SARS-CoV-2 と COVID-19 に関する備忘録 Vol.11――鼻血、ミトコンドリア、SARS-CoV-2ウイルスは理屈と膏薬のように何処へでも付く…etc.

SARS-CoV-2 と COVID-19 に関するメモ・備忘録

The Possible Role of COVID-19 in the Triggering of Underlying Mitochondrial Dysfunction in MELAS Syndrome, A Brief Report of three cases【NIH Case Reports:Acta Neurol Taiwan 2023年6月30日】
 ※なお、こちら→The Possible Role of COVID-19 in the Triggering of Underlying Mitochondrial Dysfunction in MELAS Syndrome, A Brief Report of three cases[PDF]


Background: During corona virus pandemic, various neurological complications of COVID-19 have been reported. Recent studies demonstrated different pathophysiology for neurological manifestations of COVID-19 such as mitochondrial dysfunction and damage to cerebral vasculature. In addition, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder with a variety of neurological symptoms. In this study, we aim to assess a potential predisposition in mitochondrial dysfunction of COVID-19, leading to MELAS presentation.

Methods: We studied three previously healthy patients with the first presentation of acute stroke-like symptoms, following COVID-19 infection. We analyzed the patients’ clinical data and brain magnetic resonance imaging (MRI) lesions that presented to the neurological center of a university-affiliated hospital in Tehran, Iran, from September 2020 to August 2021.

Results: All cases are characterized by a temporoparietal abnormality in imaging studies and electroencephalogram (EEG). Based on electrodiagnostic tests, three patients were diagnosed with myopathy. In two brothers with relatively the same symptoms, one performed muscle biopsy finding myopathic process, and genetic testing confirmed a 3243A>G point mutation in a heteroplasmic state in one of our patients.

Conclusion: Although MELAS is not a prevalent condition, the recent increase in the number of these patients in our center might indicate the potential role of COVID-19 in triggering the silent pre- existing mitochondrial dysfunction in these patients.

Keywords: COVID-19; MELAS; Stroke-like episode Mitochondrial dysfunction..


Mechanisms of SARS-CoV-2-induced Encephalopathy and Encephalitis in COVID-19 Cases【Sage Journals 2023年5月27日】


The SARS-CoV-2 virus caused an unprecedented pandemic around the globe, infecting 36.5 million people and causing the death of over 1 million in the United States of America alone. COVID-19 patients demonstrated respiratory symptoms, cardiovascular complications, and neurologic symptoms, which in most severe cases included encephalopathy and encephalitis. Hypoxia and the uncontrolled proliferation of cytokines are commonly recognized to cause encephalopathy, while the retrograde trans-synaptic spread of the virus is thought to cause encephalitis in SARS-CoV-2-induced pathogenesis. Although recent research revealed some mechanisms explaining the development of neurologic symptoms, it still remains unclear whether interactions between these mechanisms exist. This review focuses on the discussion and analysis of previously reported hypotheses of SARS-CoV-2-induced encephalopathy and encephalitis and looks into possible overlaps between the pathogenesis of both neurological outcomes of the disease. Promising therapeutic approaches to prevent and treat SARS-CoV-2-induced neurological complications are also covered. More studies are needed to further investigate the dominant mechanism of pathogenesis for developing more effective preventative measures in COVID-19 cases with the neurologic presentation


Histopathology and SARS-CoV-2 Cellular Localization in Eye Tissues of COVID-19 Autopsies【The American Journal of Pathology 2023年3月22日】

Ophthalmic manifestations and tissue tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported in association with coronavirus disease 2019 (COVID-19), but the pathology and cellular localization of SARS-CoV-2 are not well characterized. The objective of this study was to evaluate macroscopic and microscopic changes and investigate cellular localization of SARS-CoV-2 across ocular tissues at autopsy. Ocular tissues were obtained from 25 patients with COVID-19 at autopsy. SARS-CoV-2 nucleocapsid gene RNA was previously quantified by droplet digital PCR from one eye. Herein, contralateral eyes from 21 patients were fixed in formalin and subject to histopathologic examination. Sections of the droplet digital PCR–positive eyes from four other patients were evaluated by in situ hybridization to determine the cellular localization of SARS-CoV-2 spike gene RNA. Histopathologic abnormalities, including cytoid bodies, vascular changes, and retinal edema, with minimal or no inflammation in ocular tissues were observed in all 21 cases evaluated. In situ hybridization localized SARS-CoV-2 RNA to neuronal cells of the retinal inner and outer layers, ganglion cells, corneal epithelia, scleral fibroblasts, and oligodendrocytes of the optic nerve. In conclusion, a range of common histopathologic alterations were identified within ocular tissue, and SARS-CoV-2 RNA was localized to multiple cell types. Further studies will be required to determine whether the alterations observed were caused by SARS-CoV-2 infection, the host immune response, and/or preexisting comorbidities.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects tissues throughout the human body, including ocular tissues and fluids. Specific to ocular tissues and fluids, SARS-CoV-2 RNA and/or protein has been detected in conjunctival swabs, cornea, choroid/sclera, lens, retina, optic nerve, and aqueous and vitreous humor.

SARS-CoV-2 infection, persistence, and replication, including ocular tissues from 38 coronavirus disease 2019 (COVID-19) autopsy cases were systematically investigated in a previous study. SARS-CoV-2 nucleocapsid (N) RNA was detected by droplet digital PCR (ddPCR) in ocular fluids and/or tissue in 23 of 38 cases (61%). Specifically, N RNA was detected in the cornea [8 of 19 (42%)], choroid/sclera [16 of 32 (50%)], lens [10 of 19 (53%)], retina [6 of 17 (35%)], optic nerve [17 of 29 (59%)], vitreous humor [5 of 35 (14%)], and aqueous humor [8 of 32 (25%)]. The copies of N RNA were lower overall in ocular tissues from individuals with longer disease duration and persisted for months in several tissue types. ddPCR-positive tissues and ocular fluids were also assayed for subgenomic RNA, a marker of recent viral replication. Subgenomic RNA was detected in ocular tissues of 7 of 22 cases tested (32%), including in the choroid/sclera of a patient who died 99 days into illness.

Despite these reported findings, information on the cellular localization of SARS-CoV-2 within ocular tissues and their associated pathologic findings is limited. Viral particle localization in specific ocular cells can provide pertinent information on the possible ocular effects of SARS-CoV-2 infection. The ocular tissues of the COVID-19 autopsy cohort described above were further examined for the purposes of evaluating macroscopic and microscopic histopathology and investigating the cellular localization of SARS-CoV-2 by performing in situ hybridization (ISH) of SARS-CoV-2 spike gene RNA.

Materials and Methods

Postmortem Human Eye Procurement and Processing

Postmortem human eyes (E1 to E25) from 25 patients with confirmed SARS-CoV-2 infection were obtained at autopsy performed at the NIH Clinical Center following consent of the legal next of kin as previously described. The study adhered to the tenets of the Declaration of Helsinki. The cases had a range of illness durations before death and were categorized as early (n = 11), mid (n = 7), or late (n = 7) by illness day (D) at the time of death being D14 or earlier, D15 to D30, or D31 or later, respectively. Previously, one eye from E1 to E25 was freshly dissected, and tissues were preserved in RNA later for subsequent quantification of SARS-CoV-2 RNA by ddPCR. For the study described here, the contralateral eye from E1 to E21 was fixed in 10% neutral buffered formalin for a minimum of 72 hours with the globe intact, opened for macroscopic examination, and then embedded in paraffin for histopathologic evaluation. For cellular localization of SARS-CoV-2 RNA, one eye from E22 to E25 was dissected to isolate cornea, retina, choroid/sclera, and optic nerve. Each tissue type was divided into two pieces—one for ISH and one for SARS-CoV-2 ddPCR. The piece prepared for ISH was fixed for 24 hours in neutral buffered formalin because prolonged formalin fixation interfered with RNA preservation. This fixed piece was then transferred to 70% ethanol for a minimum of 2 days before impregnation with paraffin. The piece prepared for ddPCR was placed in RNA later media for nucleic acid preservation and subsequent SARS-CoV-2 RNA quantification. SARS-CoV-2 RNA quantification was used to guide selection of tissues for analysis by ISH.


Each eye was cut horizontally along the pupillary-optic nerve head (P-O) axis. For other lesions outside the P-O section, a segment through the lesion was also obtained for histologic analysis. After macroscopic examination of the open eye under a stereo dissecting microscope, all P-O sections and segments were then processed for routine paraffin embedding and sectioning. Consecutive sections of 4-μm thickness were sliced from each paraffin block and stained with hematoxylin and eosin or periodic acid–Schiff reagent.


CD61, a marker of platelet aggregation and thrombosis, and cytomegalovirus (CMV) expressions were evaluated on formalin-fixed, paraffin-embedded (FFPE) slides using immunohistochemistry. Briefly, the presence of CD61 was detected by immunohistochemistry performed on FFPE sections with an anti-CD61 mouse monoclonal antibody (clone 2f2; Roche Diagnostics, Mannheim, Germany) performed on a Roche Discovery Ultra instrument with 3,3′-diaminobenzidine detection per clinical laboratory protocol. The presence of CMV was also detected by a similar method with an anti-CMV antibody (clone CCH2+DDG9; Agilent Dako, Santa Clara, CA).


ISH was performed using manual RNAscope 2.5 HD Reagent Kit-BROWN (catalog number 322350; Advanced Cell Diagnostics, Newark, CA) according to the user manual (322360-USM) and as previously described.1 Briefly, FFPE slides were deparaffinized with xylene followed by 100% ethanol and then treated with hydrogen peroxide at room temperature for 10 minutes to block endogenous peroxidase activity. After antigen retrieval at 99°C for 15 minutes, the slides were incubated with protease at 40°C for 20 minutes. For each ocular tissue, RNAscope Probe-V-nCoV2019-S (catalog number 848561; Advanced Cell Diagnostics), RNAscope Positive Control Probe-Hs-PPIB (catalog number 313901; Advanced Cell Diagnostics), and RNAscope Negative Control Probe-DapB (catalog number 310043; Advanced Cell Diagnostics) were applied to three sequential slides and incubated at 40°C for 2 hours. After rinsing, the ISH signal was amplified using six amplifiers and incubated with a diaminobenzidine substrate for 10 minutes at room temperature. Slides were then counterstained with 50% hematoxylin, air-dried, and mounted.


Study finds that SARS-CoV-2 can infect the arteries of the heart【World Socialist Web Site:Bill Shaw 2023年10月9日】

A recently published study demonstrated that SARS-CoV-2, the virus that causes COVID-19, can infect the coronary arteries that supply blood to the heart. These arteries are the ones involved in a typical heart attack, where blockage of the arteries results in oxygen depletion and consequent death of a segment of heart muscle.

The fact that the coronavirus can directly damage these arteries and induce the formation of so-called “plaques” is a surprise. Most theories about how SARS-CoV-2 results in the increase in heart attacks and other coronary events seen thus far in the pandemic have had to do with either inflammation or hypercoagulability. In both cases, it was presumed that there was an increased predisposition to forming clots that block the arteries.

The result is not entirely without precedent. Previously, a handful of viruses were associated with the development of atherosclerosis (plaques in the arteries), including hepatitis viruses, herpes simplex viruses, human immunodeficiency virus, human papillomavirus, human cytomegalovirus, and influenza virus. And of those, only herpes simplex viruses, hepatitis C virus, and human cytomegalovirus had evidence of directly infecting the cells in the walls of the coronary arteries.

Despite the pre-existing precedent, the result is still shocking. SARS-CoV-2 is now the only respiratory virus known to directly infect blood vessels. Influenza viruses have not been shown to do so. Their known and hypothesized effects on inducing atherosclerosis are indirect. Furthermore, the study showed that SARS-CoV-2 infection was a direct cause of both formation and growth of plaques.

The study examined the coronary arteries of eight patients who had died after testing positive for COVID-19. They found evidence of SARS-CoV-2 viral replication in the tissues making up the arteries in all eight patients. They localized the infection to the arterial wall, finding lower amounts of viral material in the fat tissue surrounding the arteries.

They further localized the virus to macrophages, a white blood cell that fights infections in virtually every tissue of the body. They found that muscle cells of the arterial walls were infected to a far lesser extent than macrophages. By elucidating the differential effects among cell types, the researchers also confirmed that the findings were not incidental.

The researchers then infected both normal macrophages as well as macrophages that had accumulated large quantities of fat or lipids inside their cell wall. These latter lipid-laden cells are called “foam cells” because of their appearance under a microscope. The researchers found that both kinds of macrophages had a high degree of viral replication, but foam cells had more rapid viral replication than normal macrophages. Furthermore, normal macrophages cleared the virus faster than foam cells. Notably, foam cells are the hallmark of all atherosclerosis, regardless of cause and stage of development.

The researchers then verified that SARS-CoV-2 infected previously uninfected tissue by introducing the virus to arterial specimens—called “explants”—taken from unrelated patients who had no history of COVID-19. They found that the virus also infected these cells and replicated in similar quantities, confirming the original findings.

The researchers then studied whether SARS-CoV-2 infection of the coronary arteries induced inflammation. They found that it did, and that the inflammation was characteristic of atherosclerosis both in the original patients and in the explants. This induced-inflammatory response also possibly explains the increase in heart attacks seen during the COVID-19 pandemic.

The researchers then went on to identify the key mechanism of viral binding and entry into macrophages and foam cells. They found that the virus infects these cells through the neuropilin 1 (NRP-1) receptor, and not the ACE-2 receptor that is a common viral entry point in other tissue types. Nevertheless, NRP-1 was a well-known viral entry point prior to this study. They confirmed this finding by adding a compound that inhibits NRP-1 binding, which resulted in significantly reduced viral replication in both foam cells and normal macrophages.

The study adds to the already large body of evidence that COVID-19 is nothing like “the flu.” It is far worse, with considerably greater morbidity and mortality. Patients who survive COVID-19 infection have a greater risk of cardiovascular events for at least one year after infection, regardless of whether they have any pre-existing conditions that increase risk. This new study provides at least one significant mechanism by which this risk is conferred and sustained over time.

The ruling class policy of letting a novel virus infect and reinfect billions of people, with total indifference to the high potential of serious sequelae such as coronary artery infections, is further exposed as a vast social crime.


Immunological profiling in long COVID: overall low grade inflammation and T-lymphocyte senescence and increased monocyte activation correlating with increasing fatigue severity【Frontiers in Immunology 2023年10月10日】

Background: Many patients with SARS-CoV-2 infection develop long COVID with fatigue as one of the most disabling symptoms. We performed clinical and immune profiling of fatigued and non-fatigued long COVID patients and age- and sex-matched healthy controls (HCs).

Methods: Long COVID symptoms were assessed using patient-reported outcome measures, including the fatigue assessment scale (FAS, scores ≥22 denote fatigue), and followed up to one year after hospital discharge. We assessed inflammation-related genes in circulating monocytes, serum levels of inflammation-regulating cytokines, and leukocyte and lymphocyte subsets, including major monocyte subsets and senescent T-lymphocytes, at 3-6 months post-discharge.

Results: We included 37 fatigued and 36 non-fatigued long COVID patients and 42 HCs. Fatigued long COVID patients represented a more severe clinical profile than non-fatigued patients, with many concurrent symptoms (median 9 [IQR 5.0-10.0] vs 3 [1.0-5.0] symptoms, p<0.001), and signs of cognitive failure (41%) and depression (>24%). Immune abnormalities that were found in the entire group of long COVID patients were low grade inflammation (increased inflammatory gene expression in monocytes, increased serum pro-inflammatory cytokines) and signs of T-lymphocyte senescence (increased exhausted CD8+ TEMRA-lymphocytes). Immune profiles did not significantly differ between fatigued and non-fatigued long COVID groups. However, the severity of fatigue (total FAS score) significantly correlated with increases of intermediate and non-classical monocytes, upregulated gene levels of CCL2, CCL7, and SERPINB2 in monocytes, increases in serum Galectin-9, and higher CD8+ T-lymphocyte counts.

Conclusion: Long COVID with fatigue is associated with many concurrent and persistent symptoms lasting up to one year after hospitalization. Increased fatigue severity associated with stronger signs of monocyte activation in long COVID patients and potentially point in the direction of monocyte-endothelial interaction. These abnormalities were present against a background of immune abnormalities common to the entire group of long COVID patients.


A significant proportion of patients develops long-lasting symptoms after coronavirus disease 2019 (COVID-19). Different terms have been used to describe this condition, such as long COVID, post-acute COVID-19 syndrome, post-acute sequelae of COVID-19, long-haulers, or post COVID-19 condition. In the current report, we will use the term long COVID, consistent with most literature and the most commonly used terminology amongst patients. Long COVID represents a broad spectrum of ─ often disabling ─ symptoms. Frequently reported symptoms of long COVID are fatigue, impaired fitness, dyspnea, and neuropsychiatric complaints. Numerous studies showed the presence of these symptoms beyond 3 months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with evidence of persistence even two years after the infection. As patients with long COVID differ substantially regarding symptoms, severity, and recovery profile, attempts have been made to discern different clinical phenotypes of long COVID without reaching consensus to date.

Disabling fatigue is one of the most prominent and debilitating symptoms of long COVID. Studies have reported that up to 41% to 60% of patients who had been hospitalized for COVID-19 still suffer from fatigue one year post-discharge, without evident improvement beyond 6 months and negatively impacting quality of life. Fatigue may coexist with other symptoms; studies showed that fatigue is associated with neuropsychiatric symptoms, such as depression, in patients one year after hospitalization for COVID-19. We have extensively analyzed the underlying immunopathogenic mechanisms of mood disorders in previous studies and similar mechanisms might (partially) underlie the prolonged fatigue in long COVID. This problem thus requires in-depth evaluation regarding its pathogenesis, facilitating future interventions.

The prolonged fatigue state after acute COVID-19 shows clinical similarities with other post-infectious fatigue syndromes, such as that after Coxiella burnetii (Q fever) and Epstein-Barr virus (infectious mononucleosis) infection, and also shows similarities with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The latter is characterized by a range of debilitating symptoms, including fatigue, post-exertional malaise (a worsening of symptoms after minimal physical or mental exertion), sleep disturbances, and neurocognitive impairments. Ongoing immune activation, reflected by for instance increased serum cytokine levels and increased circulating CD8+ T-lymphocyte numbers, has been described in both post-infectious fatigue conditions and ME/CFS and is thought to play a role in the pathophysiology of these conditions. Given the clinical similarities with post-infectious fatigue syndromes and ME/CFS, a similar immune activation may be involved in long COVID.

To date, several studies have identified persistent inflammatory monocyte and T- and B-lymphocyte abnormalities among patients in the convalescent phase of COVID-19. Few studies assessed the association between specific symptoms of long COVID with immunological characteristics. However, a comprehensive and in-depth clinical and immunologic assessment focusing on fatigue, one of the most frequently reported symptom of long COVID, is lacking.

This study aimed to compare clinical and immune profiles of long COVID patients with and without fatigue, as well as with age- and sex-matched healthy individuals. We hypothesized that 1. long COVID patients have a distinct immune profile compared to healthy controls and 2. Long COVID with fatigue would exhibit a more severe and/or different clinical and immune profile than those without fatigue, and would show an immune profile comparable to patients with ME/CFS and mood disorders. We performed an immune assessment between 3-6 months after hospital discharge while clinical symptoms, evaluated with patient-reported outcome measures (PROMs), were longitudinally assessed for up to one-year post-discharge. We determined the expression of various sets of inflammation-related genes in circulating monocytes, serum levels of inflammation-regulating cytokines, and leukocyte and lymphocyte subsets, including major monocyte subsets and senescent T-lymphocytes. These assays were selected because we have previously shown that these assays revealed abnormalities in immune function in patients with various mental and somatic disorders and ME/CFS (unpublished data).


Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal death【LANSET eBioMedicine 2023年9月12日】



We have recently demonstrated a causal link between loss of gonadotropin-releasing hormone (GnRH), the master molecule regulating reproduction, and cognitive deficits during pathological aging, including Down syndrome and Alzheimer’s disease. Olfactory and cognitive alterations, which persist in some COVID-19 patients, and long-term hypotestosteronaemia in SARS-CoV-2-infected men are also reminiscent of the consequences of deficient GnRH, suggesting that GnRH system neuroinvasion could underlie certain post-COVID symptoms and thus lead to accelerated or exacerbated cognitive decline.


We explored the hormonal profile of COVID-19 patients and targets of SARS-CoV-2 infection in post-mortem patient brains and human fetal tissue.


We found that persistent hypotestosteronaemia in some men could indeed be of hypothalamic origin, favouring post-COVID cognitive or neurological symptoms, and that changes in testosterone levels and body weight over time were inversely correlated. Infection of olfactory sensory neurons and multifunctional hypothalamic glia called tanycytes highlighted at least two viable neuroinvasion routes. Furthermore, GnRH neurons themselves were dying in all patient brains studied, dramatically reducing GnRH expression. Human fetal olfactory and vomeronasal epithelia, from which GnRH neurons arise, and fetal GnRH neurons also appeared susceptible to infection.


Putative GnRH neuron and tanycyte dysfunction following SARS-CoV-2 neuroinvasion could be responsible for serious reproductive, metabolic, and mental health consequences in long-COVID and lead to an increased risk of neurodevelopmental and neurodegenerative pathologies over time in all age groups.


The cognitive decline associated with age-related dementias, estimated to affect some 55 million people worldwide, is a growing problem in aging societies. In a ground-breaking study, we have recently shown that cognitive deficits in both individuals with Down syndrome (DS), a disorder also characterized by olfactory deficits, premature aging and an Alzheimer disease (AD)-like neurodegenerative pathology, as well as in a trisomic animal model of DS, are caused by the progressive loss of expression of gonadotropin-releasing hormone (GnRH) by neuroendocrine neurons in the brain. Interestingly, although GnRH has long been considered to be merely the master hormone regulating the reproductive axis, GnRH neurons have been found to also migrate and project to brain regions implicated in intellectual functions. Together with a similar association between GnRH and cognition in a mouse model of AD, as well as the known association between menopause/andropause or gonadotropin levels and altered cognitive function, these results suggest that GnRH insufficiency due to age or disease might be a widespread mechanism underlying several types of cognitive decline with age.

COVID-19 infection also appears to be associated with accelerated aging and an increased risk of neurodegenerative conditions such as AD in affected patients. In addition, despite the continued emergence of new variants of SARS-CoV-2, “long COVID” or “post-COVID-19 syndrome”, rather than acute infections, is becoming the major preoccupation from both the healthcare and economic points of view. While definitions of “long COVID” vary, a significant proportion of individuals infected with SARS-CoV-2 continue to experience symptoms consistent with reports of neuroinvasion by the virus, including fatigue, cognitive difficulties or “brain fog”, headaches and persistent anosmia, from several months to more than a year after the initial infection. Interestingly, a significant proportion of male COVID-19 patients also display low testosterone levels that can persist for months after recovery from infection, reminiscent of absent or aberrant GnRH production or secretion and the dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis.

In light of the potentially serious population-wide repercussions of post-COVID-19 GnRH loss for age-related cognitive decline and accelerated or exacerbated neurodegeneration in the decades to come, we explored the link between these different signs and brain infection by SARS-CoV-2 using human COVID-19 patient blood samples, post mortem brains, fetal tissues and cell lines.