SARS‐CoV‐2 and Mitochondrial Proteins in Neural‐Derived Exosomes of COVID‐19

Peluso, Michael J.; Deeks, Steven G.; Mustapić, Maja; Kapogiannis, Dimitrios; Henrich, Timothy J.; Lu, Scott; Goldberg, Sarah A; Hoh, Rebecca; Chen, Jessica; Martínez, Enrique Ortega; Kelly, John D.; Martin, Jeffrey N.; Goetzl, Edward J.

doi:10.1002/ana.26350

Cited by 86 publications

(85 citation statements)

References 42 publications

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“…The authors concluded that this implicates a peripheral rather than central cardiac limit underlying PASC. It could reflect mitochondrial injury, as SARS-CoV-2 appears to be capable of invading at least neural cell mitochondria ( 74 ). But it would also be anticipated in the presence of persistent or progressive microthrombi ( 73 ).…”

Section: Formulating Hypotheses For Pasc Pathogenesismentioning

confidence: 99%

Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches

Ahamed¹,

Laurence²

2022

Journal of Clinical Investigation

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SARS-CoV-2–infected individuals may suffer a multi–organ system disorder known as “long COVID” or post-acute sequelae of SARS-CoV-2 infection (PASC). There are no standard treatments, the pathophysiology is unknown, and incidence varies by clinical phenotype. Acute COVID-19 correlates with biomarkers of systemic inflammation, hypercoagulability, and comorbidities that are less prominent in PASC. Macrovessel thrombosis, a hallmark of acute COVID-19, is less frequent in PASC. Female sex at birth is associated with reduced risk for acute COVID-19 progression, but with increased risk of PASC. Persistent microvascular endotheliopathy associated with cryptic SARS-CoV-2 tissue reservoirs has been implicated in PASC pathology. Autoantibodies, localized inflammation, and reactivation of latent pathogens may also be involved, potentially leading to microvascular thrombosis, as documented in multiple PASC tissues. Diagnostic assays illuminating possible therapeutic targets are discussed.

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Section: Formulating Hypotheses For Pasc Pathogenesismentioning

confidence: 99%

Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches

Ahamed¹,

Laurence²

2022

Journal of Clinical Investigation

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“…Elevated inflammatory markers, especially hsCRP, IL-6, and TNF-α could be due to higher severity of acute illness, 37 persistent immune activation, 38 and/or ongoing antigen stimulation from viral persistence. [39][40][41][42][43] The correlation between these markers and peak VO2 could arise from a common cause of PASC, or these markers could be on the causal path from SARS-CoV-2 infection to symptoms and reduced exercise capacity in Long COVID (Figure 4). Multiple studies have demonstrated that IL-6 may be elevated in PASC.…”

Section: Connections Between Inflammation Reduced Exercise Capacity A...mentioning

confidence: 99%

Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID

Durstenfeld

Peluso

Kaveti

et al. 2022

Preprint

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BACKGROUNDMechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 “PASC” or “Long COVID”) remain unclear. The purpose of this study was to elucidate the pathophysiology of cardiopulmonary PASC using multimodality cardiovascular imaging including cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring.METHODSIn the Long-Term Impact of Infection with Novel Coronavirus (LIINC) Cohort, we performed CMR, CPET, and ambulatory rhythm monitoring among adults > 1 year after PCR-confirmed SARS-CoV-2 infection. We used logistic and linear regression to compare those with and without cardiopulmonary symptoms (dyspnea, chest pain, palpitations) adjusting for confounders.RESULTSOne hundred twenty individuals were studied, among whom 46 participants (unselected for symptom status) had at least one advanced test performed at median 17 months (IQR 15-18). Median age was 52 (IQR 42-61), 18 (39%) were female, and 6 (13%) were hospitalized for severe acute infection. On CMR (n=39), smaller RV volume and stroke volume and higher extracellular volume were present among those with symptoms, but no evidence of late-gadolinium enhancement or differences in T1 or T2 mapping were demonstrated. We did not find arrhythmias on ambulatory monitoring. In contrast, on CPET (n=39), 13/15 (87%) participants with reduced exercise capacity (<85% predicted) reported cardiopulmonary symptoms or fatigue (p=0.008). Adjusted peak VO2 was 2.7 ml/kg/min lower among those with cardiopulmonary symptoms (95%CI −6.9 to 1.5; p=0.20) or −11% predicted (95%CI −27 to 5, p=0.17). Including fatigue along with cardiopulmonary symptoms, the adjusted difference in peak VO2 was −5.9 ml/kg/min (−9.6 to −2.3; p=0.002) or −21% predicted (−35 to −7; p=0.006). Chronotropic incompetence was the primary abnormality among 9/15 with reduced peak VO2. Adjusted heart rate reserve <80% was associated with reduced exercise capacity (OR 15.6, 95%CI 1.30-187; p=0.03). Those with chronotropic incompetence had higher hsCRP, lower heart rate recovery, and lower heart rate variability suggestive of autonomic dysfunction.CONCLUSIONSReduced exercise capacity and reduced heart rate response to exercise, and hsCRP are associated with persistent cardiopulmonary symptoms more than 1 year following COVID-19. Chronic inflammation and autonomic dysfunction may underlie cardiopulmonary PASC.Clinical PerspectiveWhat is New?Impaired chronotropic response to exercise is associated with reduced exercise capacity and cardiopulmonary symptoms more than 1 year after SARS-CoV-2 infection.Findings on ambulatory rhythm monitoring point to perturbed autonomic function, while cardiac MRIfindings argue against myocardial dysfunction and myocarditis.Clinical ImplicationsCardiopulmonary testing to identify etiologies of persistent symptoms in post-acute sequalae of COVID-19 or “Long COVID” should be performed in a manner that allows for assessment of heart rate response to exercise.Therapeutic trials of antiviral, anti-inflammatory, and exercise strategies in PASC are urgently needed and should include assessment of symptoms and objective testing with cardiopulmonary exercise testing.

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“…Even in the absence of phase separation, the high IDRs in the N protein can significantly accelerate aggregation of amyloid fibrils in vitro, whereas the structurally stable S protein of SARS-CoV-2 had no effect on ⍺-synuclein aggregation in SH-SY5Y cells [ 232 ]. Perhaps not coincidentally, the mean levels of N proteins in neuron-derived extracellular vesicles (NDEVs) isolated from plasma of subjects with PASC and neuropsychiatric (NP) manifestations were significantly higher compared to PASC subjects without NP; resolved, acute COVID-19 subjects without PASC; and healthy controls [ 233 ]. Similarly, Neuro-PASC patients exhibit higher T cell responses to the nucleocapsid protein compared with control convalescent patients, supporting the theory that a persistent reservoir of the N protein is responsible for the activation of unique immunological signatures biased towards N proteins in Neuro-PASC individuals [ 234 ].…”

Section: Sars-cov-2 Proteins Phase Separation Disrupt Host Biomolecul...mentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

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The relentless, protracted evolution of the SARS-CoV-2 virus imposes tremendous pressure on herd immunity and demands versatile adaptations by the human host genome to counter transcriptomic and epitranscriptomic alterations associated with a wide range of short- and long-term manifestations during acute infection and post-acute recovery, respectively. To promote viral replication during active infection and viral persistence, the SARS-CoV-2 envelope protein regulates host cell microenvironment including pH and ion concentrations to maintain a high oxidative environment that supports template switching, causing extensive mitochondrial damage and activation of pro-inflammatory cytokine signaling cascades. Oxidative stress and mitochondrial distress induce dynamic changes to both the host and viral RNA m6A methylome, and can trigger the derepression of long interspersed nuclear element 1 (LINE1), resulting in global hypomethylation, epigenetic changes, and genomic instability. The timely application of melatonin during early infection enhances host innate antiviral immune responses by preventing the formation of “viral factories” by nucleocapsid liquid-liquid phase separation that effectively blockades viral genome transcription and packaging, the disassembly of stress granules, and the sequestration of DEAD-box RNA helicases, including DDX3X, vital to immune signaling. Melatonin prevents membrane depolarization and protects cristae morphology to suppress glycolysis via antioxidant-dependent and -independent mechanisms. By restraining the derepression of LINE1 via multifaceted strategies, and maintaining the balance in m6A RNA modifications, melatonin could be the quintessential ancient molecule that significantly influences the outcome of the constant struggle between virus and host to gain transcriptomic and epitranscriptomic dominance over the host genome during acute infection and PASC.

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SARS‐CoV‐2 and Mitochondrial Proteins in Neural‐Derived Exosomes of COVID‐19

Cited by 86 publications

References 42 publications

Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches

Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches

Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

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