SARS-CoV-2 と COVID-19 に関する備忘録 Vol.3

SARS-CoV-2 と COVID-19 に関するメモ・備忘録

Long COVID and New Migraines: What’s the Link?【Medscape:Lisa Mulcahy 2023年9月7日】

Intense throbbing, sensitivity to light and sound, nausea: these were the symptoms Nathan Solomon experienced during his first-ever migraine about a month after receiving a diagnosis of long COVID.

“I’ve also noticed visual disturbances, like flickering lights or blurred vision, which I later learned are called auras,” the 30-year-old medical billing specialist in Seattle told Medscape Medical News.

Solomon isn’t alone. It’s estimated that 1 out of 8 people with COVID develop long COVID. Of those persons, 44% also experience headaches. Research has found that many of those headaches are migraines — and many patients who are afflicted say they had never had a migraine before. These migraines tend to persist for at least 5 or 6 months, according to data from the American Headache Society.

What’s more, other patients may suddenly have more frequent or intense versions of headaches they’ve not noticed before.

The mechanism as to how long COVID could manifest migraines is not yet fully understood, but many doctors believe that inflammation caused by the virus plays a key role.

“To understand why some patients have migraine in long COVID, we have to go back to understand the role of inflammation in COVID-19 itself,” says Emad Estemalik, MD, clinical assistant professor of neurology at Cleveland Clinic Lerner College of Medicine and section head of headache medicine at Cleveland Clinic.

In COVID-19, inflammation occurs because of a cytokine storm. Cytokines, which are proteins essential for a strong immune system, can be overproduced in a patient with COVID, which causes too much inflammation in any organ in the body, including the brain. This can result in new daily headache for some patients.

A new study from Italian researchers found that many patients who develop migraines for the first time while ill with long COVID are middle-aged women (traditionally a late point in life for a first migraine) who have a family history of migraine. Potential causes could have to do with the immune system remaining persistently activated from inflammation during long COVID, as well as the activation of the trigeminovascular system in the brain, which contains neurons that can trigger a migraine.

What Treatments Can Work for Migraines Related to Long COVID?

Long COVID usually causes a constellation of other symptoms at the same time as migraine.

“It’s so important for patients to take an interdisciplinary approach,” Estemalik stresses. “Patients should make sure their doctors are addressing all of their symptoms.”

When it comes to specifically targeting migraines, standard treatments can be effective.

“In terms of treating migraine in long COVID patients, we don’t do anything different or special,” says Matthew E. Fink, MD, chair of neurology at Weill Cornell Medicine and chief of the Division of Stroke and Critical Care Neurology at New York–Presbyterian Hospital/Weill Cornell Medicine in New York City. “We treat these patients with standard migraine medications.”

Solomon is following this course of action.

“My doctor prescribed triptans, which have been somewhat effective in reducing the severity and duration of the migraines,” he says. A daily supplement of magnesium and a daily dose of aspirin can also work for some patients, according to Fink.

Lifestyle modification is also a great idea.

“Patients should keep regular sleep hours, getting up and going to bed at the same time every day,” Fink continues. “Daily exercise is also recommended.”

Solomon suggests tracking migraine triggers and patterns in a journal.

“Try to identify lifestyle changes that help, like managing stress and staying hydrated,” Nathan advises. “Seeking support from healthcare professionals and support groups can make a significant difference.”

The best news of all: for patients are diligent in following these strategies, they’ve been proven to work.

“We doctors are very optimistic when it comes to good outcomes for patients with long COVID and migraine,” Fink says. “I reassure my patients by telling them, ‘You will get better long-term.’ “


Human iPS cell-derived sensory neurons can be infected by SARS-CoV-2【Cell:iScience 2023年8月18日】


  • Sensory neurons can be infected by SARS-CoV-2
  • Infectability differs between WA1/2020 strain as well as the delta and omicron variants
  • Infected sensory neurons synthesize SARS-CoV-2 RNA but do not produce progeny virion


COVID-19 has impacted billions of people since 2019 and unfolded a major healthcare crisis. With an increasing number of deaths and the emergence of more transmissible variants, it is crucial to better understand the biology of the disease-causing virus, the SARS-CoV-2. Peripheral neuropathies appeared as a specific COVID-19 symptom occurring at later stages of the disease. In order to understand the impact of SARS-CoV-2 on the peripheral nervous system, we generated human sensory neurons from induced pluripotent stem cells that we infected with the SARS-CoV-2 strain WA1/2020 and the variants delta and omicron. Using single-cell RNA sequencing, we found that human sensory neurons can be infected by SARS-CoV-2 but are unable to produce infectious viruses. Our data indicate that sensory neurons can be infected by the original WA1/2020 strain of SARS-CoV-2 as well as the delta and omicron variants, yet infectability differs between the original strain and the variants.

Graphical abstract


Infection with SARS-CoV-2 has been reported to impact the entire body and cause COVID-19. In addition to causing severe damage to the respiratory system, SARS-CoV-2 acutely affects the nervous system with symptoms including loss of taste and smell, headaches, stroke, delirium, and brain inflammation. Among these symptoms, anosmia emerged as an early indication of SARS-CoV-2 infection. The observed anosmia was highly prevalent in COVID-19 patients but reversible, with most patients recovering their senses of smell and taste in about 6 weeks. However, in about 10% of COVID-19 patients, olfactory dysfunction becomes either persistent or poorly recovered. Recent in vivo studies suggested that SARS-CoV-2 can disrupt the nuclear architecture of the olfactory epithelium, inducing the dysregulation of olfactory receptor genes in a non-cell autonomous manner. In this study, using a model of SARS-CoV-2 intranasal injection of hamsters, the authors also noted that sensory neurons of the olfactory epithelium were poorly infected (<5% positivity). Although olfactory sensory neurons appear to not express the receptor for virus entry, it remains unclear whether other types of peripheral sensory neurons may be susceptible to SARS-CoV-2 infection. Additional COVID-related peripheral neuropathies have been described recently including small-fiber neuropathy, multifocal demyelinating neuropathy, and critical illness axonal neuropathy. It is estimated that 59% of COVID-19 patients show signs of neuropathy in the mid- or long-term. The available data suggest that neurons are not highly infected by SARS-CoV-2 due to the lack of ACE2 expression and that neuropathies could be due to an inflammatory response affecting sensory neurons in a non-cell-autonomous manner. However, neuropathy disorders generally occur at a late stage of the disease when the inflammatory response is dimmed. In order to address the mechanism by which SARS-CoV-2 impacts the peripheral nervous system, we generated a heterogeneous population of human sensory neurons using induced pluripotent stem (iPS) cells that were infected with either the WA1/2020 strain of SARS-CoV-2 or the delta and omicron variants. Single-cell RNA sequencing (scRNA-seq) analysis showed that about 20% of human sensory neurons were infected by SARS-CoV-2 with the omicron variant having the lowest infection rate. We further show that although SARS-CoV-2 infects human sensory neurons, it does not actively replicate to shed progeny virion. This study reveals how SARS-CoV-2 may initiate a non-productive infection in sensory neurons which has the potential to explain the neuropathies associated with COVID-19.


Multiple COVID infections can lead to chronic health issues. Here’s what to know.――A previous SARS-CoV-2 infection can protect you for a little while, but the immunity wanes—and each new infection, no matter how mild, takes a toll on your body.【National Geographic:Sanjay Mishra 2023年9月13日】

Mehnaz Qureshi has caught COVID-19 seven times, despite being fully vaccinated and boosted. A veterinarian and a virologist at The Pirbright Institute in England, she first caught the disease in March 2020 when the COVID-19 pandemic was just beginning; then everyone in her family got sick.

While Qureshi’s own symptoms were mild, her family members fared worse—some requiring hospitalization and supplemental oxygen to breathe. As the mother of two children and the family’s primary care giver she didn’t have much time to think, or treat, her own symptoms. “I almost forgot about myself,” says Qureshi. But COVID-19 hadn’t forgotten her.

“For me, it has been just four to six months of window between each reinfection,” says Qureshi. Aside from disrupting her life seven times, her symptoms during subsequent reinfections have been more severe.

While a previous SARS-CoV-2 infection can protect against a reinfection for an average of seven months, the immunity wanes afterwards. Repeated bouts of COVID-19 are harmful—even if the episodes are mild—because the long-term consequences add up for each additional infection, as demonstrated in a study of U.S. veterans. While veterans don’t necessarily reflect the broader public—because they tend to be older, white, and male—the research shows that patients who were reinfected with any SARS-CoV-2 variant are much more likely to develop chronic health issues like diabetes, kidney disease, organ failure, and even mental health problems.

Qureshi’s first infection was mild, with a fever that lasted a couple of days, aches, and cold symptoms, she recalls. “My major symptom was that I lost smell and taste.” But the most recent infection was disabling. She was bedridden for a week, could barely stand, and had severe cognitive impairment. “I couldn’t think straight,” says Qureshi. “The most recent one was really bad.”

With reinfections rising it is good news that the U.S. Food and Drug Administration approved Pfizer’s and Moderna’s new COVID-19 boosters on September 11. The preliminary data from Moderna, which has not yet been peer reviewed and published, shows that the XBB.1.5 based booster, which could be available to the public as soon as this week generates ample levels of antibodies not only against the latest highly mutated Omicron BA.2.86 variant, but also against other currently circulating strains, EG.5.1 and FL.1.5.1.

After the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices met yesterday and voted in favor of the new shots, CDC director Mandy Cohen signed off on the panel’s recommendations. “CDC is now recommending updated COVID-19 vaccination for everyone six months and older to better protect you and your loved ones.”

“I certainly recommend at all of my preventative visits that patients complete their primary COVID series and stay up to date on the boosters,” says Natalie Paul, a family nurse practitioner at Lavender Spectrum Health in Longview, Washington. While vaccines and boosters may not block new or reinfections, they provide a strong protection against serious complications or hospitalization. “I personally would get it myself.”

Soaring reinfection rates

The CDC defines a reinfection as when someone tests positive for SARS-CoV-2—the virus that causes COVID-19—on a PCR test 45 days after recovering from a previous confirmed infection. In the United States, about 2.7 percent of all reported COVID cases during the Delta variant surge in late 2021 were reinfections. But the problem became significantly worse when Omicron emerged, and its more infectious subvariants became dominant.

A CDC analysis of lab-confirmed, adult COVID cases between September 2021 and December 2022, found that reinfection rates jumped to 10.3 percent during the Omicron BA.1 wave; 12.5 percent when BA.2 was dominant; 20.6 percent during BA.4/BA.5; and 28.8 percent during the BQ.1/BQ.1.1. The good news is that a meta-analysis of 91 published studies showed that vaccination lowered the risk of getting reinfected, although vaccines became less efficient in preventing reinfections against Omicron variants.

But the numbers of reinfections are likely to be underestimated because not everyone who gets infected with SARS-CoV-2 gets sick enough to get tested. Since reinfection often generates somewhat milder symptoms, it is even more difficult to fully assess the true tally. Being a virologist, Qureshi frequently takes COVID tests when she suspects something is off, and that’s why she knows she has had frequent re-infections.

A Canadian study estimated that 40 percent of people who had antibodies in their blood—proof that they had been infected with SARS-CoV-2—had not experienced any symptoms in the previous six months and were unaware they had gotten the disease.

Studies from various other countries also suggest that reinfection rates can range from 5 percent to 15 percent. An analysis of COVID-19 cases in Serbia, for example, found that risk of getting reinfected has steadily increased during the pandemic, but it spiked after the arrival of Omicron variants in December 2022.

Who is most likely to get reinfected?

People who work in jobs with a lot of face-to-face contact, such as teachers and other school employees, healthcare professionals, and those who live in multigenerational households often have frequent recurrent COVID infections, says Paul. For example, healthcare employees working in COVID-19 clinical units can have a four-fold higher risk of getting reinfected relative to those working in non-clinical units.

Studies show that the risk of someone getting COVID-19 are much higher among families with young children. In fact, over 70 percent of nearly 850,000 U.S. households might have caught COVID-19 through a child during the school year.

“I now treat a lot of people with multiple COVID infections,” says nurse Paul. “A lot of them have risk factors like having young children in the school system.”

Christine Micheel, like Qureshi, is also a mother of two young children. She first got COVID-19 in December 2020 just before vaccines became available. However, even after getting fully vaccinated and boosted, she ended up getting COVID-19 again in July 2022 during the BA.5 Omicron wave. Her son also got infected three times, while her daughter has caught it twice, although both children were fully vaccinated at the time.

“Their symptoms were so minor, I think only I, as their mother, could have noticed them as unusual and given them a test,” says Micheel, a cancer researcher at the Vanderbilt-Ingram Cancer Center in Nashville.

With schools reopening amidst rising numbers of COVID-19 cases, children might unknowingly be spreading the disease to their households. “How many kids have probably been walking around spreading COVID-19 with no one the wiser?” says Micheel.

The antibodies against SARS-CoV-2 wane substantially within three months, especially in patients with less severe symptoms. However, immune response to a previous infection, or vaccine, can vary a lot between individuals.

“Nobody is immune to this,” says Qureshi. “Sooner or later, you will get an infection.”


SARS-CoV-2 infection induces a long-lived pro-inflammatory transcriptional profile【Genome Medicine 2023年9月12日】



The immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in COVID-19 patients has been extensively investigated. However, much less is known about the long-term effects of infection in patients and how it could affect the immune system and its capacity to respond to future perturbations.


Using a targeted single-cell multiomics approach, we have recently identified a prolonged anti-inflammatory gene expression signature in T and NK cells in type 1 diabetes patients treated with low-dose IL-2. Here, we investigated the dynamics of this signature in three independent cohorts of COVID-19 patients: (i) the Oxford COVID-19 Multi-omics Blood Atlas (COMBAT) dataset, a cross-sectional cohort including 77 COVID-19 patients and ten healthy donors; (ii) the INCOV dataset, consisting of 525 samples taken from 209 COVID-19 patients during and after infection; and (iii) a longitudinal dataset consisting of 269 whole-blood samples taken from 139 COVID-19 patients followed for a period of up to 7 months after the onset of symptoms using a bulk transcriptomic approach.


We discovered that SARS-CoV-2 infection leads to a prolonged alteration of the gene expression profile of circulating T, B and NK cells and monocytes. Some of the genes affected were the same as those present in the IL-2-induced anti-inflammatory gene expression signature but were regulated in the opposite direction, implying a pro-inflammatory status. The altered transcriptional profile was detected in COVID-19 patients for at least 2 months after the onset of the disease symptoms but was not observed in response to influenza infection or sepsis. Gene network analysis suggested a central role for the transcriptional factor NF-κB in the regulation of the observed transcriptional alterations.


SARS-CoV-2 infection causes a prolonged increase in the pro-inflammatory transcriptional status that could predispose post-acute patients to the development of long-term health consequences, including autoimmune disease, reactivation of other viruses and disruption of the host immune system-microbiome ecosystem.


Viral-like TLR3 induction of cytokine networks and α-synuclein are reduced by complement C3 blockade in mouse brain【nature:scientific reports 2023年9月13日】


Inflammatory processes and mechanisms are of central importance in neurodegenerative diseases. In the brain, α-synucleinopathies such as Parkinson’s disease (PD) and Lewy body dementia (LBD) show immune cytokine network activation and increased toll like receptor 3 (TLR3) levels for viral double-stranded RNA (dsRNA). Brain inflammatory reactions caused by TLR3 activation are also relevant to understand pathogenic cascades by viral SARS-CoV-2 infection causing post- COVID-19 brain-related syndromes. In the current study, following regional brain TLR3 activation induced by dsRNA in mice, an acute complement C3 response was seen at 2 days. A C3 splice-switching antisense oligonucleotide (ASO) that promotes the splicing of a non-productive C3 mRNA, prevented downstream cytokines, such as IL-6, and α-synuclein changes. This report is the first demonstration that α-synuclein increases occur downstream of complement C3 activation. Relevant to brain dysfunction, post-COVID-19 syndromes and pathological changes leading to PD and LBD, viral dsRNA TLR3 activation in the presence of C3 complement blockade further revealed significant interactions between complement systems, inflammatory cytokine networks and α-synuclein changes.


Viral infections and consequent brain inflammation increase neurodegenerative disease risk

Inflammatory processes and mechanisms have emerged to be of central importance in the genesis of neurodegenerative diseases. Neuroinflammation, characterized by reactive microglia and astrocytes, and elevated levels of inflammatory mediators in the brain, was traditionally viewed as secondary to neuronal death and dysfunction in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Contrary to this conventional view, there is now robust evidence from preclinical and clinical studies that immune activation can contribute to and drives disease pathogenesis. Drivers of such inflammation can be cell-autonomous or the result of network interaction between neurons, glia, vascular and blood-derived agents. We and others have previously shown that bacterial, viral, lipid, or metabolic activators are potent initiators of such neuroinflammation1. Of particular interest are the dsRNA toll like receptor 3 (TLR3) receptor activators from viral sources that can initiate such inflammatory cascades.

Viral and other inflammatory conditions are linked to increased risk of neurodegenerative diseases and cognitive dysfunction. Systemic cytokine elevations following viral infection, such as those that cause cytokine storm in patients with COVID-19, are associated with cytokine and glial activations in the brain. Infection with Epstein-Barr virus (EBV) is associated with a 32-fold increased risk for developing multiple sclerosis, with onset of disease symptoms beginning approximately 10 years after infection. Furthermore, recent epidemiological studies provide compelling evidence that repeated viral infections causing influenza drastically increase the probability (more than tenfold) of developing neurodegenerative diseases. Viral outbreaks, including the 1918 influenza pandemic and periodic mosquito-borne flavivirus epidemics such as Japanese encephalitis virus and West Nile virus, have led to subsequent diagnoses of post-encephalitic parkinsonism among survivors of the incident viral infection. Given the risk of neurological “long-COVID” symptoms following SARS-CoV-2 infection, evidence of COVID-induced changes in brain regions that are related to cognition and neurological disorders, and association of COVID-19 with onset of neurodegenerative disease, it is highly significant to establish the underlying biological cellular brain responses that are associated with TLR3 activation and viral inflammation. In the context of historical viral outbreaks and the current COVID-19 pandemic, understanding how the long-term consequences of such viral infections could precipitate degenerative changes within vulnerable brain regions is of current and critical importance.

Several inflammatory processes have been shown to be linked to the classic pathological hallmarks of neurodegenerative diseases at post-mortem. For example, α-synuclein, which is associated with neuropathology of PD and Lewy body dementia (LBD), is increased and aggregates in response to cellular stressors, such as mitochondrial dysfunction, lipid accumulation, and inflammation. Injection of the toll like receptor 4 (TLR4) agonist, lipopolysaccharide (LPS), into the midbrain of rodents induces activation of inflammatory cytokine networks, accumulation of insoluble and aggregated α-synuclein and dopamine neuron degeneration, and long-term systemic administration of low-dose LPS administration in mice induces significant reductions of dopaminergic neurons. It has also been shown that α-synuclein is upregulated by certain viral infections. Deficiency of α-synuclein in mice increases susceptibility to infection by viral or bacterial causes, suggesting that α-synuclein can participate in anti-microbial functions. Importantly, α-synuclein accumulation has been reported in the brain of rodents and non-human primates following SARS-CoV-2 systemic infection. These connections between acute α-synuclein functional responses to potent inflammatory stimuli, and pathological α-synuclein increases that lead to aggregation associated with chronic inflammatory cytokine and glial activations in brain regions vulnerable to degeneration, highlight that inflammation is a critical driver of pathology in neurodegenerative disease.

Brain responses to viral-like TLR3 activation

The cellular milieu of the brain and periphery carries many receptors for immune activation, and it is important to understand how such receptor systems and cells can trigger neuroinflammation. Typically, evolutionarily conserved immune responses are linked to receptors specialized in recognizing bacterial and viral components. TLRs recognize specific pathogen and damage-associated molecular patterns. The function of TLRs is to surveil extracellular and intracellular environments for signs of infection or damage and to signal the activation of innate immune and inflammatory responses to clear infection and remove apoptotic cells. The up-regulation of TLRs has been demonstrated in brains with α-synucleinopathies, such as PD, LBD, and multiple system atrophy (MSA). For these reasons, it is of critical importance to experimentally model conditions that mimic viral-like activation of receptors designated for immune activation. TLR3 specifically recognizes and is activated by dsRNA, which are intermediates of viral replication, and signals downstream anti-viral immune and inflammatory responses. Brain TLR3 activation has previously been modelled in vivo by direct administration of the synthetic viral-like dsRNA mimetic, Poly(I:C), into rodent brain. TLR3 activation by the administration of Poly(I:C) into substantia nigra and striatum led to a timeline of neuroinflammatory responses, characterized by activation of astrocytes and microglia within 4 days that continued to increase until peak activation at 12 days during cytokine storm, and persisted for 33 days. While TLR3 activation by itself was not sufficient to induce neurodegeneration, priming with such viral mimetics exacerbated the degeneration of nigral dopaminergic neurons to subsequent injection of 6-OHDA and to a small molecule inducer of α-synuclein fibril formation, showing that brain inflammation increases the vulnerability of neurons to additional stress. Neutralizing the Poly(I:C) induced brain inflammation by systemic administration of IL-1 receptor antagonist protected the nigral dopaminergic neurons from the damage caused by TLR3 activation combined with 6-OHDA, demonstrating that persistent inflammation of the brain increases neuronal vulnerability to additional damage, while reducing inflammation promotes neuronal cell resilience. The clear evidence for long-term brain inflammatory and degenerative sequelae to viral infections, which has led to subsequent neurological diagnoses such as post-encephalitic parkinsonism, supports the hypothesis and findings that preventing brain inflammatory responses caused by viral-like TLR3 activation could be protective.

Targeting the complement pathway to reduce inflammatory activations

In the sequence of events that typically follow viral or bacterial perturbations, there are well-known activation cascades including the innate acute response involving complement factors. The complement system, an integral part of the innate immune system, plays a vital role in clearance of pathogens by mounting an inflammatory response. Additionally, two components of this pathway, C1q and C3, have been identified to play beneficial role in microglial regulation of synaptic pruning during neural development and excessive pruning in adult brain have been implicated in neurodegeneration. Complement can be activated by three different pathways, a C1q-dependent classical pathway, and C1q-independent alternative and lectin pathways. All three activation axes converge on the enzymatic cleavage of complement factor C3 into C3a and C3b fragments. C3b in conjunction with other proteins lead to cleavage of C5 into C5a and C5b. C5b along with C6 through C9, constitute the terminal lytic pathway that leads to the formation of the membrane attack complex (MAC). The three main effector functions of the complement cascade include opsonization of C3b, C4 and C1q tagged target cell, immune cell recruitment to the site of injury by the anaphylatoxins C3a and C5a, and lysis of the target cell by the formation of MAC. TLRs and the complement cascade are both part of the innate immune system and respond to pathogenic infections, and interactions between them are plausible.

It is of great interest to explore the influence of complement system blockade in reducing brain inflammatory processes and factors, such as α-synuclein in PD and LBD. With the presence of multiple activation pathways and downstream effects, the complement system can be targeted at several levels depending on the desired outcome. While blocking action of the anaphylatoxins C3a by the C3aR antagonist SB290157, and C5a by the C5aR antagonists PMX53 and PMX205, will inhibit inflammation and opsonization of target cells, targeting C5b, and or C6 through C9 would block the terminal lytic pathway. Being at the convergence point of multiple complement activating pathways, C3 is a good target to manipulate all branches of the complement cascade, and this was the approach utilized in this study.

The current study utilized a rodent model of TLR3 activation in combination with a C3 splice-switching antisense oligonucleotide (ASO) specific to complement C3, to reduce C3 expression in the brain in vivo. The aim of this study was to experimentally model innate brain immune responses following TLR3 viral-like activation, and to examine how blocking complement C3 activation during TLR3 stimulation can reduce acute cellular and inflammatory responses downstream of TLR3. Mice received two brain injections of C3 ASO or control ASO at separate timepoints, followed by injection of dsRNA (PolyI:C) to activate brain TLR3 receptors (see schematic in Fig. 2A). Changes in brain levels of complement pathway proteins, cytokines and α-synuclein were examined in the acute phase of TLR3 activation at 2 days following injection of dsRNA.