SARS-CoV-2 と COVID-19 に関する備忘録 Vol.60

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

◆Three-year assessment of cognitive and olfactory disturbances among COVID-19 convalescent patients grouped by olfactory hallucination status in Armenia: A qualitative and quantitative study【ScienceDirect　2025年7月16日】

Abstract

Background

Smell disturbances, memory and mood changes are frequently reported as symptoms of long COVID that can be debilitating and long-lasting, having a detrimental impact on a patient’s quality of life and possibly contributing to depression and a decline in cognitive abilities.

Study objective

This study aims to investigate long-term post-COVID cognitive and olfactory disturbances among the COVID-19 convalescent adult Armenian population aged between 18 and 65 years. The assessment extends to the differentiation of various olfactory distortions and association between various olfactory and cognitive variables, grouped by participants’ olfactory hallucination status.

Study design

Explanatory sequential mixed-methods design was employed. Through three follow-up visits, the quantitative phase evaluated olfactory and cognitive abnormalities following COVID-19, comparing those with and without olfactory hallucinations. Through in-depth interviews, the qualitative phase investigated how participants perceived these symptoms and their impact on their quality of life.

Study participants

The quantitative study participants were those who self-reported subjective disturbances in the olfactory perception 14 days following a COVID-19 diagnosis, as confirmed by a positive PCR test at the time of diagnosis. The qualitative study participants were those who self-reported persistent olfactory disturbances post-visit 3.

Results

The study found that olfactory hallucinations lead to more pronounced depression compared with non-hallucinogenic types of olfactory disturbances. It was determined that a significant predictor of parosmia is persistent anosmia up to 4 months following COVID-19 infection.

Conclusion

The long-term olfactory disturbances post-COVID-19 infection have a better prognosis among participants without olfactory hallucination compared to participants with olfactory hallucination.

◆Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response【bioRxiv　2025年8月1日】

Abstract

Open Reading Frame 9b (Orf9b), an accessory protein of SARS-CoV and -2, is involved in innate immune suppression through its binding to the mitochondrial receptor Translocase of Outer Membrane 70 (Tom70). Previous structural studies of Orf9b in isolation revealed a β-sheet-rich homodimer, however, structures of Orf9b in complex with Tom70 revealed a monomeric helical fold. Here, we developed a biophysical model that quantifies how Orf9b switches between these conformations and binds to Tom70, a requirement for suppressing the type 1 interferon response. We used this model to characterize the effect of lipid binding and mutations in variants of concern to the Orf9b:Tom70 equilibrium. We found that the binding of a lipid to the Orf9b homodimer biases the Orf9b monomer:dimer equilibrium towards the dimer by reducing the dimer dissociation rate ∼100-fold. We also found that mutations in variants of concern can alter different microscopic rate constants without significantly affecting binding to Tom70. Together our results highlight how perturbations to different steps in these coupled equilibria can affect the apparent affinity of Orf9b to Tom70, with potential downstream implications for interferon signaling in coronavirus infection.

◆Incidence and risk factors of new-onset hypertension up to 3 years post SARS-CoV-2 infection【nature : scientific reports　2025年8月6日】

Abstract

COVID-19 can trigger new cardiovascular events, including hypertension, in the acute setting. However, few studies have reported sustained new-onset hypertension post-infection. Moreover, these studies have a small sample size, inadequate controls, and a short (< 1 year) follow-up time. This retrospective cohort study of 64,000 COVID-19 patients) from the Stony Brook Health System assessed the incidence and risk factors for new-onset hypertension after COVID-19. Contemporary COVID-negative controls were obtained and propensity-matched for age, race, sex, ethnicity, and major comorbidities before analyzing outcomes. The primary outcome was new-onset hypertension up to 3 years post-index date. About 9.93% of hospitalized patients and 4.66% of non-hospitalized patients developed new-onset hypertension after COVID-19. Hospitalized COVID-positive patients were more likely to develop hypertension compared to COVID-negative controls (Hazard Ratio [HR] = 1.57, 95% Confidence Interval [CI] [1.35–1.81]) and non-hospitalized COVID-positive controls (HR: 1.42, 95%CI [1.24–1.63]). Non-hospitalized COVID-positive patients were not more likely to develop hypertension than COVID-negative controls (HR: 1.05, 95%CI [0.98–1.13]). COVID-19 was one of the five greatest risk factors for developing hypertension. COVID-19 patients are at increased risk of developing hypertension beyond the acute phase of the disease compared to controls. Long-term follow-up, holistic workups, and vigilant blood pressure screening and/or monitoring for COVID-19 patients are needed.

◆Peripheral immune progression to long COVID is associated with mitochondrial gene transcription: A meta-analysis【ScienceDirect　2025年7月28日】

Abstract

SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has led to millions of cases of Long COVID worldwide. Long COVID is a phenomenon characterized by persistent and debilitating mental and physical symptoms following acute infection. Despite ongoing research, trials, and considerable progress in understanding Long COVID, its exact causes remain only partially understood, with current hypotheses addressing specific aspects of the condition. We conducted one of the most comprehensive meta-analyses to date of all quality bulk RNA-seq studies worldwide from the COVID-19 pandemic and show significant mitochondrial transcript changes in the peripheral immune system of people with Long COVID, with unexpectedly low levels of intracellular viral RNA in Long COVID. This extensive analysis, which includes 26 studies and 1,272 individuals, shows that mononuclear cells, PBMC, and granulocytes from Long COVID patients exhibit significant alterations in mitochondrial genes and related processes. These findings likely represent the true transcriptomic landscape of Long COVID across diverse datasets, highlighting the long-lasting impacts of SARS-CoV-2 on peripheral immune function. In combination with other ex vivo and proteomics studies showing mitochondrial dysfunction, our results suggest critical new directions, such as the potential role of clonal hematopoiesis and infected seed cells. This work highlights the need for further investigation into the mechanisms underlying these immune changes and persistent symptoms in people with Long COVID. These findings will serve as a foundation for defining the paradigm underlying the biological mechanisms of Long COVID, driving research into the peripheral immune system, bone marrow, and mitochondria.

◆Epigenetic liquid biopsies reveal endothelial turnover and erythropoiesis in asymptomatic COVID-19【Life Science Alliance　2025年8月5日】

Abstract

Understanding the full spectrum of tissues affected by SARS-CoV-2 is crucial for deciphering the heterogeneous clinical course of COVID-19. We analyzed DNA methylation and histone modifications in circulating chromatin to assess cell type–specific turnover in patients ranging from asymptomatic to severe cases, in relation to clinical outcomes. Severe COVID-19 was marked by a massive elevation of circulating cell-free DNA (cfDNA) from lung epithelium, cardiomyocytes, vascular endothelium, and erythroblasts, indicating increased cell death or turnover. The immune response was reflected by elevated B-cell and monocyte/macrophage cfDNA and an interferon response before cfDNA release. Strikingly, monocyte/macrophage cfDNA (but not monocyte counts), as well as lung epithelial and endothelial cfDNA, predicted clinical deterioration and duration of hospitalization. Asymptomatic patients had elevated immune cfDNA but no evidence of pulmonary or cardiac damage. Surprisingly, these patients showed elevated endothelial and erythroblast cfDNA, suggesting subclinical vascular and erythrocyte turnover are universal features of COVID-19, independent of disease severity. Epigenetic liquid biopsies provide a noninvasive means of monitoring COVID-19 patients and reveal subclinical vascular damage and red blood cell turnover.

◆Blood-Brain barrier disruption in long COVID and cognitive correlates: A cross-sectional MRI study【ScienceDirect　2025年8月5日】

Abstract

Disruption of the blood–brain barrier (BBB) may contribute to neuropsychiatric symptoms observed in Long COVID (LC). Using a non-contrast magnetic resonance imaging (MRI) technique, we investigated BBB permeability in individuals with LC and its relationship to cognitive function. We hypothesized that LC individuals would show greater BBB permeability than recovered individuals, and that higher permeability would correlate with poorer cognition. Ninety-seven participants meeting the 2024 NASEM definition of LC with at least one neuropsychiatric symptom and 31 recovered controls completed an MRI scan and cognitive testing. BBB permeability was assessed using water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) MRI, which estimates the permeability-surface-area product (PS) of arterially labeled water entering the brain. Cognitive performance was summarized into eight factor scores derived from principal components analysis. Compared to controls, the LC group was older (M = 47 vs. 39 years, P = 0.003), less educated (P = 0.02), more likely female (P = 0.04), and had higher hospitalization rates for COVID-19 (P = 0.02). PS was significantly elevated in the LC group after adjusting for age and sex (B = 18.59, SE = 6.11, β = 0.28, P = 0.003). No significant group differences were found in cerebral blood flow, extraction fraction (E), or brain volume. Within the LC group, higher PS was associated with poorer motor function, but not with other cognitive domains. These findings indicate subtle but persistent BBB disruption in LC individuals over two years post-infection, with a potential link to motor dysfunction. This supports prior evidence of BBB changes following severe COVID-19 and suggests that BBB integrity may be a long-term biomarker of neuropsychiatric complications in LC.

◆Metabolic adaptation and fragility in healthy 3D in vitro skeletal muscle tissues exposed to chronic fatigue syndrome and Long COVID-19 sera【IOP SCIENCE　2025年8月8日】

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long Covid-19 (LC-19) are complex conditions with no diagnostic markers or consensus on disease progression. Despite extensive research, no in vitro model exists to study skeletal muscle wasting, peripheral weakness, or potential therapies. We developed 3D in vitro skeletal muscle tissues to map muscle adaptations to patient sera over time. Short exposures (48 H) to patient sera led to a significant reduction in muscle contractile strength. Transcriptomic analysis revealed the upregulation of protein translation, glycolytic enzymes, disturbances in calcium homeostasis, hypertrophy, and mitochondrial hyperfusion. Structural analyses confirmed myotube hypertrophy and elevated mitochondrial oxygen consumption In ME/CFS. While muscles initially adapted by increasing glycolysis, prolonged exposure (96–144 H) caused muscle fragility and weakness, with mitochondria fragmenting into a toroidal conformation. We propose that skeletal muscle tissue in ME/CFS and LC-19 progresses through a hypermetabolic state, leading to severe muscular and mitochondrial deterioration. This is the first study to suggest such transient metabolic adaptation.

◆ME/CFS and PASC Patient-Derived Immunoglobulin Complexes Disrupt Mitochondrial Function and Alter Inflammatory Marker Secretion【medRxiv　2025年8月10日】

Abstract

Autoimmunity is a key clinical feature in both post-infectious Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of COVID (PASC). Passive transfer of immunoglobulins from patients’ sera into mice induces some clinical features of PASC. IgG-induced transfer of disease phenotypes has long been appreciated, yet the exact mechanism of disease development remains largely elusive. Here, we demonstrate that IgG isolated from post-infectious ME/CFS patients selectively induces mitochondrial fragmentation in human endothelial cells, thereby altering mitochondrial energetics. This effect is lost upon cleavage of IgG into its Fab and Fc fragments. The digested Fab fragment from ME/CFS alone was able to alter the mitochondrial energetics, resembling the effect of intact IgG. In contrast, the Fc fragment alone induced a hypometabolic phenotype characterized by a trend towards reduced overall ATP content. IgG from ME/CFS and PASC patients induced distinct but separate cytokine secretion profiles in healthy PBMCs. Proteomics analysis of IgG-bound immune complexes revealed significant changes within the immune complexes of ME/CFS patients, affecting extracellular matrix organization, while the same from PASC patients pointed towards alterations in hemostasis and blood clot regulation. We demonstrate that IgGs from ME/CFS patients carry a chronic protective stress response that promotes mitochondrial adaptation via fragmentation, without altering mitochondrial ATP generation capacity in endothelial cells. Together, these results highlight a potential pathogenic role of IgG in post-infectious ME/CFS and point to novel therapeutic strategies targeting antibody-mediated metabolic dysregulation.

◆Association Between COVID-19 Infection and Thyroid Cancer Development: A Retrospective Cohort Study Using the TriNetX Database【MDPI　2025年8月8日】

Abstract

Background: Coronavirus Disease 2019 has been associated with dysfunction in multiple endocrine organs, including the thyroid gland. While evidence suggests SARS-CoV-2 may influence thyroid function and promote oncogenesis through inflammation and cytokine storms, its role in thyroid cancer remains unclear. This study investigates whether COVID-19 is associated with an increased risk of thyroid cancer development.
Methods: We conducted a retrospective cohort study using the TriNetX global federated health research database, encompassing data from 151 healthcare organizations. Adult patients with confirmed COVID-19 between 1 December 2019 and 31 December 2023, were included and compared to a matched cohort without COVID-19. Patients with prior thyroid cancer history or who had received COVID-19 vaccination were excluded in both groups. Propensity score matching (1:1) was performed for age, gender, and overweight/obesity status. The primary outcome was that new-onset thyroid cancer was diagnosed at least one year after COVID-19 diagnosis. Hazard ratios were calculated using Cox proportional hazards models, and subgroup analyses were performed based on age, gender, thyroid function status and treatment modalities.
Results: After matching, a significantly higher thyroid cancer incidence was observed between the post-COVID and non-COVID groups. Subgroup analysis revealed a significantly higher risk of thyroid cancer development following COVID-19 diagnosis in patients who developed hyperthyroidism (HR 2.14, 95% CI: 1.04–4.46) or hypothyroid-ism (HR 1.83, 95% CI: 1.12–2.97) compared with the non-COVID population. Male patients also exhibited a higher risk of thyroid cancer after COVID-19 (HR 1.22, 95% CI 1.02–1.46). For patients with hyperthyroidism or hypothyroidism, those who had prior COVID-19 exhibited a relatively higher risk of developing thyroid cancer than those without a history of COVID-19 (HR 4.387, 95% CI: 2.08–9.24 for hyperthyroidism; HR 2.58, 95% CI: 1.58–4.22 for hypothyroidism).
Conclusions: Patients with COVID-19 exhibited an increase in thyroid cancer risk, with specific subgroups—male adults and those with post-infectious thyroid dysfunction—also exhibiting increased risk. These findings suggest a potential relationship between SARS-CoV-2 and thyroid oncogenesis, warranting further prospective research.

◆Variability in Long COVID Definitions and Validation of Published Prevalence Rates【JAMA Network　2025年8月12日】

Abstract

Importance Long COVID definitions vary widely, and no consensus exists on how to accurately measure its prevalence, complicating both clinical care and research.

Objective To assess long COVID prevalence using various definitions from published literature.

Design, Setting, and Participants This prospective, multicenter cohort study used data from the longitudinal Innovative Support for Patients With SARS-CoV-2 Infections Registry (INSPIRE). Participants aged 18 years or older with symptoms suggestive of COVID-19 illness at the time of their index SARS-CoV-2 test enrolled at 8 sites across the US from December 11, 2020, through August 29, 2022, with follow-up surveys collected through February 28, 2023.

Exposure Positive or negative SARS-CoV-2 test result at the time of acute symptoms.

Main Outcomes and Measures Long COVID prevalence among INSPIRE participants with a positive vs negative index SARS-CoV-2 test, based on long COVID definitions in published literature. Secondary outcomes were sensitivity and specificity of published definitions compared with self-reported long COVID.

Results A total of 4575 INSPIRE participants were included (mean [SD] age, 40.40 [14.58] years). Most were female (3013 of 4448 [67.7%]) and aged 18 to 49 years (3338 of 4541 [73.5%]). Applying 5 published definitions for long COVID yielded a prevalence that ranged from 30.84% (95% CI, 29.33%-32.40%) to 42.01% (95% CI, 40.37%-43.66%) at 3 months and 14.23% (95% CI, 13.01%-15.55%) to 21.94% (95% CI, 20.47%-23.47%) at 6 months postinfection; in the 5 comparator studies, reported prevalence of long COVID at 1 to 5 months postinfection ranged from 2.6% (≥84 days) to 47.4% (3-5 months) and at 6 or more months postinfection ranged from 10.0% (95% CI, 8.8%-11.0%) to 61.9% (6-11 months). Using participants’ self-reported long COVID as a criterion standard, existing published definitions had low-to-moderate sensitivity (up to 66.32% [95% CI, 62.59%-69.90%] at 3 months and 45.53% [95% CI, 41.51%-49.60%] at 6 months) and high specificity (up to 81.29% [95% CI, 79.32%-83.15%] at 3 months and 94.26% [95% CI, 92.98%-95.37%]) at 6 months.

Conclusions and Relevance In this cohort study, variability in long COVID prevalence across published definitions highlights the need for a standardized, validated definition to improve clinical recognition and research comparability, ultimately guiding more accurate diagnosis and treatment strategies.

◆Possible long COVID biomarker: identification of SARC-CoV-2 related protein(s) in Serum Extracellular Vesicles【SPRINGER NATURE　2025年7月21日】

Abstract

Emerging evidence suggests that SARS-CoV-2 RNA and viral antigens can persist in diverse tissues- (lung, brain, muscles, lymph nodes, and plasma)- for months to years after acute infection, and may be pathogenic for common long COVID symptoms. Extracellular vesicles (EVs)- nanosized vesicles (30–1000 nm) which facilitate intracellular communication of bioactive molecules such as proteins, lipids, nucleic acids, and metabolites – have been found to harbor other viral RNA and proteins, and may potentiate viral replication, immune activation and inflammation. We propose that EVs with viral contents may serve as a potential biomarker in long COVID.

Blood samples were collected from 14 adults (aged ≥ 18 years) with a documented history of SARS-CoV-2 infection (confirmed via PCR or patient report) and persistent long COVID symptoms proposed by CDC and WHO (> 12 weeks since initial SARS-CoV-2 infection) including fatigue, dyspnea, exercise intolerance, or post-exertional malaise (PEM). The cohort was demographically and clinically diverse, including 43% women and 43% Hispanic/Latino participants. The majority (79%) were not hospitalized during their initial infection, and only one participant was unvaccinated at the time of study entry. Obesity was common (mean BMI 32.5 ± 8.4), and baseline physical activity levels were predominantly sedentary or limited to walking. The mean duration between initial SARS-CoV-2 infection and study enrollment was 17 ± 10 months. For further details about methods, see our previous publication. Samples were obtained in response to acute incremental exercise (at rest and peak exercise), both before and after completion of the exercise training program. EVs were isolated from serum using precipitation kits (EQULTRA-20A-1, SBI Inc.) and analyzed by mass spectrometry-based proteomics. To assess whether any of the detected peptides were associated with SARS-CoV-2, the SARS-CoV-2 proteome (17 reviewed entries) was obtained from UniProt (UP000464024). EV samples were queried against a predicted SARS-CoV-2 spectral library in Spectronaut using default parameters.

◆Risk Factors for Insomnia in Long COVID — Can regular exercise be protective against persistent insomnia?【MEDPAGE TODAY : Nicole Lou　2025年8月13日】

As new COVID-19 variants continue to emerge, so too does new evidence identifying people more vulnerable to persistent insomnia after viral infection.

In a recent study, a survey of medical students from China found that those with self-reported COVID-19 infections were significantly more likely to develop psychological symptoms even after pandemic restrictions were lifted in the country.

The risk factors associated with insomnia onset were moderate to severe symptoms during acute COVID-19 illness (e.g., sleep disturbances, decreased attention, and breathlessness), whereas regular exercise seemed protective against post-infection insomnia, according to Fei Wang, MD, PhD, of Nanjing Medical University, China, and colleagues.

“Despite the lack of persistent virus in the central nervous system, ongoing peripheral inflammation contributes to neurological sequelae of COVID-19. This study finds that reduced attention/memory during the acute stage predicts long-term insomnia, suggesting that cognitive impairment and sustained inflammation increase the risk of long-COVID insomnia,” study authors reported in Brain, Behavior, & Immunity-Healthopens in a new tab or window.

Their work adds to the large, and growing, literature from researchers trying to make sense of COVID-associated insomnia using real-world data.

Insomnia and Long COVID

Several years after the height of the pandemic, insomnia is often cited as one of the symptoms of long COVIDopens in a new tab or window, also known as post-acute sequelae of COVID-19 (PASC), that describes the persistent health problems lasting well after acute recovery from acute COVID-19 infection.

“Data would suggest that there is a gradual reduction in the number of persons with insomnia symptoms as time passes post infection. However, there is evidence that it may persist greater than 12 months or more in some individuals,” said Stuart Quan, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston.

In one recent report, there was a 50% prevalence of insomniaopens in a new tab or window reported among people at a COVID-specific clinic nearly 6 months after infection; persistent insomnia was prevalent in 42% in the subset of participants who had a follow-up another 6 months later, researchers found.

Other findings, this time coming from the Massachusetts General Brigham health system, showed that more than a quarter of people with sleeping difficulties after COVIDopens in a new tab or window were still having these issues beyond 12 months after infection.

Quan said the link between COVID-19 and insomnia is bidirectional: the risk of insomnia goes up with COVID-19 infection, but insomniacs are also more prone to contracting COVID-19 and developing PASC in the first place.

Investigators are still trying to understand why some people develop long COVID insomnia and not others.

In the acute phase of SARS-CoV-2 infection, temporary sleeping difficulties are often explained by disruptions in brain regions controlling sleep, respiratory symptoms like cough and shortness of breath, and stress and anxiety.

However, with persistent insomnia long past the acute infection, there is also evidence that the virus is neurotropic, such that traces of the virus can be found in various parts of the brain, Quan explained. “This might explain some insomnia symptoms with long COVID.”

Indeed, imaging evidence shows that COVID-recovered individuals can show significantly higher MRI abnormalitiesopens in a new tab or window in regions of the frontal lobe and brain stem linked with fatigue, insomnia, anxiety, depression, headaches, and cognitive problems. One study of long COVID patients with brain fog showed that structural changes in the brain accompany increased greater blood-brain barrier permeabilityopens in a new tab or window that can mean greater entry of inflammatory mediators and immune cells.

Who Is Most at Risk?

Wang and colleagues’ longitudinal study recruited Chinese medical students as a group facing “significant academic and psychosocial stressors during COVID-19, including campus closures and career uncertainty, while some also served on pandemic frontlines, raising their infection risk. This dual burden of academic pressures and frontline exposures may render them particularly susceptible to long-term psychiatric sequelae of COVID-19.”

As part of the study, participants reported their psychological symptoms during life under China’s COVID-19 restrictions (March 2020 and February 2022) and after these restrictions were lifted (August 2023).

Included were 2,359 young adults averaging just over 22 years old, of whom 63% were women and over 98% identified as Han Chinese. Over 85% reported prior COVID-19 infection at the time of one of their study questionnaires.

Compared to those with no COVID-19 history, the ever-infected group was more likely to develop insomnia (OR 1.83, 95% CI 1.05-3.21) by the second survey.

Risk factors significantly associated with insomnia after COVID-19 infection included:

  • Sleep disturbances during acute infection (OR 1.85 mild and 2.20 moderate to severe)
  • Decreased attention/memory during acute infection (OR 1.75 mild and 2.47 moderate to severe)
  • Breathlessness during acute infection (OR 2.05 moderate to severe)
  • Fear of COVID-19 virus (OR 2.23 moderate to severe)
  • Any alcohol consumption (OR 1.67)

Meanwhile, any regular physical activity was negatively associated with insomnia occurring after COVID-19, whether done 1-3 days per week (OR 0.60, 95% CI 0.38-0.95) or 4-7 days per week (OR 0.54, 95% CI 0.33-0.88).

Neither depression nor anxiety saw an uptick after COVID-19 infection in this report.

◆Severity-specific immune landscape of COVID-19 revealed by single-cell sequencing【nature scientific reports　2025年8月12日】

Abstract

The Coronavirus disease 2019 (COVID-19) has rapidly become the worst pandemic since the 1918 influenza pandemic. Studies have shown that severe COVID-19 patients have immune dysfunction. To characterize the dysregulated immune response to SARS-CoV-2 infection, we performed a comprehensive analysis of scRNA-seq and scV(D)J-seq in peripheral blood mononuclear cells from mild, moderate, and severe patients. We observed that as the severity of the disease increased, several CD8 + T cell subsets and Treg cells continued to decrease, while CD4 + T subsets, natural killer cells and plasma cells continued to increase. Several aberrantly expressed biomarkers associated with SARS-CoV-2 severity were identified. For example, RPS26 was down-regulated, while the ZFP36, IL-32, and IgM genes were up-regulated with increasing disease severity. Functional analysis showed multiple immune-related pathways, such as interleukin-2 and interleukin-10 production pathways, were dysregulated. As the disease severity increased, intercellular interactions fluctuated. Particularly, naive CD8 + T cells regulated memory and activated CD8 + T cells, and the weakening in Treg cells’ regulation of other immune cells was especially obvious. The expression of the MIF signaling pathway, mediated by CD74 + CXCR4, was higher throughout SARS-CoV-2 infection and the intensity of immune cell-cell interactions mediated by TGF-β was enhanced from mild to severe. Subsequently, scV(D)J-seq analysis showed a decreasing trend in the number of clonotypes, repertoire diversity and clonotypes overlap of monoclonal B cell receptor (BCR) and T cell receptor (TCR) as the SARS-CoV-2 progresses. The CDR3 sequence length in COVID-19-specific clonotypes showed a bias towards being longer as the severity of COVID-19 increases. Our findings may provide new clues for understanding COVID-19 immunopathogenesis and help identify optimal biomarkers for new therapeutic strategies.