Category: Overlapping Illnesses

Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches

Abstract:

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has introduced the medical community to the phenomenon of long COVID, a condition characterized by persistent symptoms following the resolution of the acute phase of infection. Among the myriad of symptoms reported by long COVID sufferers, chronic fatigue, cognitive disturbances, and exercise intolerance are predominant, suggesting systemic alterations beyond the initial viral pathology. Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms.

This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction. Through a comprehensive analysis of the literature, we highlight the significance of mitochondrial health in the pathophysiology of long COVID, drawing parallels with similar clinical syndromes linked to post-infectious states in other diseases where mitochondrial impairment has been implicated.

We discuss potential therapeutic strategies targeting mitochondrial function, including pharmacological interventions, lifestyle modifications, exercise, and dietary approaches, and emphasize the need for further research and collaborative efforts to advance our understanding and management of long COVID. This review underscores the critical role of mitochondrial dysfunction in long COVID and calls for a multidisciplinary approach to address the gaps in our knowledge and treatment options for those affected by this condition.

Source: Molnar T, Lehoczki A, Fekete M, Varnai R, Zavori L, Erdo-Bonyar S, Simon D, Berki T, Csecsei P, Ezer E. Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches. Geroscience. 2024 Apr 26. doi: 10.1007/s11357-024-01165-5. Epub ahead of print. PMID: 38668888. https://link.springer.com/article/10.1007/s11357-024-01165-5 (Full text)

Oxidative Stress is a shared characteristic of ME/CFS and Long COVID

Abstract:

More than 65 million individuals worldwide are estimated to have Long COVID (LC), a complex multisystemic condition, wherein patients of all ages report fatigue, post-exertional malaise, and other symptoms resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). With no current treatments or reliable diagnostic markers, there is an urgent need to define the molecular underpinnings of these conditions.

By studying bioenergetic characteristics of peripheral blood lymphocytes in over 16 healthy controls, 15 ME/CFS, and 15 LC, we find both ME/CFS and LC donors exhibit signs of elevated oxidative stress, relative to healthy controls, especially in the memory subset. Using a combination of flow cytometry, bulk RNA-seq analysis, mass spectrometry, and systems chemistry analysis, we also observed aberrations in ROS clearance pathways including elevated glutathione levels, decreases in mitochondrial superoxide dismutase levels, and glutathione peroxidase 4 mediated lipid oxidative damage.

Critically, these changes in redox pathways show striking sex-specific trends. While females diagnosed with ME/CFS exhibit higher total ROS and mitochondrial calcium levels, males with an ME/CFS diagnosis have normal ROS levels, but larger changes in lipid oxidative damage. Further analyses show that higher ROS levels correlates with hyperproliferation of T cells in females, consistent with the known role of elevated ROS levels in the initiation of proliferation. This hyperproliferation of T cells can be attenuated by metformin, suggesting this FDA-approved drug as a possible treatment, as also suggested by a recent clinical study of LC patients.

Thus, we report that both ME/CFS and LC are mechanistically related and could be diagnosed with quantitative blood cell measurements. We also suggest that effective, patient tailored drugs might be discovered using standard lymphocyte stimulation assays.

Source: Vishnu Shankar, Julie Wilhelmy, Basil Michael, Layla Cervantes, Vamsee Mallajosyula, Ronald Davis, Michael Snyder, Shady Younis,
William H Robinson, Sadasivan Shankar, Paul Mischel, Hector Bonilla, Mark Davis. Oxidative Stress is a shared characteristic of ME/CFS and Long COVID. bioRxiv 2024.05.04.592477; doi: https://doi.org/10.1101/2024.05.04.592477  https://www.biorxiv.org/content/10.1101/2024.05.04.592477v1https://www.biorxiv.org/content/10.1101/2024.05.04.592477v1 (Full text available as PDF file)

Long COVID: lights and shadows on the clinical characterization of this emerging pathology

Abstract:

More than 800 million individuals have contracted SARSCOV2 infection worldwide. It was estimated that almost 10-20% of these might suffer from Long COVID. It is a multisystemic syndrome, which negatively affects the quality of life with a significant burden of health loss compared to COVID negative individuals. Moreover, the risk of sequelae still remains high at 2 years in both nonhospitalized and hospitalized individuals.

This review summarizes studies regarding long COVID and clarifies the definitions, the risk factors and the management of this syndrome. Finally, it delves into the most frequent long-term outcomes, especially postural orthostatic tachycardia syndrome” (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), brain fog, and their therapeutical possibilities.

Source: Cogliandro V, Bonfanti P. Long COVID: lights and shadows on the clinical characterization of this emerging pathology. New Microbiol. 2024 May;47(1):15-27. PMID: 38700879. https://pubmed.ncbi.nlm.nih.gov/38700879/

A Narrative Review on Gut Microbiome Disturbances and Microbial Preparations in ME/CFS: Implications for Long COVID

Abstract:

Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS) and Long COVID are characterized by debilitating post-exertional malaise and other core symptoms related to immune dysregulation resultant from post-viral infection, including mitochondrial dysfunction, chronic neuroinflammation and gut dysbiosis. The reported associations between altered microbiota composition and cardinal symptoms of ME/CFS and Long COVID, suggesting that use of microbial preparations, such as probiotics, by restoring the homeostasis of the brain-immune-gut axis may help in the management of symptoms in both conditions.

Therefore, this review aims to investigate the implications of alerted gut microbiome and assess the evidence supporting use of microbial-based preparations, including probiotics, synbiotics, postbiotics alone and/or in combination with other nutraceuticals in the management of fatigue, inflammation, as well as neuropsychiatric and gastrointestinal symptoms among patients with ME/CFS and Long COVID.

Source: Jurek, J.M.; Castro-Marrero, J. A Narrative Review on Gut Microbiome Disturbances and Microbial Preparations in ME/CFS: Implications for Long COVID. Preprints 2024, 2024042021. https://doi.org/10.20944/preprints202404.2021.v1  https://www.preprints.org/manuscript/202404.2021/v1 (Full text available as PDF file)

Investigation into the restoration of TRPM3 ion channel activity in post-COVID-19 condition: a potential pharmacotherapeutic target

Abstract:

Introduction: Recently, we reported that post COVID-19 condition patients also have Transient Receptor Potential Melastatin 3 (TRPM3) ion channel dysfunction, a potential biomarker reported in natural killer (NK) cells from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients. As there is no universal treatment for post COVID-19 condition, knowledge of ME/CFS may provide advances to investigate therapeutic targets. Naltrexone hydrochloride (NTX) has been demonstrated to be beneficial as a pharmacological intervention for ME/CFS patients and experimental investigations have shown NTX restored TRPM3 function in NK cells. This research aimed to: i) validate impaired TRPM3 ion channel function in post COVID-19 condition patients compared with ME/CFS; and ii) investigate NTX effects on TRPM3 ion channel activity in post COVID-19 condition patients.

Methods: Whole-cell patch-clamp was performed to characterize TRPM3 ion channel activity in freshly isolated NK cells of post COVID-19 condition (N = 9; 40.56 ± 11.26 years), ME/CFS (N = 9; 39.33 ± 9.80 years) and healthy controls (HC) (N = 9; 45.22 ± 9.67 years). NTX effects were assessed on post COVID-19 condition (N = 9; 40.56 ± 11.26 years) and HC (N = 7; 45.43 ± 10.50 years) where NK cells were incubated for 24 hours in two protocols: treated with 200 µM NTX, or non-treated; TRPM3 channel function was assessed with patch-clamp protocol.

Results: This investigation confirmed impaired TRPM3 ion channel function in NK cells from post COVID-19 condition and ME/CFS patients. Importantly, PregS-induced TRPM3 currents were significantly restored in NTX-treated NK cells from post COVID-19 condition compared with HC. Furthermore, the sensitivity of NK cells to ononetin was not significantly different between post COVID-19 condition and HC after treatment with NTX.

Discussion: Our findings provide further evidence identifying similarities of TRPM3 ion channel dysfunction between ME/CFS and post COVID-19 condition patients. This study also reports, for the first time, TRPM3 ion channel activity was restored in NK cells isolated from post COVID-19 condition patients after in vitro treatment with NTX. The TRPM3 restoration consequently may re-establish TRPM3-dependent calcium (Ca2+) influx. This investigation proposes NTX as a potential therapeutic intervention and TRPM3 as a treatment biomarker for post COVID-19 condition.

Source: Etianne Martini Sasso, Katsuhiko Muraki, Natalie Eaton-Fitch, Peter Smith, Andrew Jeremijenko, Paul Griffin, Sonya Marshall-Gradisnik. Investigation into the restoration of TRPM3 ion channel activity in post-COVID-19 condition: a potential pharmacotherapeutic target. Front. Immunol., 02 May 2024; Sec. Multiple Sclerosis and Neuroimmunology; Volume 15 – 2024 | https://doi.org/10.3389/fimmu.2024.1264702. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1264702/full (Full text)

Quantitative Proteomics of COVID-19 Recovered Patients Identifies Long-Term Changes in Sperm Proteins Leading to Cellular Stress in Spermatozoa

Abstract:

Following an initial recovery, COVID-19 survivors struggle with a spectrum of persistent medical complications, including fatigue, breathlessness, weight loss, hair loss, and attention deficits. Additionally, there is growing evidence of adverse effects of COVID-19 on the male reproductive system. This investigation seeks to understand the long-term ramifications on male fertility by examining hormonal profiles, semen parameters, and sperm proteome of recovered COVID-19 patients compared to controls.

The serum hormone profiles between the two groups showed minimal variations except for prolactin, cortisol, and testosterone levels. Testosterone levels were slightly lower, while prolactin and cortisol were elevated in COVID-19 cases compared to controls.

Though semen parameters exhibited no significant disparities between the COVID-19 and control groups, quantitative proteomics analysis revealed changes in sperm proteins. It identified 190 differentially expressed proteins, of which 161 were upregulated and 29 downregulated in COVID-19 cases.

Western blotting analysis validated the differential expression of serpin B4 and calpain 2. Bioinformatics analysis signifies cellular stress in the spermatozoa of COVID-19 recovered patients and thus, SOD and MDA levels in semen were measured. MDA levels were found to be significantly elevated, indicating lipid peroxidation in COVID-19 samples.

While the effects of COVID-19 on semen parameters may exhibit a potential for reversal within a short duration, the alterations it inflicts on sperm proteome are persisting consequences on male fertility. This study paves the path for further research and emphasizes the significance of comprehending the complex molecular processes underlying the long-term consequences of COVID-19 on male reproductive health.

Source: Chopra P, Tomar AK, Thapliyal A, Ranjan P, Datta SK, Yadav S. Quantitative Proteomics of COVID-19 Recovered Patients Identifies Long-Term Changes in Sperm Proteins Leading to Cellular Stress in Spermatozoa. Reprod Sci. 2024 Apr 24. doi: 10.1007/s43032-024-01560-5. Epub ahead of print. PMID: 38658489. https://pubmed.ncbi.nlm.nih.gov/38658489/

Blood transcriptomic analyses reveal persistent SARS-CoV-2 RNA and candidate biomarkers in post-COVID-19 condition

Abstract:

With an estimated 65 million individuals affected by post-COVID-19 condition (also known as long COVID), non-invasive biomarkers are direly needed to guide clinical management. To address this pressing need, we used blood transcriptomics in a general practice-based case-control study. Individuals with long COVID were diagnosed according to WHO criteria, and validated clinical scales were used to quantify patient-reported outcomes.

Whole blood samples were collected from 48 individuals with long COVID and 12 control individuals matched for age, sex, time since acute COVID-19, severity, vaccination status, and comorbidities (appendix 1 p 2). Digital transcriptomic analysis was performed using the nCounter (Nanostring Technologies, Seattle, WA, USA) platform, as described for critical COVID-19.

Consequently, 212 genes were identified to be differentially expressed between individuals with long COVID and controls (figure A), of which 70 remained significant after adjustment for false discovery rate correction (appendix 1). Several viral RNAs were upregulated: nucleocapsid, ORF7a, ORF3a, Mpro (a nirmatrelvir plus ritonavir [Paxlovid] target), and antisense ORF1ab RNA. Specifically, the upregulation of antisense ORF1ab RNA suggests ongoing viral replication. SARS-CoV-2-related host RNAs (ACE2/TMPRSS2 receptors, DPP4/FURIN proteases) and RNAs prototypical for memory B-cells and platelets were also upregulated (figure A).

Multivariable logistic regression identified antisense SARS-CoV-2 and FYN RNA concentrations as independent predictors of long COVID (corrected for age and sex; appendix 1 p 2). Receiver operating characteristic curve analysis showed significant discrimination (area under curve [AUC] 0·94, 95% CI 0·86–1·00) between individuals with long COVID (n=48) and controls (n=12), with 93·8% sensitivity and 91·7% specificity (figure B).

Single biomarkers antisense SARS-CoV-2 (AUC 0·78, 0·65–0·90) and FYN RNA (AUC 0·89, 0·79–0·99) were significant predictors with lower sensitivity (52·1% and 72·9%, respectively) but similar specificity (91·7% and 100%, respectively; figure B). Upon summarising transcriptomic results into biological pathways, we found significantly decreased immunometabolism in individuals with long COVID, which was negatively correlated with the blood viral load (appendix 1 p 3).

A qualitative analysis of individual SARS-CoV-2 transcript positivity revealed significant differences between individuals with long COVID and controls for antisense (65% vs 25%), ORF7a (60% vs 25%), and nucleocapsid (50% vs 8%) RNAs (figure C). Similarly, the SARS-CoV-2 transcript positivity with respect to the total blood viral load was also significantly different (60% vs 8%).

By use of multivariable logistic regression, we found that age and sex were not associated with the distinction between a low and high viral RNA load status. Conversely, the number of comorbidities (odds ratio [OR] 1·61, 95% CI 1·14–2·49) and COVID vaccine doses (OR 0·36, 0·14–0·79) emerged as independent predictors of distinguishing between low and high viral RNA load status (appendix 2).

We found that viral and immune parameters, such as the antisense Orf1ab RNA concentrations and immunometabolism score, were also linked to the patient-reported anxiety or depression score. Individuals classified as having severe anxiety or depression (with a score of 4 and 5) displayed significantly higher antisense RNA concentrations and lower immunometabolism scores (p<0·05) than those categorised as mild (with scores of 1–3; figure D).

In conclusion, the associations among persistent viral RNA, immunometabolism, and patient-reported outcomes provide mechanistic insights for addressing the challenges posed by long COVID.

Source: Menezes SM, Jamoulle M, Carletto MP, Moens L, Meyts I, Maes P, Van Weyenbergh J. Blood transcriptomic analyses reveal persistent SARS-CoV-2 RNA and candidate biomarkers in post-COVID-19 condition. Lancet Microbe. 2024 Apr 24:S2666-5247(24)00055-7. doi: 10.1016/S2666-5247(24)00055-7. Epub ahead of print. PMID: 38677304. https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(24)00055-7/fulltext (Full text)

SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19

Abstract:

To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey of the cellular metabolic pathways modulated by SARS-CoV-2 infection and confirmed their importance for SARS-CoV-2 propagation by cataloging the effects of specific pathway inhibitors. This revealed that SARS-CoV-2 strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased mitochondrial reactive oxygen species (mROS) production.

The elevated mROS stabilizes HIF-1α which redirects carbon molecules from mitochondrial oxidation through glycolysis and the pentose phosphate pathway (PPP) to provide substrates for viral biogenesis. mROS also induces the release of mitochondrial DNA (mtDNA) which activates innate immunity. The restructuring of cellular energy metabolism is mediated in part by SARS-CoV-2 Orf8 and Orf10 whose expression restructures nuclear DNA (nDNA) and mtDNA OXPHOS gene expression.

These viral proteins likely alter the epigenome, either by directly altering histone modifications or by modulating mitochondrial metabolite substrates of epigenome modification enzymes, potentially silencing OXPHOS gene expression and contributing to long-COVID.

Source: Guarnieri JW, Haltom JA, Albrecht YES, Lie T, Olali AZ, Widjaja GA, Ranshing SS, Angelin A, Murdock D, Wallace DC. SARS-CoV-2 Mitochondrial Metabolic and Epigenomic Reprogramming in COVID-19. Pharmacol Res. 2024 Apr 11:107170. doi: 10.1016/j.phrs.2024.107170. Epub ahead of print. PMID: 38614374. https://www.sciencedirect.com/science/article/pii/S1043661824001142 (Full text)

Long COVID-19 and Peripheral Serotonin: A Commentary and Reconsideration

Abstract:

We believe there are serious problems with a recently published and highly publicized paper entitled “Serotonin reduction in post-acute sequelae of viral infection.” The blood centrifugation procedure reportedly used by Wong et al would produce plasma that is substantially (over 95%) depleted of platelets. Given this, their published mean plasma serotonin values of 1.2 uM and 2.4 uM for the control/contrast groups appear to be at least 30 to 60 times too high and should be disregarded. The plasma serotonin values reported for the long COVID and viremia patients also should be disregarded, as should any comparisons to the control/contrast groups.

We also note that the plasma serotonin means for the two control/contrast groups are not in good agreement. In the “Discussion” section, Wong et al state that their results tend to support the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of COVID-19, and they encourage further clinical trials of SSRIs. While they state that, “Our animal models demonstrate that serotonin levels can be restored and memory impairment reversed by precursor supplementation or SSRI treatment”, it should be noted that no data are presented showing an increase or restoration in circulating serotonin with SSRI administration.

In fact, one would expect a marked decline in platelet serotonin due to SSRIs’ effective inhibition of the platelet serotonin transporter. Wong et al hypothesize that problems of long COVID arise from too little peripheral serotonin. However, given the frequent presence of a hyperaggregation state in long COVID, and the known augmenting effects of platelet serotonin on platelet aggregation, it is plausible to suggest that reductions in platelet serotonin might be associated with a lessening of the cardiovascular sequelae of COVID-19.

Source: Anderson GM, Cook EH, Blakely RD, Sutcliffe JS, Veenstra-VanderWeele J. Long COVID-19 and Peripheral Serotonin: A Commentary and Reconsideration. J Inflamm Res. 2024 Apr 11;17:2169-2172. doi: 10.2147/JIR.S456000. PMID: 38628604; PMCID: PMC11019386. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11019386/ (Full text)

Recovery of neurophysiological measures in post-COVID fatigue: a 12-month longitudinal follow-up study

Abstract:

One of the major consequences of the COVID-19 pandemic has been the significant incidence of persistent fatigue following resolution of an acute infection (i.e. post-COVID fatigue). We have shown previously that, in comparison to healthy controls, those suffering from post-COVID fatigue exhibit changes in muscle physiology, cortical circuitry, and autonomic function. Whether these changes preceded infection, potentially predisposing people to developing post-COVID fatigue, or whether the changes were a consequence of infection was unclear.

Here we present results of a 12-month longitudinal study of 18 participants from the same cohort of post-COVID fatigue sufferers to investigate these correlates of fatigue over time. We report improvements in self-perception of the impact of fatigue via questionnaires, as well as significant improvements in objective measures of peripheral muscle fatigue and autonomic function, bringing them closer to healthy controls. Additionally, we found reductions in muscle twitch tension rise times, becoming faster than controls, suggesting that the improvement in muscle fatigability might be due to a process of adaptation rather than simply a return to baseline function.

Source: Maffitt NJ, Germann M, Baker AME, Baker MR, Baker SN, Soteropoulos DS. Recovery of neurophysiological measures in post-COVID fatigue: a 12-month longitudinal follow-up study. Sci Rep. 2024 Apr 17;14(1):8874. doi: 10.1038/s41598-024-59232-y. PMID: 38632415; PMCID: PMC11024107. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11024107/ (Full text)