affinity for S1R, ER-resident protein sigma-1 receptor, which has also been reported to have anti-inflammatory properties. In one set of experiments, a high dose of LPS (6 mg/kg) was administered with FLV (20 mg/kg) at the same time. FLV treatment protected mice from mortality and reduced serum IL-6. S1R can also dampen inflammation in human cells. Heparinized peripheral blood from healthy donors was stimulated in the test tube with LPS (10 ng/ml) in the presence or absence of FLV (20 micromolar), and the production of inflammatory mediators was measured. FLV significantly reduced LPS-induced IL-6, IL-1beta and IL-12, and decreased IL-8 production in cells from all donors. These data indicated that the anti-inflammatory action of the FLV S1R ligand is conserved across species. Taken together, these anti- inflammatory effects and the benefits to COVID treatments, correlate with what I have said about the inflammatory effects and mechanisms of COVID in earlier posts and provides hope these off-the-shelf drugs will provide relief to both acutely severely affected patients as well as long haulers with neurological symptoms.
Global Biosurveillance 