SARS-CoV-2 と COVID-19 に関する備忘録 Vol.33

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Impact of SARS-CoV-2 Infection on Physical Fitness in Air Force Basic Trainees【OXFORD ACADEMIC　2024年12月5日】

Abstract

Introduction

The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on physical fitness in previously healthy adults is not well understood. In this study, we assess the impact of SARS-CoV-2 infection on the physical fitness test (PT) scores of Air Force basic trainees.

Materials and Methods

SARS-CoV-2 testing data and trainee fitness test scores for the calendar year 2021 were obtained from U.S. Air Force basic military trainees. Trainees perform a standardized fitness test including push-ups, sit-ups, and a 2.4 kilometer run at the beginning and end of their training. For this study, basic trainees who performed 2 fitness tests in 2021 and also tested positive for SARS-CoV-2 were defined as the infected cohort. These were 1:1 matched by sex to an uninfected control group of basic trainees. Changes in fitness test scores and pass–fail rates were then compared across the infected and control groups.

Results

A total of 23,450 basic trainees performed a PT in calendar year 2021, 975 (4%) of whom tested positive for SARS-CoV-2. A total of 621 (64%) had completed 2 fitness tests during the defined study period and were included in the infected cohort. There were 96 females (15.5%) in each group and 525 males (84.5%) in each group. There was no difference in body mass index between the infected and the control groups (24.0 [Interquartile range (IQR) 21.8 to 36.0] vs. 24.3 [IQR 21.7–36.9], P = .253). The infected group had a higher rate of failing their PT at the end of training when compared to control (15.7% vs. 4.3%, P < .001). When comparing those who passed their first fitness test and went on to fail their second fitness test, this occurred more frequently in the infected group (2.3% vs. 0.81%, P = .037). When comparing trainees who failed their first fitness test and went on to pass their second fitness test, this occurred more frequently in the control group (46.3% vs. 39.6%, P = .016). Among the infected group, there were no differences in second test failure rates when comparing symptomatic to asymptomatic trainees (16.9% vs. 11.8%, P = .143). Conclusions

SARS-CoV-2 infection was associated with an increased risk of PT failure as well as conversion from a passing to failing test score. There were no differences in second test failure rates in symptomatic compared to asymptomatic trainees. A key confounder to the data was the effect deconditioning had on fitness during isolation.

◆Long COVID is associated with lower percentages of mature, cytotoxic NK cell phenotypes【The Journal of Clinical Investigation　2024年12月17日】

Following SARS-CoV-2 infection, approximately 5% of individuals develop long COVID (LC), defined as ongoing symptoms present at least 3 months after infection that are disruptive to everyday functioning. There is growing evidence that SARS-CoV-2 persistence is associated with LC and that people with LC have dysregulated adaptive immune function that may originate from or potentiate viral persistence. NK cells, a critical component of the viral innate immune response, can exhibit dysfunctional phenotypes during acute COVID-19, and these alterations may hinder clearance of SARS-CoV-2–infected cells. COVID-19 can also induce adaptive NK cell responses during acute infection, but there is a critical lack of knowledge about NK cell phenotypes in the postacute phase and their relationship to LC.

◆Hamsters with long Covid exhibits a neurodegenerative signature in the brainstem【bioRxiv　2024年12月16日】

Abstract

After infection with SARS-CoV-2, patients may present with one or more symptoms that appear or persist over time, including fatigue, respiratory, cardiovascular and neurological disorders. Neurological symptoms include anxiety, depression and impaired short-term memory. However, the exact underlying mechanisms of long Covid are not yet decrypted. Using the golden hamster as a model, we provide further evidence that SARS-CoV-2 is neuroinvasive and can persist in the central nervous system, as we found viral RNA and replicative virus in the brainstem after 80 days of infection. Infected hamsters presented a neurodegenerative signature in the brainstem, with overexpression of innate immunity genes, impacted dopaminergic and glutamatergic synapses, altered energy metabolism. Finally, the infected hamsters manifested persistent signs of depression and impaired short-term memory, as well as late-onset signs of anxiety, as a valuable model to study long Covid. Conclusively, we provide evidence that virus-related and neurodegenerative and immunometabolic mechanisms coexist in the brainstem of infected hamsters and contribute to the manifestation of neuropsychiatric and cognitive symptoms.

◆Skeletal muscle adaptations and post-exertional malaise in long COVID【Trends in Endocrinology & Metabolism　2024年12月17日】

Highlights

Long COVID occurs when symptoms persist for more than 3 months after acute SARS-CoV-2 infection. Symptoms include fatigue, brain fog, myalgia, and post-exertional malaise (PEM), which worsens with physical, mental, or cognitive exertion.
Long COVID shares many characteristics with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), particularly PEM, which is necessary for ME/CFS diagnosis.
Long COVID is associated with intrinsic skeletal muscle mitochondrial dysfunction, endothelial abnormalities, and a shift towards more glycolytic muscle fibers, which contribute to a lower exercise capacity.
Several potential mechanisms may explain skeletal muscle abnormalities in long COVID, including local hypoxia, deconditioning, autoimmunity, electrophysiological changes, and central fatigue.
There are no treatments for long COVID or PEM, but ongoing trials include immunoadsorption, dietary supplements, and anti-inflammatory/antiviral drugs.

Abstract

When acute SARS-CoV-2 infections cause symptoms that persist longer than 3 months, this condition is termed long COVID. Symptoms experienced by patients often include myalgia, fatigue, brain fog, cognitive impairments, and post-exertional malaise (PEM), which is the worsening of symptoms following mental or physical exertion. There is little consensus on the pathophysiology of exercise-induced PEM and skeletal-muscle-related symptoms. In this opinion article we highlight intrinsic mitochondrial dysfunction, endothelial abnormalities, and a muscle fiber type shift towards a more glycolytic phenotype as main contributors to the reduced exercise capacity in long COVID. The mechanistic trigger for physical exercise to induce PEM is unknown, but rapid skeletal muscle tissue damage and intramuscular infiltration of immune cells contribute to PEM-related symptoms.

◆A Rare Pediatric Case of COVID-19-Associated Guillain-Barré Syndrome With Multiple Cranial Neuropathies and Without Pulmonary Symptoms【Cureus Journal of Medical Science　2024年12月18日】

Abstract

Coronavirus disease (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that primarily affects the respiratory system but can also lead to neurological complications such as Guillain-Barré syndrome (GBS). This case report describes an eight-year-old boy with COVID-19-associated GBS involving multiple cranial nerves (third, seventh, and ninth) without pulmonary symptoms. The patient initially presented with flu-like symptoms along with right facial paralysis, which progressed to bilateral facial paralysis, limb weakness, and sensory loss. Neurologic examination revealed a loss of deep tendon reflexes, while cerebrospinal fluid analysis showed albuminocytologic dissociation. The SARS-CoV-2 polymerase chain reaction (PCR) test was positive in the nasopharyngeal swab but negative in the cerebrospinal fluid. The patient was treated with intravenous immunoglobulin (IVIG) and showed marked improvement, regaining the ability to walk unassisted within a week. This case highlights the neuroinvasive potential of SARS-CoV-2 and demonstrates that COVID-19 in pediatric patients can be associated with neurological complications such as GBS, even without respiratory symptoms.

◆SARS-CoV-2 Causes Mitochondrial Dysfunction and Mitophagy Impairment【Frontiers in Microbiology　2022年1月6日】

Mitochondria, which is essential for adequate innate immune response, energy metabolism and mitochondria reactive oxygen species (ROS) production, might be in the cross fire of Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and host cell defense. However, little is known about interactions between mitochondria and SARS-CoV-2. We performed fluorescent microscopy and found an enrichment of SARS-CoV-2 replication products double stranded RNA (dsRNA) within mitochondria. The entry process of dsRNA might be mediated by Tom20 as observed by reduced mitochondrial localization of SARS-CoV-2 dsRNA in Tom20 knockdown cells. Importantly, decreased mitochondrial localization of dsRNA, as well as mitochondrial membrane stabilizers mdivi-1 and cyclosporin A, inhibited viral load in cells. Next, we detected mitochondrial dysfunction caused by SARS-CoV-2 infection, including mitochondrial membrane depolarization, mitochondrial permeability transition pore opening and increased ROS release. In response to mitochondrial damage, we observed an increase in expression and mitochondrial accumulation of Pink1 and Parkin proteins, as well as Pink-1-mediated recruitment of P62 to mitochondria, suggesting initiated mitophagy for mitochondrial quality control and virus clearance. Nevertheless, we observed that mitophagy was inhibited and stayed in early stage with an unchanged Hsp60 expression post SARS-CoV-2 infection. This might be one of the anti-autophagy strategies of SARS-CoV-2 and we used co-immunoprecipitation to found that SARS-CoV-2 infection inhibited P62 and LC3 binding which plays a critical role in selective envelopment of substrates into autophagosomes. Our results suggest that mitochondria are closely involved in SARS-CoV-2 replication and mitochondrial homeostasis is disrupted by SARS-CoV-2 in the virus-cell confrontation.

◆How the Replication and Transcription Complex Functions in Jumping Transcription of SARS-CoV-2【Frontiers in Microbiology　2022年5月30日】

Background: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although unprecedented efforts are underway to develop therapeutic strategies against this disease, scientists have acquired only a little knowledge regarding the structures and functions of the CoV replication and transcription complex (RTC). Ascertaining all the RTC components and the arrangement of them is an indispensably step for the eventual determination of its global structure, leading to completely understanding all of its functions at the molecular level.

Results: The main results include: 1) hairpins containing the canonical and non-canonical NSP15 cleavage motifs are canonical and non-canonical transcription regulatory sequence (TRS) hairpins; 2) TRS hairpins can be used to identify recombination regions in CoV genomes; 3) RNA methylation participates in the determination of the local RNA structures in CoVs by affecting the formation of base pairing; and 4) The eventual determination of the CoV RTC global structure needs to consider METTL3 in the experimental design.

Conclusions: In the present study, we proposed the theoretical arrangement of NSP12-15 and METTL3 in the global RTC structure and constructed a model to answer how the RTC functions in the jumping transcription of CoVs. As the most important finding, TRS hairpins were reported for the first time to interpret NSP15 cleavage, RNA methylation of CoVs and their association at the molecular level. Our findings enrich fundamental knowledge in the field of gene expression and its regulation, providing a crucial basis for future studies.

◆Pathophysiological involvement of host mitochondria in SARS-CoV-2 infection that causes COVID-19: a comprehensive evidential insight【SPRINGER NATURE　2022年10月29日】

Abstract

SARS-CoV-2 is a positive-strand RNA virus that infects humans through the nasopharyngeal and oral route causing COVID-19. Scientists left no stone unturned to explore a targetable key player in COVID-19 pathogenesis against which therapeutic interventions can be initiated. This article has attempted to review, coordinate and accumulate the most recent observations in support of the hypothesis predicting the altered state of mitochondria concerning mitochondrial redox homeostasis, inflammatory regulations, morphology, bioenergetics and antiviral signalling in SARS-CoV-2 infection. Mitochondria is extremely susceptible to physiological as well as pathological stimuli, including viral infections. Recent studies suggest that SARS-CoV-2 pathogeneses alter mitochondrial integrity, in turn mitochondria modulate cellular response against the infection. SARS-CoV-2 M protein inhibited mitochondrial antiviral signalling (MAVS) protein aggregation in turn hinders innate antiviral response. Viral open reading frames (ORFs) also play an instrumental role in altering mitochondrial regulation of immune response. Notably, ORF-9b and ORF-6 impair MAVS activation. In aged persons, the NLRP3 inflammasome is over-activated due to impaired mitochondrial function, increased mitochondrial reactive oxygen species (mtROS), and/or circulating free mitochondrial DNA, resulting in a hyper-response of classically activated macrophages. This article also tries to understand how mitochondrial fission–fusion dynamics is affected by the virus. This review comprehends the overall mitochondrial attribute in pathogenesis as well as prognosis in patients infected with COVID-19 taking into account pertinent in vitro, pre-clinical and clinical data encompassing subjects with a broad range of severity and morbidity. This endeavour may help in exploring novel non-canonical therapeutic strategies to COVID-19 disease and associated complications.

◆SARS-CoV-2 can cause lasting damage to cells’ energy production【National Institutes of Health　2023年8月22日】

At the beginning of the COVID-19 pandemic, the virus responsible for the disease, SARS-CoV-2, was feared for its devastating damage to the lungs. But it quickly became apparent that the virus can infect organs and tissues throughout the body, including the heart, brain, kidneys, and blood vessels.

Much of the resulting dysfunction was thought to be the result of inflammation, the immune system’s response to infection. But research has suggested that effects on mitochondria may also play a role in organ damage from SARS-CoV-2 infection. Mitochondria are the powerhouses of cells, producing most of the energy they need.

It’s been known that parts of SARS-CoV-2 bind to proteins in the mitochondria. But how this affects mitochondrial function hasn’t been clear. Dr. Afshin Beheshti, president of the nonprofit COVID-19 International Research Team and visiting researcher at Broad Institute, and Dr. Douglas Wallace from Children’s Hospital of Philadelphia led an international team, including NIH researchers, to look more closely at the phenomenon.

The researchers compared mitochondrial gene expression€”when genes were activated€”in tissue samples taken from the nasopharynx of 216 people with COVID-19 and 519 uninfected people. They also looked at mitochondrial function in autopsy samples from the hearts, kidneys, livers, lungs, and lymph nodes of 35 people who died from COVID-19 compared with that from 5 people who died from other causes. The results were published on August 9, 2023, in Science Translational Medicine.

The team found that the expression of mitochondrial genes involved in energy production was suppressed in the nasopharynx during acute infection. This shifted cells into a state where they produced more of the substances the virus needs for replication. The researchers did not find this suppression in lung tissue samples taken after the virus had been cleared from the body.

Tissue samples taken during autopsies from the heart, kidney, liver, and lymph nodes continued to show suppression of these mitochondrial genes long after the virus had been cleared from the body. The reason for this continued suppression is unclear. In tandem with reduced mitochondrial function in these tissues, the researchers saw an upregulation of genes related to cellular stress.

“The continued dysfunction we observed in organs other than the lungs suggests that mitochondrial dysfunction could be causing long-term damage to the internal organs of these patients,” Wallace says.

The team next used hamsters and mice to track mitochondrial function over the entire course of infection with SARS-CoV-2. They saw similar results in these animal models. Mitochondrial energy production was suppressed in the lungs during early SARS-CoV-2 infection, then bounced back once the immune system brought the virus under control. During early infection, mitochondrial gene expression was altered in the brain even though no SARS-CoV-2 was detected there, consistent with a systemic response to the virus.

The researchers also found a potential new target for treatment. They found that SARS-CoV-2 boosted expression of a regulatory molecule called miR-2392. This, in turn, lowered expression of mitochondrial genes involved in energy production.

“Neutralizing this microRNA might be able to impede the replication of the virus, providing an additional therapeutic option for patients who are at risk for more serious complications related to the disease,” Beheshti says.

◆Sex differences and immune correlates of Long Covid development, symptom persistence, and resolution【Science Translational Medicine　2024年11月13日】

Abstract

Sex differences have been observed in acute coronavirus disease 2019 (COVID-19) and Long Covid (LC) outcomes, with greater disease severity and mortality during acute infection in males and greater proportions of females developing LC. We hypothesized that sex-specific immune dysregulation contributes to LC pathogenesis. To investigate the immunologic underpinnings of LC development and symptom persistence, we performed multiomic analyses on blood samples obtained during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 3 and 12 months after infection in a cohort of 45 participants who either developed LC or recovered. Several sex-specific immune pathways were associated with LC. Males who would later develop LC exhibited increases in transforming growth factor–β (TGF-β) signaling during acute infection, whereas females who would go on to develop LC had reduced TGFB1 expression. Females who developed LC demonstrated increased expression of XIST, an RNA gene implicated in autoimmunity, during acute infection compared with females who recovered. Many immune features of LC were also conserved across sexes, such as alterations in monocyte phenotype and activation state. Nuclear factor κB (NF-κB) transcription factors were up-regulated in many cell types at acute and convalescent time points. Those with ongoing LC demonstrated reduced ETS1 expression across lymphocyte subsets and elevated intracellular IL-4 in T cell subsets, suggesting that ETS1 alterations may drive aberrantly elevated T helper cell 2–like responses in LC. Altogether, this study describes multiple innate and adaptive immune correlates of LC, some of which differ by sex, and offers insights toward the pursuit of tailored therapeutics.

◆Can COVID-19 Cause Ulcerative Colitis or Make Symptoms Worse?【healthline　2024年12月18日】

COVID-19 might be a trigger for new ulcerative colitis for some people. It may also be a trigger for symptom flare-ups for people previously diagnosed with UC.

COVID-19 is a respiratory illness caused by the virus SARS-CoV-2. It primarily causes respiratory symptoms, but it’s well-established that it can also affect other parts of your body, such as your gastrointestinal tract.

Research suggests that COVID-19 and other viral infections may contribute to the development of ulcerative colitis in some genetically prone people. Viral infections are also a common trigger for symptom flare-ups.

Let’s examine what’s known about the connection between COVID-19 and ulcerative colitis.

Can COVID-19 cause ulcerative colitis?

Ulcerative colitis is a type of inflammatory bowel disease (IBD) that occurs when the immune system attacks the lining of the large intestine. The course of the disease usually alternates between periods where symptoms flare up and periods where symptoms decrease.

The underlying cause of ulcerative colitis isn’t known, but some people are thought to be more genetically prone when exposed to certain environmental factors.

When you get a virus, your immune system triggers the release of molecules like cytokines that lead to inflammation throughout your body. Dysregulation of your immune system is a potential trigger of ulcerative colitis. In reverse, people with ulcerative colitis seem to be at higher risk of viral infections.

Additionally, COVID-19 and other viral infections cause psychological stress for some people, and stress is a known trigger for ulcerative colitis symptoms.

What research shows

Although many viral infections may trigger ulcerative colitis, it has also been specifically linked to COVID-19.

In a 2022 study, researchers reported two cases of IBD diagnosed shortly after recovery from COVID-19. In the first case, a 37-year-old male developed symptoms of ulcerative colitis 2 months after recovering from a COVID-19 infection that required a short course of steroids.

The second case was a 64-year-old male who developed a form of ulcerative colitis called proctosigmoiditis.

In another case report, researchers reported a 74-year-old male who developed new ulcerative colitis a month after having COVID-19.

In a 2024 review of studies, researchers examined the connection between ulcerative colitis and COVID-19 in a sample of 224,520 people from 19 studies. The researchers found that the overall risk of hospitalization in people with COVID-19 and ulcerative colitis was 28% higher than in the general population. The chances of getting severe COVID-19 were 30% higher.

Can COVID-19 make ulcerative colitis worse?

Some people can experience ulcerative colitis flare-ups with confirmed COVID-19 infection. For example, in a 2022 study, researchers reported two cases of people who experienced mild and severe symptom flare-ups associated with COVID-19 infection.

In a 2024 study, researchers found statistically significant evidence of an association between COVID-19 and either ulcerative colitis or Crohn’s disease flare-ups. Crohn’s disease is another type of IBD.

Can COVID-19 vaccines cause UC or worsen symptoms?

Vaccines come with some risks. Evidence suggests that COVID-19 vaccines approved for use in the United States have a much smaller risk of complications than COVID-19 infection, but some serious side effects have been reported, such as:

  • anaphylaxis (severe allergic reaction)
  • myocarditis (heart inflammation)
  • pericarditis (inflammation of tissue that surrounds the heart)

Receiving a COVID-19 vaccine can help prevent serious infection in people with ulcerative colitis, since they may be more likely to develop severe infection.

In rare cases, it’s plausible that vaccination could trigger ulcerative colitis by modulating immune activity. For example, researchers reported a suspected caseTrusted Source in a 37-year-old woman in Japan after her third vaccination dose.

However, the benefits of the vaccine far outweigh the risks in people with IBD, and those with IBD can have much more severe infections of COVID-19.

How to protect against COVID-19 if you have ulcerative colitis

People with ulcerative colitis seem to be more susceptible to viral infections than people without ulcerative colitis. Ways you can help prevent COVID-19 infection include:

  • receiving COVID-19 vaccination
  • receiving vaccination for other infections that could weaken immune activity, such as influenza
  • avoiding symptom triggers
  • taking UC medications as prescribed
  • washing your hands regularly and thoroughly with soapy water
  • avoiding physical contact with sick people when possible
  • avoiding areas where you might be susceptible to infection, such as public transport, when possible
  • wearing a mask in areas where you have a high risk of COVID-19 infection

When to contact a doctor

It’s important to speak with a doctor if you have potential symptoms of ulcerative colitis without a known cause, such as persistent and unexplained abdominal pain and diarrhea. You should also consult a healthcare professional if your symptoms are getting worse or you develop new symptoms.

The American Medical Association Trusted Source recommends getting emergency medical attention for COVID-19 if you or somebody you’re with has:

  • trouble breathing
  • persistent chest pain or pressure
  • new confusion
  • trouble walking or staying awake
  • pale, gray, or blue-colored skin, lips, or nail beds, which may be more difficult to spot on darker skin tones

Takeaway

COVID-19 and other viral infections appear to be a potential trigger for ulcerative colitis for some people. In reverse, having ulcerative colitis seems to make you more susceptible to viral infections.

COVID-19 vaccines also seem to trigger ulcerative colitis symptoms for a small number of people. However, the potential benefits of vaccination for people with ulcerative colitis outweigh the risks for most.

◆Coronavirus biology and replication: implications for SARS-CoV-2【nature reviews microbiology　2020年10月28日】

Abstract

The SARS-CoV-2 pandemic and its unprecedented global societal and economic disruptive impact has marked the third zoonotic introduction of a highly pathogenic coronavirus into the human population. Although the previous coronavirus SARS-CoV and MERS-CoV epidemics raised awareness of the need for clinically available therapeutic or preventive interventions, to date, no treatments with proven efficacy are available. The development of effective intervention strategies relies on the knowledge of molecular and cellular mechanisms of coronavirus infections, which highlights the significance of studying virus–host interactions at the molecular level to identify targets for antiviral intervention and to elucidate critical viral and host determinants that are decisive for the development of severe disease. In this Review, we summarize the first discoveries that shape our current understanding of SARS-CoV-2 infection throughout the intracellular viral life cycle and relate that to our knowledge of coronavirus biology. The elucidation of similarities and differences between SARS-CoV-2 and other coronaviruses will support future preparedness and strategies to combat coronavirus infections.

◆The Role of Immunomodulatory Nutrients in Alleviating Complications Related to SARS-CoV-2: A Scoping Review【Advances in Nutrition　2021年10月20日】

Abstract

The recent coronavirus disease 2019 (COVID-19) pandemic has warranted the need to investigate potential therapies or prophylaxis against this infectious respiratory disease. There is emerging evidence about the potential role of nutrients on COVID-19 in addition to using medications such as hydroxychloroquine and azithromycin. This scoping review aims to explore the literature evaluating the effect of immunomodulatory nutrients on the outcomes including hospitalization, intensive care unit admission, oxygen requirement, and mortality in COVID-19 patients. A literature search of databases including Medline, EMBASE, CINAHL, Web of Science, Cochrane, Scopus, and PubMed, as well as hand-searching in Google Scholar (up to 10 February 2021) was conducted. All human studies with different study designs and without limitation on publication year were included except for non-English-language and review articles. Overall, out of 4412 studies, 19 met our inclusion criteria. Four studies examined the impact of supplementation with vitamin C, 4 studies – zinc, 8 studies – vitamin D, and 3 studies investigated the combination of 2 (zinc and vitamin C) or 3 (vitamin D, vitamin B-12, and magnesium) nutrients. Although limited data exist, available evidence demonstrated that supplementation with immune-supportive micronutrients such as vitamins D and C and zinc may modulate immunity and alleviate the severity and risk of infection. The effectiveness of vitamin C, vitamin D, and zinc on COVID-19 was different based on baseline nutrient status, the duration and dosage of nutrient therapy, time of administration, and severity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease. This review indicated that supplementation with high-dose vitamin C, vitamin D, and zinc may alleviate the complications caused by COVID-19, including inflammatory markers, oxygen therapy, length of hospitalization, and mortality; however, studies were mixed regarding these effects. Further randomized clinical trials are necessary to identify the most effective nutrients and the safe dosage to combat SARS-CoV-2.

◆Cleavage of the selective autophagy receptor SQSTM1/p62 by the SARS-CoV-2 main protease NSP5 prevents the autophagic degradation of viral membrane proteins【SPRINGER NATURE　2022年6月3日】

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the coronavirus disease 2019 (COVID-19) global pandemic. Omicron, a new variant of SARS-CoV-2, has the characteristics of strong transmission and pathogenicity, short incubation period, and rapid onset progression, and has spread rapidly around the world. The high replication rate and intracellular accumulation of SARS-CoV-2 are remarkable, but the underlying molecular mechanisms remain unclear. Autophagy acts as a conservative cellular defence mechanism against invading pathogens. Here, we provide evidence that the main protease of SARS-CoV-2, NSP5, effectively cleaves the selective autophagy receptor p62. NSP5 targets p62 for cleavage at glutamic acid 354 and thus abolishes the capacity of p62 to mediate selective autophagy. It was further shown that p62 specifically interacted with ubiquitinated SARS-CoV-2 M, the viral membrane protein, to promote its autophagic degradation. In the presence of NSP5, p62-mediated autophagic degradation of the M protein was inhibited. The cleaved products of p62 also cannot facilitate the degradation of the M protein. Collectively, our findings reveal that p62 is a novel host target of SARS-CoV-2 NSP5 and suggest that selective autophagy targets viruses and potential strategies by which the virus evades autophagic clearance. Our results may provide new ideas for the development of anti-COVID-19 drugs based on autophagy and NSP5.

◆Role and clinical implication of autophagy in COVID-19【BMC Virology Journal　2023年6月16日】

Abstract

The ongoing coronavirus disease 2019 (COVID-19) pandemic constitutes a serious public health concern worldwide. Currently, more than 6 million deaths have occurred despite drastic containment measures, and this number is still increasing. Currently, no standard therapies for COVID-19 are available, which necessitates identifying effective preventive and therapeutic agents against COVID-19. However, developing new drugs and vaccines is a time-consuming process, and therefore, repurposing the existing drugs or redeveloping related targets seems to be the best strategy to develop effective therapeutics against COVID-19. Autophagy, a multistep lysosomal degradation pathway contributing to nutrient recycling and metabolic adaptation, is involved in the initiation and progression of numerous diseases as a part of an immune response. The key role of autophagy in antiviral immunity has been extensively studied. Moreover, autophagy can directly eliminate intracellular microorganisms by selective autophagy, that is, “xenophagy.” However, viruses have acquired diverse strategies to exploit autophagy for their infection and replication. This review aims to trigger the interest in the field of autophagy as an antiviral target for viral pathogens (with an emphasis on COVID-19). We base this hypothesis on summarizing the classification and structure of coronaviruses as well as the process of SARS-CoV-2 infection and replication; providing the common understanding of autophagy; reviewing interactions between the mechanisms of viral entry/replication and the autophagy pathways; and discussing the current state of clinical trials of autophagy-modifying drugs in the treatment of SARS-CoV-2 infection. We anticipate that this review will contribute to the rapid development of therapeutics and vaccines against COVID-19.

◆Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency【Journal of Biological Chemistry　2020年4月13日】

Abstract

Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed to control this current pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Replication of SARS-CoV-2 depends on the viral RNA-dependent RNA polymerase (RdRp), which is the likely target of the investigational nucleotide analogue remdesivir (RDV). RDV shows broad-spectrum antiviral activity against RNA viruses, and previous studies with RdRps from Ebola virus and Middle East respiratory syndrome coronavirus (MERS-CoV) have revealed that delayed chain termination is RDV’s plausible mechanism of action. Here, we expressed and purified active SARS-CoV-2 RdRp composed of the nonstructural proteins nsp8 and nsp12. Enzyme kinetics indicated that this RdRp efficiently incorporates the active triphosphate form of RDV (RDV-TP) into RNA. Incorporation of RDV-TP at position i caused termination of RNA synthesis at position i+3. We obtained almost identical results with SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A unique property of RDV-TP is its high selectivity over incorporation of its natural nucleotide counterpart ATP. In this regard, the triphosphate forms of 2′-C-methylated compounds, including sofosbuvir, approved for the management of hepatitis C virus infection, and the broad-acting antivirals favipiravir and ribavirin, exhibited significant deficits. Furthermore, we provide evidence for the target specificity of RDV, as RDV-TP was less efficiently incorporated by the distantly related Lassa virus RdRp, and termination of RNA synthesis was not observed. These results collectively provide a unifying, refined mechanism of RDV-mediated RNA synthesis inhibition in coronaviruses and define this nucleotide analogue as a direct-acting antiviral.

◆Bidirectional interplay between SARS-CoV-2 and autophagy【ASM Journals　2023年7月12日】

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as the causative agent of the recent COVID-19 pandemic, continues representing one of the main health concerns worldwide. Autophagy, in addition to its role in cellular homeostasis and metabolism, plays an important part for the host antiviral immunity. However, viruses including SARS-CoV-2 have evolved diverse mechanisms to not only overcome autophagy’s antiviral pressure but also manipulate its machinery in order to enhance viral replication and propagation. Here, we discuss our current knowledge on the impact that autophagy exerts on SARS-CoV-2 replication, as well as the different counteracting measures that this virus has developed to manipulate autophagy’s complex machinery. Some of the elements regarding this interplay may become future therapeutic targets in the fight against SARS-CoV-2.