Tag: 2021

Plasma proteome of Long-COVID patients indicates HIF-mediated vasculo-proliferative disease with impact on brain and heart function

Abstract:

Aims: Long-COVID occurs after SARS-CoV-2 infection and results in diverse, prolonged symptoms. The present study aimed to unveil potential mechanisms, and to inform prognosis and treatment.

Methods: Plasma proteome from Long-COVID outpatients was analyzed in comparison to matched acutely ill COVID-19 (mild and severe) inpatients and healthy control subjects. The expression of 3072 protein biomarkers was determined with proximity extension assays and then deconvoluted with multiple bioinformatics tools into both cell types and signaling mechanisms, as well as organ specificity.

Results: Compared to age- and sex-matched acutely ill COVID-19 inpatients and healthy control subjects, Long-COVID outpatients showed natural killer cell redistribution with a dominant resting phenotype, as opposed to active, and neutrophils that formed extracellular traps. This potential resetting of cell phenotypes was reflected in prospective vascular events mediated by both angiopoietin-1 (ANGPT1) and vascular-endothelial growth factor-A (VEGFA). Several markers (ANGPT1, VEGFA, CCR7, CD56, citrullinated histone 3, elastase) were validated by serological methods in additional patient cohorts. Signaling of transforming growth factor-β1 with probable connections to elevated EP/p300 suggested vascular inflammation and tumor necrosis factor-α driven pathways. In addition, a vascular proliferative state associated with hypoxia inducible factor 1 pathway suggested progression from acute COVID-19 to Long-COVID. The vasculo-proliferative process predicted in Long-COVID might contribute to changes in the organ-specific proteome reflective of neurologic and cardiometabolic dysfunction.

Conclusions: Taken together, our findings point to a vasculo-proliferative process in Long-COVID that is likely initiated either prior hypoxia (localized or systemic) and/or stimulatory factors (i.e., cytokines, chemokines, growth factors, angiotensin, etc). Analyses of the plasma proteome, used as a surrogate for cellular signaling, unveiled potential organ-specific prognostic biomarkers and therapeutic targets.

Source: Iosef C, Knauer MJ, Nicholson M, Van Nynatten LR, Cepinskas G, Draghici S, Han VKM, Fraser DD. Plasma proteome of Long-COVID patients indicates HIF-mediated vasculo-proliferative disease with impact on brain and heart function. J Transl Med. 2023 Jun 10;21(1):377. doi: 10.1186/s12967-023-04149-9. PMID: 37301958; PMCID: PMC10257382. https://pmc.ncbi.nlm.nih.gov/articles/PMC10257382/ (Full text)

Inflammation-type dysbiosis of the oral microbiome associates with the duration of COVID-19 symptoms and long COVID

Abstract:

In the COVID-19 pandemic, caused by SARS-CoV-2, many individuals experience prolonged symptoms, termed long-lasting COVID-19 symptoms (long COVID). Long COVID is thought to be linked to immune dysregulation due to harmful inflammation, with the exact causes being unknown. Given the role of the microbiome in mediating inflammation, we aimed to examine the relationship between the oral microbiome and the duration of long COVID symptoms.

Tongue swabs were collected from patients presenting with COVID-19 symptoms. Confirmed infections were followed until resolution of all symptoms. Bacterial composition was determined by metagenomic sequencing. We used random forest modeling to identify microbiota and clinical covariates that are associated with long COVID symptoms. Of the patients followed, 63% developed ongoing symptomatic COVID-19 and 37% went on to long COVID.

Patients with prolonged symptoms had significantly higher abundances of microbiota that induced inflammation, such as members of the genera Prevotella and Veillonella, which, of note, are species that produce LPS. The oral microbiome of patients with long COVID was similar to that of patients with chronic fatigue syndrome.

Altogether, our findings suggest an association with the oral microbiome and long COVID, revealing the possibility that dysfunction of the oral microbiome may have contributed to this draining disease.

Source: Haran JP, Bradley E, Zeamer AL, Cincotta L, Salive MC, Dutta P, Mutaawe S, Anya O, Meza-Segura M, Moormann AM, Ward DV, McCormick BA, Bucci V. Inflammation-type dysbiosis of the oral microbiome associates with the duration of COVID-19 symptoms and long COVID. JCI Insight. 2021 Oct 22;6(20):e152346. doi: 10.1172/jci.insight.152346. PMID: 34403368; PMCID: PMC8564890. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564890/ (Full text)

Is Central Sensitisation the Missing Link of Persisting Symptoms after COVID-19 Infection?

Abstract:

Patients recovered from a COVID-19 infection often report vague symptoms of fatigue or dyspnoea, comparable to the manifestations in patients with central sensitisation. The hypothesis was that central sensitisation could be the underlying common aetiology in both patient populations. This study explored the presence of symptoms of central sensitisation, and the association with functional status and health-related quality of life, in patients post COVID-19 infection.

Patients who were previously infected with COVID-19 filled out the Central Sensitisation Inventory (CSI), the Post-COVID-19 Functional Status (PCFS) Scale and the EuroQol with five dimensions, through an online survey. Eventually, 567 persons completed the survey. In total, 29.73% of the persons had a score of <40/100 on the CSI and 70.26% had a score of ≥40/100. Regarding functional status, 7.34% had no functional limitations, 9.13% had negligible functional limitations, 37.30% reported slight functional limitations, 42.86% indicated moderate functional limitations and 3.37% reported severe functional limitations.

Based on a one-way ANOVA test, there was a significant effect of PCFS Scale group level on the total CSI score (F(4,486) = 46.17, p < 0.001). This survey indicated the presence of symptoms of central sensitisation in more than 70% of patients post COVID-19 infection, suggesting towards the need for patient education and multimodal rehabilitation, to target nociplastic pain.

Source: Goudman L, De Smedt A, Noppen M, Moens M. Is Central Sensitisation the Missing Link of Persisting Symptoms after COVID-19 Infection? J Clin Med. 2021 Nov 28;10(23):5594. doi: 10.3390/jcm10235594. PMID: 34884296; PMCID: PMC8658135. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8658135/ (Full text)

Long COVID: an estrogen-associated autoimmune disease?

Introduction:

Some people who have had severe to a moderate or mild form of COVID-19 disease may suffer from variable and debilitating symptoms for many months after the initial infection. This condition is commonly called “Long COVID”. An exact definition is missing, but symptoms with a duration of more than 2 months are typically considered as Long COVID. The condition is characterized by long-term sequelae and can involve a range of symptoms such as persistent fatigue, headache, shortness of breath, anosmia, muscle weakness, fever, cognitive dysfunction (brain fog), tachycardia, intestinal disorders, and skin manifestations. Long COVID syndrome bears a similarity to the post-infectious syndromes that followed the outbreaks of chikungunya and Ebola.

In general, women appear to be twice as likely to develop Long COVID as men, but only until around age 60, when the risk level becomes similar. In addition to being a woman, older age and a higher body mass index also seem to be risk factors for having Long COVID.

Source: Ortona E, Buonsenso D, Carfi A, Malorni W; Long Covid Kids study group. Long COVID: an estrogen-associated autoimmune disease? Cell Death Discov. 2021 Apr 13;7(1):77. doi: 10.1038/s41420-021-00464-6. PMID: 33850105; PMCID: PMC8042352.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042352/ (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back!

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown.

Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome. New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS. Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.

Source: Ariza ME. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back! Biomolecules. 2021 Jan 29;11(2):185. doi: 10.3390/biom11020185. PMID: 33572802; PMCID: PMC7912523. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912523/ (Full text)

Long-haul COVID: heed the lessons from other infection-triggered illnesses

According to the Johns Hopkins Coronavirus Resource Center, more than 115 million people worldwide have been infected with SARS-CoV-2 during the COVID-19 pandemic, with extensive implications for morbidity and mortality. Description of long-term effects of COVID-19 are apparing in the medical literature; the first large cohort study with 6-months’ follow-up has been published, and more data are sure to follow. A small number of studies point not only to persistent imaging and testing abnormalities across several organ systems in the postacute period, but to a high frequency of patient-reported symptoms such as fatigue, insomnia, anxiety and depression, autonomic disturbances, cognitive difficulties, pain, and others. The presence of patient support groups, and the rapid expansion of clinics to manage or treat these symptoms, validate further their existence and impact.
Although the frequency, severity, and potentially the etiology of persistent symptoms can vary, sequelae after COVID-19 appears poised to join the range of other postinfectious syndromes described in the field of infectious diseases.

These often share a common symptom phenotype, which might also meet case definitions for myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, or post-treatment Lyme disease. We hope that researchers and clinicians will draw on these other conditions as they continue to advance scientific understanding of so-called long-haul or persistent COVID-19. We would also argue that there are important lessons to learn and pitfalls to avoid; our specific area of clinical care and research (post-treatment Lyme disease) has remained a fiercely contentious condition for more than 30 years.

Read the rest of this article HERE.
Source: John N Aucott, Alison W Rebman. Long-haul COVID: heed the lessons from other infection-triggered illnesses. The Lancet, CORRESPONDENCE| VOLUME 397, ISSUE 10278, P967-968, MARCH 13, 2021 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00446-3/fulltext (Full text) 

Even mild COVID-19 may have long-term brain impacts

Research presented at the Alzheimer’s Association International Conference suggests even mild cases of COVID-19 may be associated with cognitive deficits months after recovery.

One Argentinian study of 234 seniors who previously had COVID-19 found that more than half showed some degree of cognitive impairment months later. One in three had severe “dementia-like” impairments in memory, attention and executive function — a much higher proportion than the 5%–8% of seniors in the general population who have dementia at a given time.

“This could be the start of a dementia-related epidemic fueled by this latest coronavirus,” stated presenting author Dr. Gabriel de Erausquin of the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases at UT Health San Antonio. Researchers will follow the study participants over the next three to five years to see if these problems resolve or worsen.

The study didn’t look at participants’ cognitive performance prior to infection. However, those who lost their sense of smell while sick with COVID-19 tended to have more severe cognitive impairments months later, even if their other symptoms had been mild. According to de Erausquin, “once the virus has affected the olfactory bulb and caused effects there — changes that we can see with imaging — then other places in the brain that are connected to it also become abnormal, either in function or structure or both.”

Other research presented linked SARS-CoV-2 infection with an uptick in biomarkers of brain injury, neuroinflammation and Alzheimer disease. One American study of 310 patients with COVID-19 found that those with new neurological symptoms had higher levels of t-tau, NfL, GFAP, pTau-181, and UCH-L1 in their blood, as well as indicators of inflammation such as C-reactive protein, compared to patients without neurological symptoms. “These findings suggest patients who had COVID-19 may have an acceleration of Alzheimer-related symptoms and pathology,” according to presenting author Dr. Thomas Wisniewski of the New York University Grossman School of Medicine.

Earlier this year, de Erausquin and others reported that brain inflammation, stroke and other common complications of viral infections have longstanding links with neurodegenerative disorders. “Therefore, it seems likely to expect that COVID-19-related cardiovascular and cerebrovascular disease will also contribute to a higher longterm risk of cognitive decline and dementia in recovered individuals.”

Several recent studies have documented cognitive deficits post-COVID but like the research presented at the Alzheimer’s Association conference, data on patients’ performance before infection are lacking.

One British study of 81 337 people in EClinicalMedicine found that those who previously had COVID-19 tended to score lower on measures of intelligence, reasoning, problem-solving and planning than people who were never infected.

“These results accord with reports of long-COVID, where ‘brain fog,’ trouble concentrating and difficulty finding the correct words are common,” according to the authors. People who had been hospitalized and put on ventilators had the greatest impairments, but even those who had relatively mild symptoms showed some deficit.

In another study of 57 Americans receiving inpatient rehabilitation after hospitalization for COVID-19, four in five had mild to severe cognitive impairments. More than half had deficits in working memory, while two in five had impaired processing speed, divided attention, and trouble switching between mental tasks.

Similar deficits have also been noted in patients after recovery from other coronaviruses. A 2020 systematic review and meta-analysis found that delirium was common in the acute stage of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19. Following up with patients six weeks to 39 months later, more than 15% reported sleep disorders, mood swings, trouble concentrating, impaired memory and other mental challenges.

Based on this growing body of evidence, British researchers warned in March that health systems will likely see an “influx of patients with psychiatric and cognitive problems who were otherwise healthy prior to COVID-19.” They urged doctors to consider detailed cognitive evaluations for anyone reporting new neurological symptoms after infection with SARS-CoV-2.

In the meantime, the Alzheimer’s Association has formed an international consortium to study the long-term effects of COVID-19 on the brain.

“These new data point to disturbing trends showing COVID-19 infections leading to lasting cognitive impairment and even Alzheimer’s symptoms,” stated Heather Snyder of the Alzheimer’s Association. “It is imperative that we continue to study what this virus is doing to our bodies and brains.”

Source: Duong D. Even mild COVID-19 may have long-term brain impacts. CMAJ. 2021 Aug 30;193(34):E1360-E1361. doi: 10.1503/cmaj.1095958. PMID: 34462298; PMCID: PMC8432319.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432319/ (Full text)

Effect of SARS-CoV-2 proteins on vascular permeability

Abstract:

Severe acute respiratory syndrome (SARS)-CoV-2 infection leads to severe disease associated with cytokine storm, vascular dysfunction, coagulation, and progressive lung damage. It affects several vital organs, seemingly through a pathological effect on endothelial cells. The SARS-CoV-2 genome encodes 29 proteins, whose contribution to the disease manifestations, and especially endothelial complications, is unknown.

We cloned and expressed 26 of these proteins in human cells and characterized the endothelial response to overexpression of each, individually. Whereas most proteins induced significant changes in endothelial permeability, nsp2, nsp5_c145a (catalytic dead mutant of nsp5), and nsp7 also reduced CD31, and increased von Willebrand factor expression and IL-6, suggesting endothelial dysfunction. Using propagation-based analysis of a protein-protein interaction (PPI) network, we predicted the endothelial proteins affected by the viral proteins that potentially mediate these effects. We further applied our PPI model to identify the role of each SARS-CoV-2 protein in other tissues affected by coronavirus disease (COVID-19).

While validating the PPI network model, we found that the tight junction (TJ) proteins cadherin-5, ZO-1, and β-catenin are affected by nsp2, nsp5_c145a, and nsp7 consistent with the model prediction. Overall, this work identifies the SARS-CoV-2 proteins that might be most detrimental in terms of endothelial dysfunction, thereby shedding light on vascular aspects of COVID-19.

Source: Rauti R, Shahoha M, Leichtmann-Bardoogo Y, Nasser R, Paz E, Tamir R, Miller V, Babich T, Shaked K, Ehrlich A, Ioannidis K, Nahmias Y, Sharan R, Ashery U, Maoz BM. Effect of SARS-CoV-2 proteins on vascular permeability. Elife. 2021 Oct 25;10:e69314. doi: 10.7554/eLife.69314. PMID: 34694226; PMCID: PMC8545399. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545399/ (Full text)

Broken Connections: The Evidence for Neuroglial Failure in ME/CFS

Abstract:

In spite of decades of research, the pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is still poorly understood. Several pathomechanisms have been identified, yet, it remains unclear how they are related and which of them may be upstream or downstream.

In this paper, we present a theoretical strategy that may help clarify the causal chain of pathophysiological events in ME/CFS. We propose to focus on the common final histological pathway of ME/CFS and suggest to ask: Which cellular compartment may explain the pathological processes and clinical manifestations observed in ME/CFS? Any functional unit consistently identified through this search may then be a plausible candidate for further exploration.

For this “histological” approach we have compiled a list of 22 undisputed clinical and pathophysiological features of ME/CFS that need to be plausibly and most directly explained by the dysfunctional cellular unit in question. For each feature we have searched the literature for pathophysiological explanations and analyzed if they may point to the same functional cellular unit. Through this search we have identified the CNS neuroglia – microglia and astroglia – as the one functional unit in the human body which may best explain all and any of the clinical and pathological features, dysfunctions and observations described for ME/CFS.

While this points to neuroinflammation as the central hub in ME/CFS, it also points to a novel understanding of the neuroimmune basis of ME/CFS. After all, the neuroglial cells are now understood as the functional matrix of the human brain connectome which operates beyond and above specific brain centers, receptor units or neurotransmitter systems and integrates innate immune functions with CNS regulatory functions pertaining to autonomous regulation, cellular metabolism and the stress response.

Source: Renz-Polster, H. (2021, August 3). Broken Connections: The Evidence for Neuroglial Failure in ME/CFS. https://doi.org/10.31219/osf.io/ef3n4 https://osf.io/ef3n4/ (Full text)

Dorsal root ganglia: fibromyalgia pain factory?

Abstract:

This perspective article focuses on dorsal root ganglia (DRG) as potential fibromyalgia main pain source. Humans possess 31 pairs of DRG lying along the spine. These ganglia have unique anatomical and physiological features. During development, DRG are extruded from the central nervous system and from the blood-brain barrier but remain surrounded by meningeal layers and by cerebrospinal fluid. DRG house the pain-transmitting small nerve fiber nuclei; each individual nucleus is tightly enveloped by metabolically active glial cells. DRG possess multiple inflammatory/pro-nociceptive molecules including ion channels, neuropeptides, lymphocytes, and macrophages. DRG neurons have pseudo-unipolar structure making them able to generate pain signals; additionally, they can sequester antigen-specific antibodies thus inducing immune-mediated hyperalgesia. In rodents, diverse physical and/or environmental stressors induce DRG phenotypic changes and hyperalgesia.

Unfolding clinical evidence links DRG pathology to fibromyalgia and similar syndromes. Severe fibromyalgia is associated to particular DRG ion channel genotype. Myalgic encephalomyelitis patients with comorbid fibromyalgia have exercise-induced DRG pro-nociceptive molecules gene overexpression. Skin biopsy demonstrates small nerve fiber pathology in approximately half of fibromyalgia patients. A confocal microscopy study of fibromyalgia patients disclosed strong correlation between corneal denervation and small fiber neuropathy symptom burden. DRG may be fibromyalgia neural hub where different stressors can be transformed in neuropathic pain. Novel neuroimaging technology and postmortem inquest may better define DRG involvement in fibromyalgia and similar maladies. DRG pro-nociceptive molecules are attractive fibromyalgia therapeutic targets.

Source: Martínez-Lavín M. Dorsal root ganglia: fibromyalgia pain factory? Clin Rheumatol. 2021 Jan 6:1–5. doi: 10.1007/s10067-020-05528-z. Epub ahead of print. PMID: 33409721; PMCID: PMC7787228.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787228/ (Full text)