Exploring the mechanisms of long COVID: Insights from computational analysis of SARS-CoV-2 gene expression and symptom associations

Abstract:

Long coronavirus disease (COVID) has emerged as a global health issue, affecting a substantial number of people worldwide. However, the underlying mechanisms that contribute to the persistence of symptoms in long COVID remain obscure, impeding the development of effective diagnostic and therapeutic interventions.

In this study, we utilized computational methods to examine the gene expression profiles of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their associations with the wide range of symptoms observed in long COVID patients. Using a comprehensive data set comprising over 255 symptoms affecting multiple organ systems, we identified differentially expressed genes and investigated their functional similarity, leading to the identification of key genes with the potential to serve as biomarkers for long COVID.

We identified the participation of hub genes associated with G-protein-coupled receptors (GPCRs), which are essential regulators of T-cell immunity and viral infection responses. Among the identified common genes were CTLA4, PTPN22, KIT, KRAS, NF1, RET, and CTNNB1, which play a crucial role in modulating T-cell immunity via GPCR and contribute to a variety of symptoms, including autoimmunity, cardiovascular disorders, dermatological manifestations, gastrointestinal complications, pulmonary impairments, reproductive and genitourinary dysfunctions, and endocrine abnormalities. GPCRs and associated genes are pivotal in immune regulation and cellular functions, and their dysregulation may contribute to the persistent immune responses, chronic inflammation, and tissue abnormalities observed in long COVID.

Targeting GPCRs and their associated pathways could offer promising therapeutic strategies to manage symptoms and improve outcomes for those experiencing long COVID. However, the complex mechanisms underlying the condition require continued study to develop effective treatments. Our study has significant implications for understanding the molecular mechanisms underlying long COVID and for identifying potential therapeutic targets. In addition, we have developed a comprehensive website (https://longcovid.omicstutorials.com/) that provides a curated list of biomarker-identified genes and treatment recommendations for each specific disease, thereby facilitating informed clinical decision-making and improved patient management. Our study contributes to the understanding of this debilitating disease, paving the way for improved diagnostic precision, and individualized therapeutic interventions.

Source: Das S, Kumar S. Exploring the mechanisms of long COVID: Insights from computational analysis of SARS-CoV-2 gene expression and symptom associations. J Med Virol. 2023 Sep;95(9):e29077. doi: 10.1002/jmv.29077. PMID: 37675861. https://pubmed.ncbi.nlm.nih.gov/37675861/

Reactive gliosis and neuroinflammation: prime suspects in the pathophysiology of post-acute neuroCOVID-19 syndrome

Abstract:

Introduction: As the repercussions from the COVID-19 pandemic continue to unfold, an ever-expanding body of evidence suggests that infection also elicits pathophysiological manifestations within the central nervous system (CNS), known as neurological symptoms of post-acute sequelae of COVID infection (NeuroPASC). Although the neurological impairments and repercussions associated with NeuroPASC have been well described in the literature, its etiology remains to be fully characterized.

Objectives: This mini-review explores the current literature that elucidates various mechanisms underlining NeuroPASC, its players, and regulators, leading to persistent neuroinflammation of affected individuals. Specifically, we provide some insights into the various roles played by microglial and astroglial cell reactivity in NeuroPASC and how these cell subsets potentially contribute to neurological impairment in response to the direct or indirect mechanisms of CNS injury.

Discussion: A better understanding of the mechanisms and biomarkers associated with this maladaptive neuroimmune response will thus provide better diagnostic strategies for NeuroPASC and reveal new potential mechanisms for therapeutic intervention. Altogether, the elucidation of NeuroPASC pathogenesis will improve patient outcomes and mitigate the socioeconomic burden of this syndrome.

Source: Saucier J, Comeau D, Robichaud GA, Chamard-Witkowski L. Reactive gliosis and neuroinflammation: prime suspects in the pathophysiology of post-acute neuroCOVID-19 syndrome. Front Neurol. 2023 Aug 24;14:1221266. doi: 10.3389/fneur.2023.1221266. PMID: 37693763; PMCID: PMC10492094. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10492094/ (Full text)

Neuroimmunological Effect of Vitamin D on Neuropsychiatric Long COVID Syndrome: A Review

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19). COVID-19 is now recognized as a multiorgan disease with a broad spectrum of manifestations. A substantial proportion of individuals who have recovered from COVID-19 are experiencing persistent, prolonged, and often incapacitating sequelae, collectively referred to as long COVID. To date, definitive diagnostic criteria for long COVID diagnosis remain elusive.
An emerging public health threat is neuropsychiatric long COVID, encompassing a broad range of manifestations, such as sleep disturbance, anxiety, depression, brain fog, and fatigue. Although the precise mechanisms underlying the neuropsychiatric complications of long COVID are presently not fully elucidated, neural cytolytic effects, neuroinflammation, cerebral microvascular compromise, breakdown of the blood–brain barrier (BBB), thrombosis, hypoxia, neurotransmitter dysregulation, and provoked neurodegeneration are pathophysiologically linked to long-term neuropsychiatric consequences, in addition to systemic hyperinflammation and maladaptation of the renin–angiotensin–aldosterone system.
Vitamin D, a fat-soluble secosteroid, is a potent immunomodulatory hormone with potential beneficial effects on anti-inflammatory responses, neuroprotection, monoamine neurotransmission, BBB integrity, vasculometabolic functions, gut microbiota, and telomere stability in different phases of SARS-CoV-2 infection, acting through both genomic and nongenomic pathways.
Here, we provide an up-to-date review of the potential mechanisms and pathophysiology of neuropsychiatric long COVID syndrome and the plausible neurological contributions of vitamin D in mitigating the effects of long COVID.
Source: Chen T-B, Chang C-M, Yang C-C, Tsai I-J, Wei C-Y, Yang H-W, Yang C-P. Neuroimmunological Effect of Vitamin D on Neuropsychiatric Long COVID Syndrome: A Review. Nutrients. 2023; 15(17):3802. https://doi.org/10.3390/nu15173802 https://www.mdpi.com/2072-6643/15/17/3802 (Full text)

Long COVID: A Molecular, Cellular and Histopathology Overview

Abstract:

Long COVID has been studied as different sequelae that some individuals can develop after the acute phase of the disease. Persistent symptoms such as dry cough, fatigue, and dyspnea can remain after six months of COVID-19 cure. Others such as lung fibrosis, kidney injury, and thrombotic risk also are observed. Here, a deep review of each human organ and system infected by the virus was performed aiming to show how molecules expression and cell signaling can induce the organism cure or injuries and, subsequently sequelae. The review also suggests the importance of public health surveillance for these cases including a more comprehensive analysis of molecular biology tools that can clarify and assist in the prognosis, treatment, and preventive methods for potentially more serious disorders in post-COVID-19 patients.

Source: da Silva Barros, B. , de Oliveira Cruz, L. , de Sousa, G. , Souza-Silva, G. , de Lima, M. , Oliveira, E. , Silva, A. , Macêdo, L. , Leal, L. , Marcos, B. , Elsztein, C. , Invenção, M. , de Freitas, A. and Moutinho-Melo, C. (2023) Long COVID: A Molecular, Cellular and Histopathology Overview. Journal of Biosciences and Medicines, 11, 90-113. doi: 10.4236/jbm.2023.119009. https://www.scirp.org/journal/paperinformation.aspx?paperid=127523 (Full text)

Neutrophil Extracellular Traps and Long COVID

Abstract:

Post-acute COVID-19 sequelae, commonly known as long COVID, encompasses a range of systemic symptoms experienced by a significant number of COVID-19 survivors. The underlying pathophysiology of long COVID has become a topic of intense research discussion. While chronic inflammation in long COVID has received considerable attention, the role of neutrophils, which are the most abundant of all immune cells and primary responders to inflammation, has been unfortunately overlooked, perhaps due to their short lifespan.

In this review, we discuss the emerging role of neutrophil extracellular traps (NETs) in the persistent inflammatory response observed in long COVID patients. We present early evidence linking the persistence of NETs to pulmonary fibrosis, cardiovascular abnormalities, and neurological dysfunction in long COVID.

Several uncertainties require investigation in future studies. These include the mechanisms by which SARS-CoV-2 brings about sustained neutrophil activation phenotypes after infection resolution; whether the heterogeneity of neutrophils seen in acute SARS-CoV-2 infection persists into the chronic phase; whether the presence of autoantibodies in long COVID can induce NETs and protect them from degradation; whether NETs exert differential, organ-specific effects; specifically which NET components contribute to organ-specific pathologies, such as pulmonary fibrosis; and whether senescent cells can escape clearance and drive NET formation in long COVID. Answering these questions may pave the way for the development of clinically applicable strategies targeting NETs, providing relief for this emerging health crisis.

Source: Shafqat, A., Omer, M., Albalkhi, I., Alabdul Razzak, G., Abdulkader, H., Abdul Rab, S., … & Yaqinuddin, A. Neutrophil Extracellular Traps and Long COVID. Frontiers in Immunology, 14, 1254310. https://www.frontiersin.org/articles/10.3389/fimmu.2023.1254310/abstract

Impaired parasympathetic function in long-COVID postural orthostatic tachycardia syndrome – a case-control study

Abstract:

Purpose: Eighty percent of patients infected by SARS-CoV-2 report persistence of one symptom beyond the 4-week convalescent period. Those with orthostatic tachycardia and orthostatic symptoms mimicking postural tachycardia syndrome, they are defined as Long-COVID POTS [LCP]. This case-control study investigated potential differences in autonomic cardiovascular regulation between LCP patients and healthy controls.

Methods: Thirteen LCP and 16 healthy controls, all female subjects, were studied without medications. Continuous blood pressure and ECG were recorded during orthostatic stress test, respiratory sinus arrhythmia, and Valsalva maneuver. Time domain and power spectral analysis of heart rate [HR] and systolic blood pressure [SBP] variability were computed characterizing cardiac autonomic control and sympathetic peripheral vasoconstriction.

Results: LCP had higher deltaHR (+ 40 ± 6 vs. + 21 ± 3 bpm, p = 0.004) and deltaSBP (+ 8 ± 4 vs. -1 ± 2 mmHg, p = 0.04) upon standing; 47% had impaired Valsalva maneuver ratio compared with 6.2% in controls (p = 0.01). Spectral analysis revealed that LCP had lower RMSSD (32.1 ± 4.6 vs. 48.9 ± 6.8 ms, p = 0.04) and HFRRI, both in absolute (349 ± 105 vs. 851 ± 253ms2, p = 0.03) and normalized units (32 ± 4 vs. 46 ± 4 n.u., p = 0.02). LFSBP was similar between groups.

Conclusions: LCP have reduced cardiovagal modulation, but normal sympathetic cardiac and vasoconstrictive functions. Impaired parasympathetic function may contribute to the pathogenesis of Long-COVID POTS syndrome.

Source: Rigo S, Urechie V, Diedrich A, Okamoto LE, Biaggioni I, Shibao CA. Impaired parasympathetic function in long-COVID postural orthostatic tachycardia syndrome – a case-control study. Bioelectron Med. 2023 Sep 6;9(1):19. doi: 10.1186/s42234-023-00121-6. PMID: 37670400; PMCID: PMC10481607. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10481607/ (Full text)

The global challenges of the long COVID-19

Abstract:

COVID-19 may lead to a perseverance of symptoms after recovery from the disease, a condition known as long COVID, characterized by continual cognitive, somatic and behavioral symptoms. SARS-CoV-2 infection triggers different molecular to tissue level events, given by the inherent features of each patient. The potential pathological changes which determine the array of symptoms are arduous to anticipate.

There is an increasing interest to develop treatment strategies for survivors who experience a long COVID. In this respect, considering the anti-inflammatory, anti-oxidative and cytoprotective effects of melatonin (MEL) on viral infections, its potential links with COVID-19 should be researched. Several studies suggest that administration of MEL may prevent clinical deterioration and even death in patients with acute and long COVID-19.

This paper briefly reviews the current status of knowledge of the pathogenic, clinical, and therapeutic features of Long COVID-19 and forthcoming directions for research and implications for the management and therapy of the disease are analyzed.

Source: Leonor Chacin-Bonilla. The global challenges of the long COVID-19. Journal of Clinical Images and Medical Case Reports. ISSN 2766-7820 https://jcimcr.org/pdfs/JCIMCR-v4-2512.pdf (Full text)

Post-COVID symptoms are associated with endotypes reflecting poor inflammatory and hemostatic modulation

Abstract:

Introduction: Persistent symptoms after COVID-19 infection (“long COVID”) negatively affects almost half of COVID-19 survivors. Despite its prevalence, its pathophysiology is poorly understood, with multiple host systems likely affected. Here, we followed patients from hospital to discharge and used a systems-biology approach to identify mechanisms of long COVID.

Methods: RNA-seq was performed on whole blood collected early in hospital and 4-12 weeks after discharge from 24 adult COVID-19 patients (10 reported post-COVID symptoms after discharge). Differential gene expression analysis, pathway enrichment, and machine learning methods were used to identify underlying mechanisms for post-COVID symptom development.

Results: Compared to patients with post-COVID symptoms, patients without post-COVID symptoms had larger temporal gene expression changes associated with downregulation of inflammatory and coagulation genes over time. Patients could also be separated into three patient endotypes with differing mechanistic trajectories, which was validated in another published patient cohort. The “Resolved” endotype (lowest rate of post-COVID symptoms) had robust inflammatory and hemostatic responses in hospital that resolved after discharge. Conversely, the inflammatory/hemostatic responses of “Suppressive” and “Unresolved” endotypes (higher rates of patients with post-COVID symptoms) were persistently dampened and activated, respectively. These endotypes were accurately defined by specific blood gene expression signatures (6-7 genes) for potential clinical stratification.

Discussion: This study allowed analysis of long COVID whole blood transcriptomics trajectories while accounting for the issue of patient heterogeneity. Two of the three identified and externally validated endotypes (“Unresolved” and “Suppressive”) were associated with higher rates of post-COVID symptoms and either persistently activated or suppressed inflammation and coagulation processes. Gene biomarkers in blood could potentially be used clinically to stratify patients into different endotypes, paving the way for personalized long COVID treatment.

Source: An AY, Baghela A, Zhang PGY, Blimkie TM, Gauthier J, Kaufmann DE, Acton E, Lee AHY, Levesque RC, Hancock REW. Post-COVID symptoms are associated with endotypes reflecting poor inflammatory and hemostatic modulation. Front Immunol. 2023 Aug 23;14:1243689. doi: 10.3389/fimmu.2023.1243689. PMID: 37680625; PMCID: PMC10482103. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10482103/ (Full text)

Structural and functional impairments of skeletal muscle in patients with post-acute sequelae of SARS-CoV-2 infection

Abstract:

Background: Following acute COVID-19, a substantial proportion of patients showed symptoms and sequelae for several months, namely the post-acute sequelae of COVID-19 (PASC) syndrome. Major phenomena are exercise intolerance, muscle weakness and fatigue. We aimed to investigate the physiopathology of exercise intolerance in patients with PASC syndrome by structural and functional analyses of skeletal muscle.

Methods: At least 3 months after infection, non-hospitalized patients with PASC (n=11,ys:54±11; PASC) and patients without long-term symptoms (n=12,ys:49±9; CTRL) visited the laboratory on four non-consecutive days. Spirometry, lung diffusion capacity and quality of life were assessed at rest. Cardiopulmonary incremental exercise test was performed. Oxygen consumption (VO2) kinetics were determined by moderate-intensity exercises. Muscle oxidative capacity (k) was assessed by near-infrared spectroscopy. Histochemical analysis, O2 flux (JO2) by high-resolution respirometry, and quantification of key molecular markers of mitochondrial biogenesis and dynamics were performed in vastus lateralis biopsies.

Results: Pulmonary and cardiac functions were within normal range in all patients. VO2peak was lower in PASC than CTRL (24.7±5.0vs32.9±7.4mL*min-1*kg-1, respectively, P<.05). VO2 kinetics was slower in PASC than CTRL (41±12vs30±9s-1, P<.05). k was lower in PASC than CTRL (1.54±0.49vs2.07±0.51min-1, P<.05). Citrate synthase, PGC1alfa and JO2 for mitochondrial complex II were significantly lower in PASC vs CTRL (all P<.05).

Conclusion: In our cohort of patients with PASC, we showed limited exercise tolerance mainly due to “peripheral” determinants. Substantial reductions were observed for biomarkers of mitochondrial function, content, and biogenesis. PASC syndrome appears to negatively impact skeletal muscle function, although the disease is an heterogenous condition.

Source: Colosio M, Brocca L, Gatti M, Neri M, Crea E, Cadile F, Canepari M, Pellegrino MA, Polla B, Porcelli S, Bottinelli R. Structural and functional impairments of skeletal muscle in patients with post-acute sequelae of SARS-CoV-2 infection. J Appl Physiol (1985). 2023 Sep 7. doi: 10.1152/japplphysiol.00158.2023. Epub ahead of print. PMID: 37675472. https://journals.physiology.org/doi/abs/10.1152/japplphysiol.00158.2023 (Full text available as PDF file)

Unveiling the Mysteries of Long COVID Syndrome: Exploring the Distinct Tissue and Organ Pathologies Linked to Prolonged COVID-19 Symptoms

Abstract:

The ongoing battle against the coronavirus disease 2019 (COVID-19) pandemic has encountered a complex aspect with the emergence of long COVID syndrome. There has been a growing prevalence of COVID-19-affected individuals experiencing persistent and diverse symptoms that extend beyond the initial infection phase. The phenomenon known as long COVID syndrome raises significant questions about the underlying mechanisms driving these enduring symptoms.

This comprehensive analysis explores the complex domain of long COVID syndrome with a view to shed light on the specific tissue and organ pathologies contributing to its intricate nature. This review aims to analyze the various clinical manifestations of this condition across different bodily systems and explore potential mechanisms such as viral persistence, immune dysregulation, autoimmunity, and molecular mimicry. The goal is to gain a better understanding of the intricate network of pathologies contributing to long COVID syndrome.

Understanding these distinct pathological indicators provides valuable insights into comprehending the complexities of long COVID and presents opportunities for developing more accurate diagnostic and therapeutic strategies, thereby improving the quality of patient care by effectively  addressing the ever-changing medical challenge in a more focused manner.

Source: Sapna F, Deepa F, Sakshi F, et al. (September 02, 2023) Unveiling the Mysteries of Long COVID Syndrome: Exploring the Distinct Tissue and Organ Pathologies Linked to Prolonged COVID-19 Symptoms. Cureus 15(9): e44588. DOI 10.7759/cureus.44588. https://assets.cureus.com/uploads/review_article/pdf/182615/20230903-23556-1g56qsl.pdf (Full text)