Tag: Hanson

Are enteroviruses behind mysterious outbreaks of chronic fatigue syndrome?

Chronic fatigue syndrome is a long-term illness with a wide range of symptoms, no known treatment, and undetermined origins. However, with as many as 65m people across the world living with the illness, researchers continue to search for answers.

Now, Prof Maureen Hanson of Cornell University discusses how she and graduate student James O’Neal searched through the research archives to see whether a genus of RNA viruses called enteroviruses are the most likely culprits and whether the findings have implications in future ‘long Covid’ research.

Like SARS-CoV-2, which causes Covid-19, viruses, enteroviruses (EVs) are RNA viruses that can lead to cause serious illness and death. One type of EV causes poliomyelitis, which is now largely conquered through near-universal vaccination.

But no vaccine exists against many other types of EVs, which are free to circulate widely. Indeed, the Centers for Disease Control and Prevention estimates between 10m-15m enteroviral infections occur each year in the US.

EVs have long been suspected as causal agents in outbreaks of an illness that is now usually named ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome). Outbreaks have been documented since the turn of the previous century and may have occurred earlier.

Many are unaware that ME/CFS can occur in epidemic form. The pathogen(s) inciting most of these outbreaks remain unidentified. One reason for this lamentable situation is that earlier virus identification technology was not as powerful as today’s methods.

Consider how quickly the complete sequence of SARS-CoV-2 was obtained not long after a new illness arose. But another reason that ME/CFS triggers are not known is the existing technology was not deployed to identify the agents causing multiple outbreaks in the mid-1980s. The failure of federal agencies to nor investigate these outbreaks, often dismissed as hysteria or unimportant, is well documented in investigative journalist Hillary Johnson’s Osler’s Web.

Read the rest of this article HERE.

Source: Frontiers Science News, August 12, 2o21. https://blog.frontiersin.org/2021/08/12/chronic-fatigue-syndrome-viruses-maureen-hanson-cornell-university/

The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established. Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in secondary infection sites, including the central nervous system, muscle, and heart. To date, the body of research that has investigated enterovirus infections in relation to ME/CFS supports an increased prevalence of chronic or persistent enteroviral infections in ME/CFS patient cohorts than in healthy individuals. Nevertheless, inconsistent results have fueled a decline in related studies over the past two decades.

This review covers the aspects of ME/CFS pathophysiology that are consistent with a chronic enterovirus infection and critically reviews methodologies and approaches used in past EV-related ME/CFS studies. We describe the prior sample types that were interrogated, the methods used and the limitations to the approaches that were chosen. We conclude that there is considerable evidence that prior outbreaks of ME/CFS were caused by one or more enterovirus groups. Furthermore, we find that the methods used in prior studies were inadequate to rule out the presence of chronic enteroviral infections in individuals with ME/CFS. Given the possibility that such infections could be contributing to morbidity and preventing recovery, further studies of appropriate biological samples with the latest molecular methods are urgently needed.

Source: O’Neal AJ, Hanson MR. The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review. Front Med (Lausanne). 2021 Jun 18;8:688486. doi: 10.3389/fmed.2021.688486. PMID: 34222292; PMCID: PMC8253308. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253308/  (Full text)

In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease with worldwide prevalence and limited therapies exclusively aimed at treating symptoms. To gain insights into the molecular disruptions in ME/CFS, we utilized an aptamer-based technology that quantified 4790 unique human proteins, allowing us to obtain the largest proteomics dataset yet available for this disease, detecting highly abundant proteins as well as rare proteins over a nine-log dynamic range.

We report a pilot study of 20 ME/CFS patients and 20 controls, all females. Significant differences in the levels of 19 proteins between cohorts implicate pathways related to the extracellular matrix, the immune system and cell–cell communication. Outputs of pathway and cluster analyses robustly highlight the ephrin pathway, which is involved in cell–cell signaling and regulation of an expansive variety of biological processes, including axon guidance, angiogenesis, epithelial cell migration, and immune response. Receiver Operating Characteristic (ROC) curve analyses distinguish the plasma proteomes of ME/CFS patients from controls with a high degree of accuracy (Area Under the Curve (AUC) > 0.85), and even higher when using protein ratios (AUC up to 0.95), that include some protein pairs with established biological relevance. Our results illustrate the promise of plasma proteomics for diagnosing and deciphering the molecular basis of ME/CFS.

Source: Germain A, Levine SM, Hanson MR. In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling. Proteomes. 2021; 9(1):6. https://doi.org/10.3390/proteomes9010006 (Full text)

Cytokine profiling of extracellular vesicles isolated from plasma in myalgic encephalomyelitis/chronic fatigue syndrome: a pilot study

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease of unknown etiology lasting for a minimum of 6 months but usually for many years, with features including fatigue, cognitive impairment, myalgias, post-exertional malaise, and immune system dysfunction. Dysregulation of cytokine signaling could give rise to many of these symptoms. Cytokines are present in both plasma and extracellular vesicles, but little investigation of EVs in ME/CFS has been reported. Therefore, we aimed to characterize the content of extracellular vesicles (EVs) isolated from plasma (including circulating cytokine/chemokine profiling) from individuals with ME/CFS and healthy controls.

Methods: We included 35 ME/CFS patients and 35 controls matched for age, sex and BMI. EVs were enriched from plasma by using a polymer-based precipitation method and characterized by Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM) and immunoblotting. A 45-plex immunoassay was used to determine cytokine levels in both plasma and isolated EVs from a subset of 19 patients and controls. Linear regression, principal component analysis and inter-cytokine correlations were analyzed.

Results: ME/CFS individuals had significantly higher levels of EVs that ranged from 30 to 130 nm in size as compared to controls, but the mean size for total extracellular vesicles did not differ between groups. The enrichment of typical EV markers CD63, CD81, TSG101 and HSP70 was confirmed by Western blot analysis and the morphology assessed by TEM showed a homogeneous population of vesicles in both groups. Comparison of cytokine concentrations in plasma and isolated EVs of cases and controls yielded no significant differences. Cytokine-cytokine correlations in plasma revealed a significant higher number of interactions in ME/CFS cases along with 13 inverse correlations that were mainly driven by the Interferon gamma-induced protein 10 (IP-10), whereas in the plasma of controls, no inverse relationships were found across any of the cytokines. Network analysis in EVs from controls showed 2.5 times more significant inter-cytokine interactions than in the ME/CFS group, and both groups presented a unique negative association.

Conclusions: Elevated levels of 30-130 nm EVs were found in plasma from ME/CFS patients and inter-cytokine correlations revealed unusual regulatory relationships among cytokines in the ME/CFS group that were different from the control group in both plasma and EVs. These disturbances in cytokine networks are further evidence of immune dysregulation in ME/CFS.

Source: Giloteaux L, O’Neal A, Castro-Marrero J, Levine SM, Hanson MR. Cytokine profiling of extracellular vesicles isolated from plasma in myalgic encephalomyelitis/chronic fatigue syndrome: a pilot study. J Transl Med. 2020 Oct 12;18(1):387. doi: 10.1186/s12967-020-02560-0. PMID: 33046133. https://pubmed.ncbi.nlm.nih.gov/33046133/

Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids

Abstract:

The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an illness with known effects on the functioning of the immune and nervous systems. We performed an extensive metabolomics analysis on the plasma of 52 female subjects, equally sampled between controls and ME/CFS patients, which delivered data for about 1750 blood compounds spanning 20 super-pathways, subdivided into 113 sub-pathways.

Statistical analysis combined with pathway enrichment analysis points to a few disrupted metabolic pathways containing many unexplored compounds. The most intriguing finding concerns acyl cholines, belonging to the fatty acid metabolism sub-pathway of lipids, for which all compounds are consistently reduced in two distinct ME/CFS patient cohorts. We compiled the extremely limited knowledge about these compounds and regard them as promising in the quest to explain many of the ME/CFS symptoms.

Another class of lipids with far-reaching activity on virtually all organ systems are steroids; androgenic, progestin, and corticosteroids are broadly reduced in our patient cohort. We also report on lower dipeptides and elevated sphingolipids abundance in patients compared to controls. Disturbances in the metabolism of many of these molecules can be linked to the profound organ system symptoms endured by ME/CFS patients.

Source: Germain A, Barupal DK, Levine SM, Hanson MR. Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids. Metabolites. 2020 Jan 14;10(1). pii: E34. doi: 10.3390/metabo10010034. https://www.ncbi.nlm.nih.gov/pubmed/31947545

Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and post-exertional malaise. There is little known about the metabolism of specific immune cells in ME/CFS patients. To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 ME/CFS patients and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism, and plasma cytokines.

We found that ME/CFS CD8+ T cells have reduced mitochondrial membrane potential compared to healthy controls. Both CD4+ and CD8+ T cells from ME/CFS patients had reduced glycolysis at rest, while CD8+ T cells also had reduced glycolysis following activation. ME/CFS patients had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from healthy control subjects.

Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.

Source: Mandarano AH, Maya J, Giloteaux L, Peterson DL, Maynard M, Gottschalk CG, Hanson MR. Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations. J Clin Invest. 2019 Dec 12. pii: 132185. doi: 10.1172/JCI132185. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31830003

Study finds differences in energy use by immune cells in ME/CFS

Press Release: New findings published in the Journal of Clinical Investigation suggest that specific immune T cells from people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) show disruptions in the way they produce energy. The research was supported by the National Institutes of Health.

“This research gives us additional evidence for the role of the immune system in ME/CFS and may provide important clues to help us understand the mechanisms underlying this devastating disease,” said Vicky Whittemore, Ph.D., program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which partially funded the study.

ME/CFS is a severe, chronic, and debilitating disease that can cause a range of symptoms including pain, severe exhaustion, cognitive impairment, and post-exertional malaise, the worsening of symptoms after physical or mental activity. Estimates suggest that between 836,000 and 2.5 million people in the United States may be affected by ME/CFS. It is unknown what causes the disease and there are no treatments.

Research by Alexandra Mandarano and collaborators in the laboratory of Maureen Hanson, Ph.D., professor of molecular biology and genetics at Cornell University in Ithaca, New York, examined biochemical reactions involved in energy production, or metabolism, in two specific types of immune cells obtained from 45 healthy controls and 53 people with ME/CFS. Investigators focused on CD4 T cells, which alert other immune cells about invading pathogens, and CD8 T cells, which attack infected cells. Dr. Hanson’s team used state-of-the-art methods to look at energy production by the mitochondria within T cells, when the cells were in a resting state and after they had been activated. Mitochondria are biological powerhouses and create most of the energy that drives cells.

Dr. Hanson and her colleagues did not see significant differences in mitochondrial respiration, the cell’s primary energy-producing method, between healthy and ME/CFS cells at rest or after activation. However, results suggest that glycolysis, a less efficient method of energy production, may be disrupted in ME/CFS. Compared to healthy cells, CD4 and CD8 cells from people with ME/CFS had decreased levels of glycolysis at rest. In addition, ME/CFS CD8 cells had lower levels of glycolysis after activation.

“Our work demonstrates the importance of looking at particular types of immune cells that have different jobs to do, rather than looking at them all mixed together, which can hide problems specific to particular cells,” said Dr. Hanson. “Additional studies focusing on specific cell types will be important to unravel what’s gone wrong with immune defenses in ME/CFS.”

Dr. Hanson’s group also looked at mitochondrial size and membrane potential, which can indicate the health of T cell mitochondria. CD4 cells from healthy controls and people with ME/CFS showed no significant differences in mitochondrial size nor function. CD8 cells from people with ME/CFS showed decreased membrane potential compared to healthy cells during both resting and activated states.

Dr. Hanson’s team examined associations between cytokines, chemical messengers that send instructions from one cell to another, and T cell metabolism. The findings revealed different, and often opposite, patterns between healthy and ME/CFS cells, suggesting changes in the immune system. In addition, the presence of cytokines that cause inflammation unexpectedly correlated with decreased metabolism in T cells.

This study was supported in part by the NIH’s ME/CFS Collaborative Research Network, a consortium supported by multiple institutes and centers at NIH, consisting of three collaborative research centers and a data management coordinating center. The research network was established in 2017 to help advance research on ME/CFS.

“In addition to providing valuable insights into the immunology of ME/CFS, we hope that the results coming out of the collaborative research network will inspire more researchers, particularly those in the early stages of their careers, to work on this disease,” said Joseph Breen, Ph.D., section chief, Immunoregulation Section, Basic Immunology Branch, National Institute of Allergy and Infectious Diseases (NIAID), which partially funded the study.

Future research studies will examine metabolism in other subsets of immune cells. In addition, researchers will investigate ways in which changes in metabolism affect the activity of T cells.

This study was supported by NINDS grant U54NS105541, NIAID grant R21AI117595, Simmaron Research, and an anonymous private donor.

NINDS (https://www.ninds.nih.gov/) is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Reference: Mandarano et al. “Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations,” Journal of Clinical Investigation. December 12, 2019

Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease of enigmatic origin with no established cure. Its constellation of symptoms has silently ruined the lives of millions of people around the world. A plethora of hypotheses have been vainly investigated over the past few decades, so that the biological basis of this debilitating condition remains a mystery.

In this study, we investigate whether there is a disturbance in homeostasis of metabolic networks in the plasma of a female 32-patient cohort compared to 19 healthy female controls. Extensive analysis of the 832-metabolite dataset generated by Metabolon®, covering eight biological classes, generated important insight into metabolic disruptions that occur in ME/CFS.

We report on 14 metabolites with differences in abundance, allowing us to develop a theory of broad redox imbalance in ME/CFS patients, which is consistent with findings of prior work in the ME/CFS field. Moreover, exploration of enrichment analysis using www.MetaboAnalyst.ca provides information concerning similarities between metabolite disruptions in ME/CFS and those that occur in other diseases, while its biomarker analysis unit yielded prospective plasma biomarkers for ME/CFS. This work contributes key elements to the development of ME/CFS diagnostics, a crucial step required for discovering a therapy for any disease of unknown origin.

Source:  Arnaud Germain, David Ruppert , Susan M. Levine  and Maureen R. Hanson. Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology.  Metabolites 2018, 8(4), 90; doi:10.3390/metabo8040090 https://www.mdpi.com/2218-1989/8/4/90/htm (Full article)

Eukaryotes in the gut microbiota in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often suffer from gastrointestinal symptoms and many are diagnosed with irritable bowel syndrome (IBS). Previous studies, including from our laboratory, have demonstrated that the ME/CFS gut bacterial composition is altered and less diverse when compared to healthy individuals. Patients have increased biomarkers of inflammation and leaky gut syndrome. To further investigate dysbiosis in the ME/CFS gut microbiome, we sought to characterize the eukaryotes present in the gut of 49 individuals with ME/CFS and 39 healthy controls. Using 18S rRNA sequencing, we have identified eukaryotes in stool samples of 17 healthy individuals and 17 ME/CFS patients. Our analysis demonstrates a small, nonsignificant decrease in eukaryotic diversity in ME/CFS patients compared to healthy individuals. In addition, ME/CFS patients show a nonsignificant increase in the ratio of fungal phyla Basidiomycota to Ascomycota, which is consistent with ongoing inflammation in ME/CFS. We did not identify specific eukaryotic taxa that are associated with ME/CFS disease status.

Source: Alexandra H. Mandarano, Ludovic Giloteaux, Betsy A. Keller, Susan M. Levine, Maureen R. Hanson. Eukaryotes in the gut microbiota in myalgic encephalomyelitis/chronic fatigue syndrome. Peer J. January 22, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784577/https://peerj.com/articles/4282/ (Full article)

Discovery Forum 2017: An Interview with Dr. Maureen Hanson

Solve ME/CFS Initiative’s 2nd Annual Discovery Forum, held on October 14th in Washington DC, brought together leaders from across industry, academia, federal agencies, and biotech companies to tackle the most pressing issues confronting ME/CFS. In this interview, Dr. Zaher Nahle discusses ME/CFS science and policy with Dr. Maureen Hanson, founder and director of the Center for Enervating Neuroimmune Disease at Cornell University and member of the Solve ME/CFS Initiative’s Research Advisory Council.