SARS-CoV-2 と COVID-19 に関する備忘録 Vol.34

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Long-COVID study shows high rates of cognitive change【University of Minnesota CIDRAP　2024年12月24日】

Two new studies add to the growing body of literature on the lasting effects of long COVID. In the first, a study of 114 patients with long COVID in Israel, researchers found high rates of depressive disorders (46%), generalized anxiety disorders (21%), sleep disturbances (76%), and reported cognitive changes (95%) among those diagnosed with the condition.

In a second study, Centers for Disease Control and Prevention (CDC) researchers find that the prevalence of long COVID-19 in the US population in 2021 was 29.9%, and 77.2% of those with long COVID had not returned to pre-COVID health within 8 to 60 weeks after infection.

The first study, published in BMC Infectious Diseases, was an online survey given to long COVID patients composed of several established questionnaires, including the Generalized Anxiety Disorder (GAD-7) for psychological distress, the Subjective Cognitive Decline (SCD) questionnaire for cognitive decline, and the Pittsburgh Sleep Quality Index (PSQI) for sleep disorders.

The participants had an average age of 44 years, and 29 were men (25.4%) and 85 were women (74.6%).

The high rates of sleep disturbances and cognitive changes, including brain fog and memory loss, were the most significant findings. Social support negatively correlated with psychological distress, with those who reported more social isolation during their long COVID illness having worse mental health outcomes.

“Personality traits and social support were found to modulate symptom severity, with conscientiousness and social support appearing to confer protective effects, while neuroticism was associated with greater risk,” the authors said. “These findings highlight the potential for psychological interventions to alleviate distress in Long COVID patients.”

◆SARS-CoV-2 Spike S1 Subunit Triggers Pericyte and Microvascular Dysfunction in Human Pancreatic Islets【American Diabetes Association　2024年12月23日】

The COVID-19 pandemic has profoundly affected human health; however, the mechanisms underlying its impact on metabolic and vascular systems remain incompletely understood. Clinical evidence suggests that SARS-CoV-2 directly disrupts vascular homeostasis, with perfusion abnormalities observed in various tissues. The pancreatic islet, a key endocrine miniorgan reliant on its microvasculature for optimal function, may be particularly vulnerable. Studies have proposed a link between SARS-CoV-2 infection and islet dysfunction, but the mechanisms remain unclear. Here, we investigated how SARS-CoV-2 spike S1 protein affects human islet microvascular function. Using confocal microscopy and living pancreas slices from organ donors without diabetes, we show that a SARS-CoV-2 spike S1 recombinant protein activates pericytes, key regulators of islet capillary diameter and β-cell function, and induces capillary constriction. These effects are driven by a loss of ACE2 from pericytes’ plasma membrane, impairing ACE2 activity and increasing local angiotensin II levels. Our findings highlight islet pericyte dysfunction as a potential contributor to the diabetogenic effects of SARS-CoV-2 and offer new insights into the mechanisms linking COVID-19, vascular dysfunction, and diabetes.

◆SARS-CoV-2 Spike S1 Subunit Triggers Pericyte and Microvascular Dysfunction in Human Pancreatic Islets【THE LANCET Regional Health Western Pacific　2024年10月10日】

Summary

Background

Research on long COVID in China is limited, particularly in terms of large-sample epidemiological data and the effects of recent SARS-CoV-2 sub-variants. China provides an ideal study environment owing to its large infection base, high vaccine coverage, and stringent pre-pandemic measures.

Methods

This retrospective study used an online questionnaire to investigate SARS-CoV-2 infection status and long COVID symptoms among 74,075 Chinese residents over one year. The relationships between baseline characteristics, vaccination status, pathogenic infection, and long COVID were analyzed using multinomial logistic regression, and propensity matching.

Findings

Analysis of 68,200 valid responses revealed that the most frequent long COVID symptoms include fatigue (30.53%), memory decline (27.93%), decreased exercise ability (18.29%), and brain fog (16.87%). These symptoms were less prevalent among those infected only once: fatigue (24.85%), memory decline (18.11%), and decreased exercise ability (12.52%), etc. Women were more likely to experience long COVID, with symptoms varying by age group, except for sleep disorders and muscle/joint pain, which were more common in older individuals. Northern China exhibits a higher prevalence of long COVID, potentially linked to temperature gradients. Risk factors included underlying diseases, alcohol consumption, smoking, and the severity of acute infection (OR > 1, FDR < 0.05). Reinfection was associated with milder symptoms but led to a higher incidence and severity of long COVID (OR > 1, FDR < 0.05). Vaccination, particularly multiple boosters, significantly reduced long-term symptoms by 30%–70% (OR < 1, FDR < 0.05). COVID-19 participants also self-reported more bacterial, influenza and mycoplasma infections, and 8%–10% of patients felt SARS-CoV-2-induced chronic diseases. Interpretation

This survey provides valuable insights into long COVID situation among Chinese residents, with 10%–30% (including repeated infection) reporting symptoms. Monitoring at-risk individuals based on identified risk factors is essential for public health efforts.

◆Depletion and Dysfunction of Dendritic Cells: Understanding SARS-CoV-2 Infection【Frontiers in immunology　2022年2月21日】

Uncontrolled severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 infection is closely related to disorders of the innate immune and delayed adaptive immune systems. Dendritic cells (DCs) “bridge” innate immunity and adaptive immunity. DCs have important roles in defending against SARS-CoV-2 infection. In this review, we summarize the latest research concerning the role of DCs in SARS-CoV-2 infection. We focus on the complex interplay between DCs and SARS-CoV-2: pyroptosis-induced activation; activation of the renin–angiotensin–aldosterone system; and activation of dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin. We also discuss the decline in DC number, the impaired antigen-presentation capability, and the reduced production of type-I interferon of DCs in severe SARS-CoV-2 infection. In addition, we discuss the potential mechanisms for pathological activation of DCs to understand the pattern of SARS-CoV-2 infection. Lastly, we provide a brief overview of novel vaccination and immunotherapy strategies based on DC targeting to overcome SARS-CoV-2 infection.

◆Three years on, COVID-19 and the skin: long-term impacts, emerging trends and clinical practice【OXFORD ACADEMIC BJD　2023年5月3日】

In early 2020 there were reports of a new and potentially fatal viral infection affecting large numbers of people in Wuhan, China. Over the following 3 months it had spread throughout most of the world, with all countries introducing emergency measures. On 11 March 2020, the World Health Organization declared that infections caused by the coronavirus SARS-CoV-2 had reached the status of a pandemic. Worldwide, more than 764 million people have been affected by the virus and more than 6.9 million people have died as a result of infection, as of 26 April 2023 (https://covid19.who.int/). As of 24 April 2023, over 13.3 billion doses of COVID-19 vaccine have been administered, which, along with other public health measures, have slowed the pandemic. However, new variants continue to emerge and ‘long COVID’ continues to cause significant morbidity across the world.

Early observations by dermatologists were key in identifying novel signs and symptoms of COVID-19. In May 2020 the BJD published the first comprehensive analysis of cases seen by Spanish dermatologists that categorized the different changes seen in the skin as a result of COVID-19. It included a classification of dermatological manifestations seen in 375 patients: pseudo-chilblains; urticaria; maculopapular eruptions; other vesicular eruptions; and livedo and necrosis. Since then, the dermatological literature has provided descriptions of other skin manifestations and research papers on pathogenesis and immunology, treatment and the after-effects of infection or post-COVID syndrome (long COVID). Longer-term skin manifestations may include chronic urticaria, recurrent pernio, telogen effluvium, capillaritis and exacerbation of pre-existing skin conditions such as eczema and seborrhoeic dermatitis, as well cutaneous changes attributable to the different COVID-19 vaccines. Three years into the pandemic, there are more than 4200 publications in PubMed on ‘COVID-19 and skin’, as of March 2023. The impact of COVID-19 stretches well beyond the toll of clinical cases alone, with paradigm changing shifts in research, clinical care and public policy.

International collaboration has been key in understanding the disease, and has led to the creation of well-organized national and international study groups. For example, the American Academy of Dermatology and International League of Dermatologic Societies COVID-19 Dermatology Registry (https://www.aad.org/member/practice/coronavirus/registry) is an active and productive global collaboration, containing the details of >2500 cases of dermatological manifestations of COVID-19 and COVID-19 vaccine skin reactions across 72 countries. More than seven registries are now active, some of which are general, while others concentrate on COVID-19 in the context of specific diseases such as psoriasis. The benefit of these initiatives has led to similar collaborations to track and record the cutaneous effects of the more recent ‘mpox’ (monkeypox) epidemic, and could provide infrastructure for future outbreaks.

Dermatologists also played a key role in identifying cutaneous reactions to novel mRNA vaccines. These reactions have included local injection site reactions, novel delayed large local reactions (7–8 days after mRNA vaccination) and more generalized eruptions, including urticaria and vaccine-related eruption of papules and plaques, although establishing causality remains challenging. In addition to identifying reactions, dermatologists’ engagement with the lay press was critical for public perception regarding vaccine skin reactions and confidence in vaccination. Engagement with the media, including social media, has been particularly important in either combatting or promoting vaccine hesitancy.

The pathogenesis of COVID-19-associated cutaneous manifestations is still not well understood, whether through binding of SARS-CoV-2 spike protein to angiotensin-converting enzyme 2 (ACE2) on target cells such as keratinocytes or through the intervention of transmembrane serine protease 2 (TMPRSS2) on the target cell, facilitating SARS-CoV-2 entry. The severity of COVID-19 has been linked to different skin manifestations, suggesting that the host immune response to the virus is critical both for viral control and also in observable viral or reactive manifestations. In severe COVID-19, ACE2-mediated endothelial damage by SARS-CoV-2 and the high level of inflammatory cytokines such as interleukin-6 in livedo reticularis may facilitate the formation of thrombi, resulting in the appearance of thrombotic multiorgan vasculopathy, which, critically, also affects the lungs. Patients with COVID-19 develop vascular damage through a variety of different mechanisms such as dysregulated type I interferon (IFN) activity, including lymphocytic perivascular cuffing, immune complex deposition leading to leukocytoclastic vasculitis, urticarial vasculitis, IgA-mediated vasculitis and antineutrophil cytoplasm antibody-associated vasculitis; some of these forms can also occur post-vaccination.

In milder COVID-19, pernio (chilblains), also known as ‘COVID toes’, has been described, with ongoing debate regarding the mechanism behind it. A robust IFN-α response may lead to perniosis and relatively rapid control of the virus with a lower antibody response. The connection between COVID-19 and perniosis (COVID toes) has been questioned as there is a weak correlation between the incidence of COVID-19 and chilblains in patients examined in the USA, as well as high rates of negative SARS-CoV-2 polymerase chain reaction tests, leading to the suggestion that this may be an epiphenomenon. This is still very much at the centre of scientific discussion as there are other factors that are difficult to ignore; for instance, there is a clear relation between COVID-19 immunization and the development of perniosis. Our knowledge of this phenomenon and the role of IFN continues to evolve.

Apart from the direct effects of the virus on skin, there have been reports of an increase in the incidence and appearance of other skin diseases, including herpes zoster, both during the pandemic and after vaccination. These are not confined to infections, and autoimmune conditions such as alopecia areata have been highlighted as possible sequelae of COVID-19, as well as immunization. Establishing a causal relationship between dermatoses and COVID-19, and between dermatoses and vaccines, will require larger-scale, rigorous epidemiological data beyond what can be provided by disease registries.

COVID-19 variants continue to emerge, and symptoms of the disease are also evolving. The early wild-type virus had a predominance of cough and anosmia symptoms; later variants such as Omicron have resulted in other symptoms such as a sore throat. Similarly, in skin, presentations have varied over time. The ZOE Skin Symptom study of > 348 000 individuals in the UK identified shifts in clinical presentation over time – patients are noting fewer skin symptoms, and certain skin symptoms, such as acral rash, were more predictive of a positive SARS-CoV-2 test earlier in the pandemic, for example with the Delta wave, than they have been later in the pandemic with the Omicron wave.

The impact of COVID-19 on dermatological practice has been broader than factors related to the expression of the disease itself, as it has affected the way in which clinical and academic duties are delivered, including the use of protective clothing, transport to workplaces and hospital behaviours. COVID-19 has changed working practices for the foreseeable future. Many of these changes were designed to limit transmission through distancing and enhanced protective measures in outpatients and surgical or biopsy rooms. The benefits and disadvantages of telemedicine (TELEderm) were also exposed. However, it is likely that the positive aspects of TELEderm are likely to remain and be absorbed into daily practice. The need to limit the number of procedures, as well as consultations during the outbreak, led to delays in the provision of care, including increased waiting times before effective surgical interventions, increased procedure complexity and a higher risk of tumour spread. Other procedures involving close contact, from iontophoresis and patch testing to phototherapy, were also affected. To what extent this has increased the health risk to our patients remains suspected but largely unmeasured.

We should recognize our colleagues in dermatology who kept working throughout this very difficult period, at the height of the pandemic and, in particular, those who volunteered to work outside their normal comfort zone, in emergency care and intensive care units. Their experience, unique as it was, will have been both shocking and rewarding, and they will not forget it. Finally, we recognize with sadness the great toll that the pandemic has taken on our patients and the more than 6.9 million people who have died worldwide as a result.

◆Early symptoms preceding post-infectious irritable bowel syndrome following COVID-19: a retrospective observational study incorporating daily gastrointestinal symptoms【BMC Gastroenterology　2023年4月5日】

Abstract

Background

Intestinal microinflammation with immune dysfunction due to severe acute respiratory syndrome coronavirus 2 reportedly precipitates post-infectious irritable bowel syndrome. This study aimed to elucidate potential risk factors for subsequent development of irritable bowel syndrome, hypothesizing that it is associated with specific symptoms or patient backgrounds.

Methods

This single-center retrospective observational study (2020–2021) included adults with confirmed coronavirus disease requiring hospital admission and was conducted using real-world data retrieved from a hospital information system. Patient characteristics and detailed gastrointestinal symptoms were obtained and compared between patients with and without coronavirus disease-induced irritable bowel syndrome. Multivariate logistic models were used to validate the risk of developing irritable bowel syndrome. Moreover, daily gastrointestinal symptoms during hospitalization were examined in patients with irritable bowel syndrome.

Results

Among the 571 eligible patients, 12 (2.1%) were diagnosed with irritable bowel syndrome following coronavirus disease. While nausea and diarrhea during hospitalization, elevated white blood cell count on admission, and intensive care unit admission were associated with the development of irritable bowel syndrome, nausea and diarrhea were identified as risk factors for its development following coronavirus disease, as revealed by the adjusted analyses (odds ratio, 4.00 [1.01–15.84] and 5.64 [1.21–26.31], respectively). Half of the patients with irritable bowel syndrome had both diarrhea and constipation until discharge, and constipation was frequently followed by diarrhea.

Conclusions

While irritable bowel syndrome was rarely diagnosed following coronavirus disease, nausea and diarrhea during hospitalization precede the early signs of irritable bowel syndrome following coronavirus disease.

◆Persisting gastrointestinal symptoms and post-infectious irritable bowel syndrome following SARS-CoV-2 infection: results from the Arizona CoVHORT【Cambridge University Press　2022年7月8日】

Abstract

In this study, we aimed to examine the association between gastrointestinal (GI) symptom presence during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the prevalence of GI symptoms and the development of post-infectious irritable bowel syndrome (PI-IBS). We used data from a prospective cohort and logistic regression to examine the association between GI symptom status during confirmed SARS-CoV-2 infection and prevalence of persistent GI symptoms at ≥45 days. We also report the incidence of PI-IBS following SARS-CoV-2 infection. Of the 1475 participants in this study, 33.8% (n = 499) had GI symptoms during acute infection. Cases with acute GI symptoms had an odds of persisting GI symptoms 4 times higher than cases without acute GI symptoms (odds ratio (OR) 4.29, 95% confidence interval (CI) 2.45–7.53); symptoms lasted on average 8 months following infection. Of those with persisting GI symptoms, 67% sought care for their symptoms and incident PI-IBS occurred in 3.0% (n = 15) of participants. Those with acute GI symptoms after SARS-CoV-2 infection are likely to have similar persistent symptoms 45 days and greater. These data indicate that attention to a potential increase in related healthcare needs is warranted.

◆Cutaneous Manifestations in Patients With COVID-19: Clinical Characteristics and Possible Pathophysiologic Mechanisms【ACTAS Dermo-Sifiliográficas　2021年1月28日】

Abstract

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections soon led to a pandemic with serious health, economic, political, and cultural repercussions across the globe. The disease caused by SARS-CoV-2, coronavirus disease 2019 (COVID-19), is a multisystemic disease that requires a multidisciplinary approach involving specialists from all fields and levels of care. In this article, we review the literature on the diverse cutaneous manifestations associated with COVID-19. We also describe the pathophysiologic mechanisms proposed to date and their possible association with these manifestations. Finally, we propose a system for classifying the cutaneous manifestations of COVID-19 according to their underlying pathophysiologic mechanisms and prognosis.

◆How COVID-19 Messes Up Your Gut Health【TIME　2024年10月1日】

When you reach for a COVID-19 test, it’s probably because you’ve got a scratchy throat, runny nose, or cough. But those are far from the only symptoms that make Dr. Rohit Jain, an internal medicine doctor at PennState Health, suspect the virus.

These days, when someone complains of nausea, diarrhea, or vomiting, “I always get a COVID test on that patient,” Jain says.

Why? Despite its reputation as a respiratory virus, SARS-CoV-2 can also have a profound impact on the gut. Although most people don’t realize it, “COVID-19 really is a GI-tract disease” as well as a respiratory illness, says Dr. Mark Rupp, chief of infectious diseases at the University of Nebraska Medical Center.

Here’s what to know about the gastrointestinal symptoms of COVID-19.

What are the GI symptoms of COVID-19?

While some people experience no gastrointestinal symptoms or mild ones, a subset of COVID-19 patients have experienced significant digestive symptoms since the early days of the pandemic.

Loss of appetite, nausea, vomiting, diarrhea, and stomach pain are common GI symptoms of COVID-19, according to Jain’s research. Some people experience these issues as their first signs of infection, he says, while others initially experience cold-like symptoms and develop gastrointestinal issues as their illness progresses.

It’s not entirely clear why the same virus can affect people so differently, but it’s good to be aware that SARS-CoV-2 can result in a wide range of symptoms, Rupp says.

How long do GI symptoms of COVID-19 last?

Some patients recover in a matter of days, Jain says, while others may suffer from diarrhea and other symptoms for weeks.

Still others may be sick for even longer. Gastrointestinal problems are a common manifestation of Long COVID, the name for chronic symptoms that follow a case of COVID-19 and can last indefinitely.

One recent study in Clinical Gastroenterology and Hepatology found that, among a small group of adults who were hospitalized when they had acute COVID-19, more than 40% who originally experienced GI problems such as stomach pain, nausea, vomiting, or diarrhea still had at least one a year or more later. Overall, whether they were hospitalized or not, adults who have had COVID-19 are about 36% more likely than uninfected people to develop gastrointestinal disorders including ulcers, pancreatitis, IBS, and acid reflux, according to a 2023 study published in Nature Communications.

GI problems are also common among kids with Long COVID. Stomach pain, nausea, and vomiting are telltale signs of the condition among children younger than 12, according to 2024 research published in JAMA.

Why a respiratory virus affects the gut

How can the same virus cause both a runny nose and the runs?

Once SARS-CoV-2 gets into your body, it infects cells by binding to a protein called ACE2, which is found throughout the body. ACE2 is prevalent in the lungs, which helps explain COVID-19’s respiratory symptoms—but it’s also found in high concentrations in the gastrointestinal tract, “so it makes sense that the GI tract would be a target for the virus,” Rupp says. It’s in part because SARS-CoV-2 collects in the gut that wastewater surveillance is a useful tool for tracking the virus’ spread, Rupp adds.

Studies have shown that the virus can hide out in the “nooks and crannies” of the digestive system for months or even years, says Ziyad Al-Aly, a clinical epidemiologist at the Washington University School of Medicine in St. Louis who co-authored the Nature Communications study on chronic post-COVID GI symptoms. This may explain why gut-related symptoms can long outlast an acute infection, Al-Aly says—but there are many potential hypotheses in play, and researchers don’t know for sure which one or ones are correct.

For example, many researchers also think the virus is capable of causing widespread and sometimes long-lasting inflammation, potentially affecting organs throughout the body. This inflammatory response may have trickle-down effects on the gut microbiome, the colony of bacteria and other microbes that live in the GI tract, Rupp says. “We’re just scratching the surface as to what happens there,” Rupp says, but studies have already shown that SARS-CoV-2 can change the composition of the gut microbiome both during an acute infection and chronically.

There’s also a complex relationship between the gut and the brain, adds Dr. Badih Joseph Elmunzer, a gastroenterologist at the Medical University of South Carolina and co-author of the Clinical Gastroenterology and Hepatology study on prolonged post-COVID GI symptoms. His research suggests people are particularly likely to suffer long-term GI problems if they also have signs of PTSD from their acute illness or hospitalization.

That’s not to say GI symptoms are all in patients’ heads; on the contrary, Elmunzer says, they are very real. But, he says, there’s a lot left to learn about the microbiome, the gut, and the myriad ways they interact with other bodily systems.

◆What Repeat COVID Infections Do to Your Body, According to Science【SELF　2024年9月23日】

These days, it’s tempting to compare COVID-19 with the common cold or flu. It can similarly leave you with a nasty cough, fever, sore throat—the full works of respiratory symptoms. And it’s also become a part of the societal fabric, perhaps something you’ve resigned yourself to catching at least a few times in your life (even if you haven’t already). But let’s not forget: SARS-CoV-2 (the virus responsible for COVID) is still relatively new, and researchers are actively investigating the toll of reinfection on the body. While there are still a lot of unknowns, one thing seems to be increasingly true: Getting COVID again and again is a good deal riskier than repeat hits of its seasonal counterparts.

It turns out, SARS-CoV-2 is more nefarious than these other contagious bugs, and our immune response to it, often larger and longer-lasting. COVID has a better ability to camouflage itself in the body, “and it has the keys to the kingdom in the sense that it can unlock any cell and get in,” says Esther Melamed, PhD, an assistant professor in the department of neurology at Dell Medical School, University of Texas Austin, and the research director of the Post-COVID-19 program at UT Health Austin. That’s because SARS-CoV-2 binds to ACE2 receptors, which exist in cells all over your body, from your heart to your gut to your brain. (By contrast, cold and flu viruses replicate mostly in your respiratory tract.)

It only follows that a bigger threat can trigger an outsize immune response. In some people, the body’s reaction to COVID can turn into a “cytokine storm,” Dr. Melamed tells SELF, which is characterized by an excessive release of inflammatory proteins that can wreak havoc on multiple organ systems—not a common scenario for your garden-variety cold or flu. But even a “mild” case of COVID can throw your immune system into a tizzy as it works to quickly shore up your defenses. And each reinfection is a fresh opportunity for the virus to win the battle.

While you develop some immunity after a COVID infection, it doesn’t just grow with each additional hit.

You might be thinking, “Aren’t I more protected against COVID and less likely to have a serious case after having been infected?” Part of that is true, to an extent. In the first couple years after COVID burst onto the scene, reinfections were generally (though not always) milder than a person’s initial bout of the virus. “The way we understand classic immunology is that your body will say to a virus [it’s seen before], ‘Oh, I know how to deal with you, and I’m now going to deal with you in a better way the second time around,’” says Ziyad Al-Aly, MD, a senior clinical epidemiologist at Washington University in St. Louis School of Medicine and the chief of research and development at the Veterans Affairs St. Louis Health Care System.

But any encounter with COVID can also cause your immune system to “go awry or develop some form of dysfunction,” Dr. Al-Aly tells SELF. Specifically, “immune imprinting” can happen, where, upon a second (or third or fourth) exposure to the virus, your immune cells launch the same response as they did for the initial infection, in turn blocking or limiting the development of new antibodies necessary to fight off the current variant that’s stirring up trouble. So, “when you get hit an [additional] time, your immune system may not behave classically,” Dr. Al-Aly says, and could struggle with mounting a good defense.

Pair that dip in immune efficiency with the fact that your antibody levels also wane with time post-infection, and it’s easy to see how another hit can rock your body in a new way. Indeed, the more time that passes after any given COVID infection, the less of a “competitive advantage” you’ll have against any future one, Richard Moffitt, PhD, an associate professor at Emory University, in Atlanta, tells SELF. His research found that, while people who got sick initially during the delta phase were less likely to get reinfected during the first omicron wave (as compared to folks who were infected in a prior period), that benefit leveled off with following omicron variants.

There’s also the fact that no matter how your immune system has responded to a prior strain (or strains!) of the virus, it could react differently to a new mutation. “We tend to think of COVID as one homogeneous thing, but it’s really not,” Dr. Al-Aly says. So even if your body successfully thwarted one of these intruders in the past, there’s no guarantee it’ll do the same for another, now or in the future, he says.

Getting COVID again and again is especially risky if it previously made you very ill.

Dr. Moffitt’s study above also found that the “severity of your first infection is very predictive of the severity of a reinfection,” he says. Meaning, you’re more likely to have a severe case of COVID—for instance, requiring hospitalization or intensive care, such as ventilation—when reinfected if you had a rough go of it the first time around.

It’s possible that some folks are more prone to an off-kilter immune response to the virus, which could then happen consistently with reinfections. The antibodies created in people who’ve had severe cases “may not function as well as those in folks who’ve had mild infections or were able to fight the virus off,” Dr. Melamed says. Though researchers don’t fully understand why, some people’s immune systems are also more likely to overreact to COVID (remember the cytokine storm?), which can cause serious symptoms—like fluid in the lungs and shortness of breath—whenever they’re infected.

Being over the age of 65, having a chronic illness or other medical condition, and lacking access to health care have all been shown to spike your risk of serious outcomes with a COVID infection, whether it’s your first or fifth fight with the virus.

But you’re not home free if you’ve only had, say, a brief fever or cough with COVID in the past; Dr. Moffitt points out that a small subset of people in his research who had minor reactions with their initial infection went on to be hospitalized with a repeat hit. The probability of that might be lower, but it’s still a possibility, he says.

Even if you’ve only had “mild” cases, each reinfection strains your body, upping your chances of developing long COVID.

A 2022 study led by Dr. Al-Aly found that COVID reinfections also increase your risk of complications across the board, regardless of whether you recovered just fine in the past or got vaccinated. In particular, it showed that reinfection raises the likelihood that you’ll need hospitalization; have heart or lung problems; or experience, among other possible issues, GI, neurological, mental health, or musculoskeletal symptoms. “We use the term ‘cumulative effects,’” Dr. Al-Aly says, “so, multiple hits accrue and then leave the body more vulnerable to all the potential long-term health effects of COVID.”

That doesn’t mean your experience of a second (or third or fourth) infection will necessarily be worse, in and of itself, than what you felt during a prior case. But with each new hit, a fresh batch of the virus seeps into your system, where, even if you have a mild case, it has another chance to trigger any of the longer-term complications above. While the likelihood of getting long COVID (a constellation of symptoms lingering for three months or longer post-infection) is likely greatest after initial infection, “The bottom line is, people are still getting diagnosed with long COVID after reinfection,” Dr. Moffitt says.

Researchers don’t totally know why one person might deal with lasting health effects over another, but it seems that, in some folks, the immune system misfires, generating not only antibodies to attack the virus but also autoantibodies that go after the body’s own healthy cells, Dr. Al-Aly says. This may be one reason why COVID has been linked to the onset of autoimmune conditions like psoriasis and rheumatoid arthritis.

A different hypothesis suggests that pieces of the virus could linger in the body, even after a person has seemingly “recovered” (reminder that SARS-CoV-2 is scarily good at weaseling its way into all sorts of cells). “Maybe the first time, your immune system was able to fully clear it, but the second time, it found a way to hang around,” Dr. Al-Aly posits. And a third theory involves your gut microbiome, the community of microbes in your GI tract, including beneficial bacteria. It’s conceivable that “when we get sick with COVID, these bacteria do, too, and perhaps they recover [on initial infection], but not on the second or third hit,” he says, throwing off your balance of good-to-bad gut bugs (which can impact your health in all sorts of ways).

Another unnerving possibility: The shock to your system triggered by COVID may “wake up” a latent (a.k.a. dormant) virus or two lurking in your body, Dr. Melamed says. We all carry anywhere from eight to 12 of these undetected bugs at a time—things like Epstein-Barr, varicella-zoster (which causes chickenpox and shingles), and herpes simplex. And research suggests their reactivation could be a contributing factor in long COVID. Separately, the systemic inflammation often created by COVID may spark the onset of high blood pressure and increased clotting (which can up your risk of stroke and pulmonary embolism), as well as type 2 diabetes, Dr. Melamed says.

There’s no guarantee that any given COVID infection snowballs into something debilitating, but each hit is like another round of Russian roulette, Dr. Al-Aly says. From a sheer numbers standpoint, the more times you play a game with the possibility of a negative outcome, the greater your chances are of that bad result occurring. And because every COVID case has at least some potential to leave you very ill or dealing with a host of persistent symptoms, why take the risk any more times than you need to?

Bottom line: You should do your best to avoid COVID reinfection and bolster your defenses against the virus.

At this stage of the pandemic’s progression, it’s not realistic to suggest you can avoid any exposure to the virus, given that societal protections against its spread have been rolled back. But what you should do is take some common-sense precautions, which can help you avoid any contagious respiratory virus. (A cold or the flu may not pose as many potential health risks as COVID, but being sick is still not fun!)

It’s a good idea to wear a mask when you’re in a crowded environment (especially indoors), choose well-ventilated or outdoor spaces for group hangouts, and test for COVID if you have cold or flu-like symptoms, Dr. Al-Aly says. If you do get infected, talk to your doctor about whether your personal risk of a severe case is enough to qualify for a Paxlovid prescription (which you need to take within the first five days of symptoms for it to be effective).

The other important thing you should do is get the updated COVID vaccine (the 2024-2025 formula was recently approved and released). Unlike getting reinfected, the vaccine triggers “a very targeted immune response…because it’s [made with] a specific tiny part of the virus,” Dr. Melamed says. Meaning, you get the immune benefit of a little exposure without the potential of your whole system going haywire. Getting the current shot also ensures you restore any protection that has waned since you received a prior jab and that you have an effective shield against the dominant circulating strains. Plus, research shows that being vaccinated doesn’t just lower your chances of catching the virus; it also reduces your risk of having a severe case or winding up with long COVID if you do get it.

So, too, can the deceivingly simple act of keeping up with healthy habits—like exercising regularly, eating nutritious foods, and clocking quality sleep. Maintaining this kind of lifestyle can help you stave off other health issues that could increase your risk of harm from COVID, Harlan Krumholz, PhD, a cardiologist at Yale University and founder of the Yale Center for Outcomes Research and Evaluation (CORE), tells SELF. “Given that we will be repetitively exposed to the virus, the best investments we can make are in our baseline health,” he says.

Doing any (or all!) of the above is a big act of compassion for yourself, the people you love, and your greater community. “For the average person, it’s like, ‘Oh, COVID is gone,’ but they’re just not seeing the impact,” Dr. Al-Aly says, noting the invisibility of long COVID symptoms like disorienting brain fog and crushing fatigue. The truth is, in plenty of people, just one more infection could be the difference between living their best life and facing a devastating chronic condition.

◆Crystal structure of SARS-CoV-2 Orf9b in complex with human TOM70 suggests unusual virus-host interactions【nature communications　2021年5月14日】

Abstract

Although the accessory proteins are considered non-essential for coronavirus replication, accumulating evidences demonstrate they are critical to virus-host interaction and pathogenesis. Orf9b is a unique accessory protein of SARS-CoV-2 and SARS-CoV. It is implicated in immune evasion by targeting mitochondria, where it associates with the versatile adapter TOM70. Here, we determined the crystal structure of SARS-CoV-2 orf9b in complex with the cytosolic segment of human TOM70 to 2.2 Å. A central portion of orf9b occupies the deep pocket in the TOM70 C-terminal domain (CTD) and adopts a helical conformation strikingly different from the β-sheet-rich structure of the orf9b homodimer. Interactions between orf9b and TOM70 CTD are primarily hydrophobic and distinct from the electrostatic interaction between the heat shock protein 90 (Hsp90) EEVD motif and the TOM70 N-terminal domain (NTD). Using isothermal titration calorimetry (ITC), we demonstrated that the orf9b dimer does not bind TOM70, but a synthetic peptide harboring a segment of orf9b (denoted C-peptide) binds TOM70 with nanomolar KD. While the interaction between C-peptide and TOM70 CTD is an endothermic process, the interaction between Hsp90 EEVD and TOM70 NTD is exothermic, which underscores the distinct binding mechanisms at NTD and CTD pockets. Strikingly, the binding affinity of Hsp90 EEVD motif to TOM70 NTD is reduced by ~29-fold when orf9b occupies the pocket of TOM70 CTD, supporting the hypothesis that orf9b allosterically inhibits the Hsp90/TOM70 interaction. Our findings shed light on the mechanism underlying SARS-CoV-2 orf9b mediated suppression of interferon responses.

◆SARS-CoV-2 NSP13 suppresses the Hippo pathway downstream effector YAP【bioRxiv　2023年11月30日】

Abstract

The Hippo pathway plays critical roles in tissue development, regeneration, and immune homeostasis. The widespread pandemic of Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has resulted in a global healthcare crisis and strained health resources. How SARS-CoV-2 affects Hippo signaling in host cells has remained poorly understood. Here, we report that SARS-CoV-2 infection in patient lung cells and cardiomyocytes derived from human induced pluripotent stem cells (iPS-CMs) suppressed YAP target gene expression, as evidenced by RNA sequencing data. Furthermore, in a screening of nonstructural proteins from SARS-CoV-2, nonstructural protein 13 (NSP13) significantly inhibited YAP transcriptional activity independent of the YAP upstream suppressor kinase Lats1/2. Consistent with this, NSP13 suppressed active YAP (YAP5SA) in vivo, whereby NSP13 expression reverted the phenotype of YAP5SA transgenic mice. From a mechanistic standpoint, NSP13 helicase activity was shown to be required for its suppression of YAP. Furthermore, through the interaction of NSP13 with TEAD4, which is the most common YAP-interacting transcription factor in the nucleus, NSP13 recruited endogenous YAP suppressors such as CCT3 and TTF2 to inactivate the YAP/TEAD4 complex. These findings reveal the function and mechanism of the SARS-CoV-2 helicase NSP13 in host cells and partially explain the toxic effect of SARS-CoV-2 in particular host tissue with high YAP activity.

◆The Orf9b protein of SARS-CoV-2 modulates mitochondrial protein biogenesis【Journal of Cell Biology　2023年9月8日】

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) expresses high amounts of the protein Orf9b to target the mitochondrial outer membrane protein Tom70. Tom70 serves as an import receptor for mitochondrial precursors and, independently of this function, is critical for the cellular antiviral response. Previous studies suggested that Orf9b interferes with Tom70-mediated antiviral signaling, but its implication for mitochondrial biogenesis is unknown. In this study, we expressed Orf9b in human HEK293 cells and observed an Orf9b-mediated depletion of mitochondrial proteins, particularly in respiring cells. To exclude that the observed depletion was caused by the antiviral response, we generated a yeast system in which the function of human Tom70 could be recapitulated. Upon expression of Orf9b in these cells, we again observed a specific decline of a subset of mitochondrial proteins and a general reduction of mitochondrial volume. Thus, the SARS-CoV-2 virus is able to modulate the mitochondrial proteome by a direct effect of Orf9b on mitochondrial Tom70-dependent protein import.

◆Orchestration of SARS-CoV-2 Nsp4 and host-cell ESCRT proteins induces morphological changes of the endoplasmic reticulum【Journal of Cell Biology　2024年12月10日】

Abstract

Upon entry into the host cell, the non-structural proteins 3, 4, and 6 (Nsp3, Nsp 4, and Nsp6) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) facilitate the formation of double- membrane vesicles (DMVs) through extensive rearrangement of the host cell endoplasmic reticulum (ER) to replicate the viral genome and translate viral proteins. To dissect the functional roles of each Nsp and the molecular mechanisms underlying the ER changes, we exploited both yeast S. cerevisiae and human cell experimental systems. Our results demonstrate that Nsp4 alone is sufficient to induce ER structural changes. Nsp4 expression led to robust activation of both the unfolded protein response (UPR) and the ER surveillance (ERSU) cell cycle checkpoint, resulting in cortical ER inheritance block and septin ring mislocalization. Interestingly, these ER morphological changes occurred independently of the canonical UPR and ERSU components but were mediated by the endosomal sorting complex for transport (ESCRT) proteins Vps4 and Vps24 in yeast. Similarly, ER structural changes occurred in human cells upon Nsp4 expression, providing a basis for a minimal experimental system for testing the involvement of human ESCRT proteins and ultimately advancing our understanding of DMV formation.

◆Metabolic and mitochondria alterations induced by SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10【Europe PMC　2023年9月26日】

Abstract

Antiviral signaling, immune response and cell metabolism in human body are dysregulated by SARS-CoV-2, the causative agent of the COVID-19. Here, we show that SARS-CoV-2 accessory proteins ORF3a, ORF9b, ORF9c and ORF10 induce a significant mitochondrial and metabolic reprogramming in A549 lung epithelial cells. While all four ORFs caused mitochondrial fragmentation and altered mitochondrial function, only ORF3a and ORF9c induced a marked structural alteration in mitochondrial cristae. ORF9b, ORF9c and ORF10 induced largely overlapping transcriptomes. In contrast, ORF3a induced a distinct transcriptome, including the downregulation of numerous genes for proteins with critical mitochondrial functions and morphology. Genome-Scale Metabolic Models predicted common and private metabolic flux reprogramming, notably a depressed amino acid metabolism, and an enhanced metabolism of specific lipids distinctly induced by ORF3a. These findings reveal metabolic dependencies and vulnerabilities prompted by SARS-CoV-2 accessory proteins that may be exploited to identify new targets for intervention.

◆SARS-CoV-2 NSP6 reduces autophagosome size and affects viral replication via sigma-1 receptor【Europe PMC　2024年10月24日】

Abstract

Autophagy is a cellular self-defense mechanism by which cells can kill invading pathogenic microorganisms and increase the presentation of components of pathogens as antigens. Contrarily, pathogens can utilize autophagy to enhance their own replication. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) NSP6 can interact with ATPase proton pump component to inhibit lysosomal acidification, which was implicated in the autophagy process. However, research on how SARS-CoV-2 NSP6 affected autophagy, and its impact on virus replication is still lacking. Coronavirus NSP6 has been reported to promote coronavirus replication by limiting autophagosome expansion. However, this finding has not been confirmed in coronavirus disease 2019 (COVID-19). We investigated the effect of NSP6 protein on autophagosomes in different mutant strains of SARS-CoV-2 and revealed that the size of autophagosomes was reduced by NSP6 of the wild-type and Delta variant of SARS-CoV-2. In addition, we found that SARS-CoV-2 NSP6 localized to the lysosome and had an inhibitory effect on the binding of autophagosomes to the lysosome, which blocked the autophagy flux; this may be related to endoplasmic reticulum (ER)-related pathways. We also found that sigma-1 receptor (SIGMAR1) knock out (KO) reversed NSP6-induced autophagosome abnormality and resisted SARS-CoV-2 infection, which responds to the fact that SIGMAR1 is likely to be used as a potential target for the treatment of SARS-CoV-2 infection. In summary, we have provided a preliminary explanation of the effects on autophagy of the SARS-CoV-2 NSP6 protein from the pre-autophagic and late stages, and also found that SIGMAR1 is likely to be used as a potential target for SARS-CoV-2 therapy to develop relevant drugs.

◆SARS-CoV-2 NSP6 reduces autophagosome size and affects viral replication via sigma-1 receptor【Taylor & Francis Online　2023年7月23日】

Abstract

SARS-CoV-2 poses a substantial global threat owing to the emergence of several highly transmissible variants. Autophagy is an intracellular degradation process that maintains cellular homeostasis and combats the invading pathogens. SARS-CoV-2 can trigger autophagy and antagonize interferon production. However, the underlying mechanisms remain elusive, particularly for different variants. Here, we found that SARS-CoV-2 nonstructural protein (NSP) 6 inhibited interferon production by promoting macroautophagy/autophagy-mediated STING1 degradation. Mechanistically, NSP6 induced endoplasmic reticulum stress and bound to HSPA5/GRP78, leading to the activation of EIF2AK3/PERK-EIF2A/EIf2α pathway-mediated autophagy, which was associated with lysosomal degradation of STING1 and downregulation of interferon production. Moreover, the 81–120 amino acid (aa) region of NSP6 is critical for autophagy induction and STING1 degradation. Interestingly, NSP6 harboring a three aa deletion in the 81–120 aa region of some SARS-CoV-2 variants led to reduced autophagy, STING1 degradation, and increased host antiviral immunity. Collectively, this study demonstrated a major function of NSP6 in the SARS-CoV-2 evasion of host antiviral immunity by triggering endoplasmic reticulum stress-induced autophagy to degrade STING1 and that enhancement of host antiviral immunity induced by NSP6 variants with a three-aa deletion might be responsible for the attenuation of SARS-CoV-2 variants.

Abbreviations

aa: amino acid; ATF6: activating transcription factor 6; ATG5: autophagy related 5; CCPG1: cell cycle progression 1; CFTR: CF transmembrane conductance regulator; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; CHX: cycloheximide; Co-IP: co-immunoprecipitation; CQ: chloroquine; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GFP: green fluorescent protein; HSPA5/GRP78: heat shock protein family A (Hsp70) member 5; HSV-1: herpes simplex virus type 1; IFIT1: interferon induced protein with tetratricopeptide repeats 1; IFNB1/IFN-β: interferon beta 1; IRF3: interferon regulatory factor 3; ISG15: ISG15 ubiquitin like modifier; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; NFKB/NF-κB: nuclear factor kappa B; NSP6: non-structural protein 6; Δ106–108: deletion of amino acids 106–108 in NSP6 of SARS-CoV-2; Δ105–107: deletion of amino acids 105–107 in NSP6 of SARS-CoV-2; RETREG1/FAM134B: reticulophagy regulator 1; RIGI/DDX58: RNA sensor RIG-I; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1.

◆SARS-CoV-2 spike protein induces abnormal inflammatory blood clots neutralized by fibrin immunotherapy.【Europe PMC　2021年10月13日】

Abstract

Blood clots are a central feature of coronavirus disease-2019 (COVID-19) and can culminate in pulmonary embolism, stroke, and sudden death. However, it is not known how abnormal blood clots form in COVID-19 or why they occur even in asymptomatic and convalescent patients. Here we report that the Spike protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the blood coagulation factor fibrinogen and induces structurally abnormal blood clots with heightened proinflammatory activity. SARS-CoV-2 Spike virions enhanced fibrin-mediated microglia activation and induced fibrinogen-dependent lung pathology. COVID-19 patients had fibrin autoantibodies that persisted long after acute infection. Monoclonal antibody 5B8, targeting the cryptic inflammatory fibrin epitope, inhibited thromboinflammation. Our results reveal a procoagulant role for the SARS-CoV-2 Spike and propose fibrin-targeting interventions as a treatment for thromboinflammation in COVID-19.

◆SARS-CoV-2 spike protein induces abnormal inflammatory blood clots neutralized by fibrin immunotherapy【bioRxiv　2021年10月13日】

Abstract

Blood clots are a central feature of coronavirus disease-2019 (COVID-19) and can culminate in pulmonary embolism, stroke, and sudden death. However, it is not known how abnormal blood clots form in COVID-19 or why they occur even in asymptomatic and convalescent patients. Here we report that the Spike protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the blood coagulation factor fibrinogen and induces structurally abnormal blood clots with heightened proinflammatory activity. SARS-CoV-2 Spike virions enhanced fibrin-mediated microglia activation and induced fibrinogen-dependent lung pathology. COVID-19 patients had fibrin autoantibodies that persisted long after acute infection. Monoclonal antibody 5B8, targeting the cryptic inflammatory fibrin epitope, inhibited thromboinflammation. Our results reveal a procoagulant role for the SARS-CoV-2 Spike and propose fibrin-targeting interventions as a treatment for thromboinflammation in COVID-19.

◆SARS-CoV-2: from its discovery to genome structure, transcription, and replication【BMC Cell & Bioscience　2021年7月19日】

Abstract

SARS-CoV-2 is an extremely contagious respiratory virus causing adult atypical pneumonia COVID-19 with severe acute respiratory syndrome (SARS). SARS-CoV-2 has a single-stranded, positive-sense RNA (+RNA) genome of ~ 29.9 kb and exhibits significant genetic shift from different isolates. After entering the susceptible cells expressing both ACE2 and TMPRSS2, the SARS-CoV-2 genome directly functions as an mRNA to translate two polyproteins from the ORF1a and ORF1b region, which are cleaved by two viral proteases into sixteen non-structural proteins (nsp1-16) to initiate viral genome replication and transcription. The SARS-CoV-2 genome also encodes four structural (S, E, M and N) and up to six accessory (3a, 6, 7a, 7b, 8, and 9b) proteins, but their translation requires newly synthesized individual subgenomic RNAs (sgRNA) in the infected cells. Synthesis of the full-length viral genomic RNA (gRNA) and sgRNAs are conducted inside double-membrane vesicles (DMVs) by the viral replication and transcription complex (RTC), which comprises nsp7, nsp8, nsp9, nsp12, nsp13 and a short RNA primer. To produce sgRNAs, RTC starts RNA synthesis from the highly structured gRNA 3′ end and switches template at various transcription regulatory sequence (TRSB) sites along the gRNA body probably mediated by a long-distance RNA–RNA interaction. The TRS motif in the gRNA 5′ leader (TRSL) is responsible for the RNA–RNA interaction with the TRSB upstream of each ORF and skipping of the viral genome in between them to produce individual sgRNAs. Abundance of individual sgRNAs and viral gRNA synthesized in the infected cells depend on the location and read-through efficiency of each TRSB. Although more studies are needed, the unprecedented COVID-19 pandemic has taught the world a painful lesson that is to invest and proactively prepare future emergence of other types of coronaviruses and any other possible biological horrors.

◆COVID-19 may Enduringly Impact Cognitive Performance and Brain Haemodynamics in Undergraduate Students【ScienceDirect　2024年12月24日】

Abstract

To date, 770 million people worldwide have contracted COVID-19, with many reporting long-term “brain fog”. Concerningly, young adults are both overrepresented in COVID-19 infection rates and may be especially vulnerable to prolonged cognitive impairments following infection. This calls for focused research on this population to better understand the mechanisms underlying cognitive impairment post-COVID-19. Addressing gaps in the literature, the current study investigated differences in neuropsychological performance and cerebral haemodynamic activity following COVID-19 infection in undergraduate students. 94 undergraduates (age in years: M = 20.58, SD = 3.33, range = 18 to 46; 89 % female) at the University of Otago reported their COVID-19 infection history before completing a neuropsychological battery while wearing a multichannel near-infrared spectroscopy (NIRS) device to record prefrontal haemodynamics. We observed that 40 % retrospectively self-reported cognitive impairment (brain fog) due to COVID-19 and 37 % exhibited objective evidence of cognitive impairment (assessed via computerised testing), with some suggestion that executive functioning may have been particularly affected; however, group-level analyses indicated preserved cognitive performance post COVID-19, which may in part reflect varying compensatory abilities. The NIRS data revealed novel evidence that previously infected students exhibited distinct prefrontal haemodynamic patterns during cognitive engagement, reminiscent of those observed in adults four decades older, and this appeared to be especially true if they reported experiencing brain fog due to COVID-19. These results provide new insights into the potential neuropathogenic mechanisms influencing cognitive impairment following COVID-19.