LongCOVID患者の体内でSARS-CoV-2は何をやってるのか？みたいな

投稿日投稿者しとらす

1度でも感染したらダメ
何度も再感染なんて以ての外
・・・
なんだけど、京都の観光地・繁華街は今日も賑わっている
・・・

 

◆Epigenetic liquid biopsies reveal elevated vascular endothelial cell turnover and erythropoiesis in asymptomatic COVID-19 patients【medRxiv　2023年7月31日】

ABSTRACT

The etiologic mechanisms of post-acute medical morbidities and unexplained symptoms (Long COVID) following SARS-CoV-2 infection are incompletely understood. There is growing evidence that viral persistence and immune dysregulation may play a major role. We performed whole-body positron emission tomography (PET) imaging in a cohort of 24 participants at time points ranging from 27 to 910 days following acute SARS-CoV-2 infection using a novel radiopharmaceutical agent, [18F]F-AraG, a highly selective tracer that allows for anatomical quantitation of activated T lymphocytes. Tracer uptake in the post-acute COVID group, which included those with and without Long COVID symptoms, was significantly higher compared to pre-pandemic controls in many anatomical regions, including the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. Although T cell activation tended to be higher in participants imaged closer to the time of the acute illness, tracer uptake was increased in participants imaged up to 2.5 years following SARS-CoV-2 infection. We observed that T cell activation in spinal cord and gut wall was associated with the presence of Long COVID symptoms. In addition, tracer uptake in lung tissue was higher in those with persistent pulmonary symptoms. Notably, increased T cell activation in these tissues was also observed in many individuals without Long COVID. Given the high [18F]F-AraG uptake detected in the gut, we obtained colorectal tissue for in situ hybridization SARS-CoV-2 RNA and immunohistochemical studies in a subset of participants with Long COVID symptoms. We identified cellular SARS-CoV-2 RNA in rectosigmoid lamina propria tissue in all these participants, ranging from 158 to 676 days following initial COVID-19 illness, suggesting that tissue viral persistence could be associated with long-term immunological perturbations.

INTRODUCTION

Some people do not return to their baseline health following SARS-CoV-2 infection. Following the acute phase, such individuals may experience an increased burden of new onset medical conditions such as cardiovascular disease or diabetes mellitus. They may also experience Long COVID (LC), defined as unexplained symptoms or changes in health not attributable to an alternative diagnosis. The U.S. Centers for Disease Control and Prevention (CDC) recently reported that approximately 15% of American adults have experienced Long COVID at any time and that 6% are currently experiencing the condition; up to 18 million adults in the U.S. alone might be affected5. Despite the scale of the problem, there are currently no accepted treatments and massive efforts are now underway to understand the pathophysiology of these post-acute sequelae, including Long COVID.

Acute COVID-19 is a highly inflammatory illness. In the post-acute phase, inflammation, immune activation and long-term dysregulation of virus-specific immune responses have consistently been identified in peripheral blood. These immune responses have been associated with a variety of factors including clotting dysfunction, reactivation of latent viral infections such as Epstein Barr Virus (EBV), and autoimmune responses. Importantly, there is a growing body of evidence that persistent SARS-CoV-2 RNA or protein can be detected in various tissue compartments for many months following acute infection. This may explain, at least in part, ongoing aberrant immune responses, inflammation, and clinical symptomatology.

Despite advances in understanding systemic inflammation in Long COVID, data regarding the role of SARS-CoV-2 persistence or aberrant T cell responses in non-blood tissues are sparse. Most studies to date have been limited to small autopsy or biopsy samples from convenience cohorts, with many individuals requiring hospitalization during acute infection or without detailed data on the post-acute course. Clinical studies that have evaluated tissue pathology in living participants have assessed limited quantities of tissue obtained through minimally invasive clinical biopsies. Furthermore, anatomic regions such as brain, spinal cord, cardiopulmonary tissue, vascular tissue, and other potential sites of SARS-CoV-2 persistence cannot be sampled in living individuals via biopsy procedures. As a result, characterization of the immune responses in these anatomical locations, including processes like T cell activation and trafficking, has been limited. When it has been attempted, it has utilized non-specific tracers or limited follow-up of clinical symptoms. Therefore, there is an urgent need to develop non-invasive techniques to identify more specific persistent and/or aberrant immune responses in highly characterized cohorts over the long-term to better understand the tissue-level biology that might drive findings observed in peripheral blood.

In this study, we performed whole-body positron emission tomography (PET) imaging in 24 highly characterized participants from the UCSF-based LIINC cohort (NCT04362150) at time points ranging from 27 to 910 days following COVID-19 symptom onset. We used a novel radiopharmaceutical agent, [F]F-AraG (Fluorine-18 labeled arabino furanosyl guanine), a selective and sensitive tracer that allows for anatomical localization of activated CD8+ and CD4+ T lymphocytes. We found that [18F]F-AraG uptake was significantly higher in many anatomical regions among post-acute COVID participants compared to pre-pandemic controls. These included the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. Increased uptake was identified up to 2.5 years following SARS-CoV-2 infection in the absence of known re-infection. Furthermore, [F]F-AraG uptake in some tissues was associated with a higher number of Long COVID symptoms. Lastly, we identified cellular SARS-CoV-2 RNA in rectosigmoid lamina propria tissue in all participants with Long COVID symptoms who underwent biopsy, ranging from 158 to 676 days following initial COVID-19 symptom onset, suggesting that tissue viral persistence could be associated with these immunologic findings.

 

◆The plasma metabolome of long COVID patients two years after infection【nature scientific reports　2023年8月1日】

Abstract

One of the major challenges currently faced by global health systems is the prolonged COVID-19 syndrome (also known as “long COVID”) which has emerged as a consequence of the SARS-CoV-2 epidemic. It is estimated that at least 30% of patients who have had COVID-19 will develop long COVID. In this study, our goal was to assess the plasma metabolome in a total of 100 samples collected from healthy controls, COVID-19 patients, and long COVID patients recruited in Mexico between 2020 and 2022. A targeted metabolomics approach using a combination of LC–MS/MS and FIA MS/MS was performed to quantify 108 metabolites. IL-17 and leptin were measured in long COVID patients by immunoenzymatic assay. The comparison of paired COVID-19/long COVID-19 samples revealed 53 metabolites that were statistically different. Compared to controls, 27 metabolites remained dysregulated even after two years. Post-COVID-19 patients displayed a heterogeneous metabolic profile. Lactic acid, lactate/pyruvate ratio, ornithine/citrulline ratio, and arginine were identified as the most relevant metabolites for distinguishing patients with more complicated long COVID evolution. Additionally, IL-17 levels were significantly increased in these patients. Mitochondrial dysfunction, redox state imbalance, impaired energy metabolism, and chronic immune dysregulation are likely to be the main hallmarks of long COVID even two years after acute COVID-19 infection.

Introduction

Historically, highly pathogenic beta-coronaviruses have been associated with severe respiratory diseases. According to the WHO, the severe acute respiratory syndrome coronavirus (SARS-CoV), and the Middle East respiratory syndrome coronavirus (MERS-CoV) were responsible for epidemics in 2002–2003 and 2015, respectively. During the SARS-CoV epidemic, the virus was reported in 29 countries with 8,437 cases and 813 fatalities. On the other hand, MERS-CoV was reported in 27 countries with 2,519 laboratory-confirmed cases between 2012 and 2020, resulting in 866 deaths. In 2019, exactly 100 years after the last pandemic caused by an H1N1 influenza A virus (the Spanish flu), a new pandemic affected almost every country around the world. As of February 26, 2023, over 758 million confirmed cases of SARS-CoV-2 and over 6.8 million deaths have been reported globally. To date, around 653 million patients have recovered. However, as early as spring 2020, people began describing their experiences of not fully recovering from SARS-CoV-2 infection. This extended version of the disease has been called “long COVID”. Interestingly, the term long COVID is a patient-created term promoted in Twitter by Elsa Perego, an archeologist at University College London.

It has been widely described that some viruses lead to persistent physiological alterations even a decade after infection. The term “post-viral syndrome” has been in use for over a century. Chronic symptoms such as fatigue, joint pain, and cardiovascular problems have been reported after recovery from other infections such as the West Nile, Polio, Dengue, Zika, seasonal flu, Epstein-Barr, Ebola, MERS, and SARS. However, none of these viruses have affected so many people in the same time window as SARS-CoV-2, which offers the scientific community a unique opportunity to understand the etiology of post-viral syndromes such as long COVID.

Long COVID (also known as post-COVID-19 syndrome or post-acute sequelae of COVID-19 (PACS)) is a condition characterized by long-term or persistent health problems appearing after the initial recovery from COVID-19 infection. The WHO has described long COVID as a condition “that occurs in individuals with a previous history of probable or confirmed SARS-CoV-2 infection, usually three months after the onset, with symptoms lasting at least two months that cannot be explained by an alternative diagnosis”. It is estimated that 30–60% of recovered patients, even after a mild disease, will experience long COVID or symptoms persistence with varying durations. Based on a conservative estimated incidence, at least 65 million individuals worldwide could be experiencing long COVID3.

Similar to COVID-19, long COVID affects multiple organ systems, including the respiratory, cardiovascular, nervous, and gastrointestinal systems. More than 50 symptoms have been reported associated with long COVID. Observational studies have reported that some symptomatic conditions are resolved within three months of hospitalization in 50% of patients, but the rate of full recovery drops to 35% between three and 6 months after hospitalization, and to 15% between 6 and 9 months. Importantly, a high proportion of that population has residual lung tissue injury, with detectable radiological abnormalities on chest computed tomography (CT) scans. Fatigue, loss of concentration, headaches, shortness of breath, anosmia, muscle weakness, joint pain are some of the symptoms most reported. Therefore, more than a homogeneous entity, long COVID could be considered as a spectrum of disorders, that affects individuals with complications directly linked to the virus (long-term residual damage in the lungs, brain, or heart), and individuals manifesting systemic unspecific signs/symptoms (fatigue, headache, and arthromyalgias). The increasing number of patients with long COVID poses a challenge for public health systems around the world, but, currently, there are no guidelines for accurately diagnosing patients with long COVID and classification is still underestimated and subjective.

Both untargeted and targeted metabolomics have proven to be valuable tools for studying of long COVID. Our results, based on an untargeted lipidomics approach,14 demonstrate that several species of phosphatidylcholines and sphingomyelins were expressed at higher levels in long COVID-19 patients compared with controls. The paired analysis, which compares patients with an active infection and two years after recovery, showed 170 dysregulated lipidic features.

In the present work we used quantitative targeted metabolomics to evaluate the metabolic reversion of patients with persistent sequelae due to confirmed SARS-CoV-2 infection. Comparison with negative controls allowed us to identify those metabolites persistently dysregulated after two years of the initial infection. Number, type of symptoms as well as metabolic signatures were different in patients experiencing long COVID (arbitrarily defined by us as long COVID class A and class B patients) and recovered patients (non-long COVID). Besides, IL-17 level was increased in patients with the worst disease evolution (class B patients). To the best of our knowledge, this is the first targeted metabolomics study of long COVID patients conducted beyond twenty months post-infection.