Excerpt: “The human pancreas is a target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Following SARS-CoV-2 infections, reduced numbers of insulin secretory granules in beta cells and impaired glucose-stimulated insulin secretion have been observed. SARS-CoV-2 may damage beta cells by triggering proinflammatory cytokines. Proinflammatory pathways leading to chronic low-grade inflammation in adipose tissue play an important role in the pathogenesis of insulin resistance and type 2 diabetes. Consequently, new-onset hyperglycaemia and insulin resistance have been reported in patients with coronavirus disease-2019 (Covid-19) without history of diabetes. However, it is unclear whether such metabolic alterations are transient or whether individuals with Covid-19 have an increased future risk of persisting diabetes. The aim of this study was to investigate diabetes incidence after Covid-19 in individuals with mostly mild disease treated in primary care. Individuals with acute upper respiratory tract infections (AURI), which are also frequently caused by viruses (e.g. rhinoviruses), were selected as a non-exposed control group. …”

Rathmann, W., Kuss, O. & Kostev, K. Incidence of newly diagnosed diabetes after Covid-19. Diabetologia(2022). https://doi.org/10.1007/s00125-022-05670-0


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Abstract: Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system underpinned by partially understood genetic risk factors and environmental triggers and their undefined interactionsHere we investigated the peripheral immune signatures of 61 monozygotic twin pairs discordant for MS to dissect the influence of genetic predisposition and environmental factors. Using complementary multimodal high-throughput and high-dimensional single-cell technologies in conjunction with data-driven computational tools, we identified an inflammatory shift in a monocyte cluster of twins with MS, coupled with the emergence of a population of IL-2 hyper-responsive transitional naive helper T cells as MS-related immune alterations. By integrating data on the immune profiles of healthy monozygotic and dizygotic twin pairs, we estimated the variance in CD25 expression by helper T cells displaying a naive phenotype to be largely driven by genetic and shared early environmental influences. Nonetheless, the expanding helper T cells of twins with MS, which were also elevated in non-twin patients with MS, emerged independent of the individual genetic makeup. These cells expressed central nervous system-homing receptors, exhibited a dysregulated CD25-IL-2 axis, and their proliferative capacity positively correlated with MS severity. Together, our matched-pair analysis of the extended twin approach allowed us to discern genetically and environmentally determined features of an MS-associated immune signature.

Ingelfinger F, Gerdes LA, Kavaka V, Krishnarajah S, Friebel E, Galli E, Zwicky P, Furrer R, Peukert C, Dutertre CA, Eglseer KM, Ginhoux F, Flierl-Hecht A, Kümpfel T, De Feo D, Schreiner B, Mundt S, Kerschensteiner M, Hohlfeld R, Beltrán E, Becher B. Twin study reveals non-heritable immune perturbations in multiple sclerosis. Nature. 2022 Mar;603(7899):152-158. doi: 10.1038/s41586-022-04419-4. Epub 2022 Feb 16. PMID: 35173329.


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Abstract: “Current knowledge on Multiple Sclerosis (MS) etiopathogenesis encompasses complex interactions between the host’s genetic background and several environmental factors that result in dysimmunity against the central nervous system. An old-aged association exists between MS and viral infections, capable of triggering and sustaining neuroinflammation through direct and indirect mechanisms. The novel Coronavirus, SARS-CoV-2, has a remarkable, and still not fully understood, impact on the immune system: the occurrence and severity of both acute COVID-19 and post-infectious chronic illness (long COVID-19) largely depends on the host’s response to the infection, that echoes several aspects of MS pathobiology. Furthermore, other MS-associated viruses, such as the Epstein-Barr Virus (EBV) and Human Endogenous Retroviruses (HERVs), may enhance a mechanistic interplay with the novel Coronavirus, with the potential to interfere in MS natural history. Studies on COVID-19 in people with MS have helped clinicians in adjusting therapeutic strategies during the pandemic; similar efforts are being made for SARS-CoV-2 vaccination campaigns. In this Review, we look over 18 months of SARS-CoV-2 pandemic from the perspective of MS: we dissect neuroinflammatory and demyelinating mechanisms associated with COVID-19, summarize pathophysiological crossroads between MS and SARS-CoV-2 infection, and discuss present evidence on COVID-19 and its vaccination in people with MS.”

Bellucci G, Rinaldi V, Buscarinu MC, Reniè R, Bigi R, Pellicciari G, Morena E, Romano C, Marrone A, Mechelli R, Salvetti M, Ristori G. Multiple Sclerosis and SARS-CoV-2: Has the Interplay Started? Front Immunol. 2021 Sep 27;12:755333. doi: 10.3389/fimmu.2021.755333. PMID: 34646278; PMCID: PMC8503550.



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Abstract: There is strong evidence for brain-related abnormalities in COVID-19. It remains unknown however whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here, we investigated brain changes in 785 UK Biobank participants (aged 51–81) imaged twice, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans, with 141 days on average separating their diagnosis and second scan, and 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including: (i) greater reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus, (ii) greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex, and (iii) greater reduction in global brain size. The infected participants also showed on average larger cognitive decline between the two timepoints. Importantly, these imaging and cognitive longitudinal effects were still seen after excluding the 15 cases who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease via olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious impact can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow up.

Douaud, G., Lee, S., Alfaro-Almagro, F. et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature (2022). https://doi.org/10.1038/s41586-022-04569-5.


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Oaklander AL et al.: Peripheral Neuropathy Evaluations of Patients With Prolonged Long COVID.  

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Abstract: Epstein-Barr virus (EBV), also known as human herpesvirus 4, is a double-stranded DNA virus that is ubiquitous in 90-95% of the population as a gamma herpesvirus. It exists in two main states, latent infection and lytic replication, each encoding viral proteins with different functions. Human B-lymphocytes and epithelial cells are EBV-susceptible host cells. EBV latently infects B cells and nasopharyngeal epithelial cells throughout life in most immunologically active individuals. EBV-infected cells, free viruses, their gene products, and abnormally elevated EBV titers are observed in the cerebrospinal fluid. Studies have shown that EBV can infect neurons directly or indirectly viainfected B-lymphocytes, induce neuroinflammation and demyelination, promote the proliferation, degeneration, and necrosis of glial cells, promote proliferative disorders of B- and T-lymphocytes, and contribute to the occurrence and development of nervous system diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, acute cerebellar ataxia, meningitis, acute disseminated encephalomyelitis, and brain tumors. However, the specific underlying molecular mechanisms are unclear. In this paper, we review the mechanisms underlying the role of EBV in the development of central nervous system diseases, which could bebeneficial in providing new research ideas and potential clinical therapeutic targets for neurological diseases.

Zhang N, Zuo Y, Jiang L, Peng Y, Huang X, Zuo L. Epstein-Barr Virus and Neurological Diseases. Front Mol Biosci. 2022 Jan 10;8:816098. doi: 10.3389/fmolb.2021.816098. PMID: 35083281; PMCID: PMC8784775.


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Novak P. et al., Multisystem Involvement in Post-Acute Sequelae of Coronavirus Disease 19.   Annals of Neurology 91(3): 367-379 (2022).



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Long-COVID refers to the lingering or protracted illness long after the acute illness. Depression, anxiety, fatigue, concentration and cognitive impairment appeared to be reported often in long COVID, psychosis seemed uncommon. Neuropsychiatric disorders in long COVID could be a consequence of direct viral insult on the central nervous system (CNS), continuous neuroinflammation, or neurodegeneration and metabolic impairment following the cerebral vascular accidents, or hypoxia from pulmonary damages and fibrotic changes. It is important to know how patients with various disorders, not only neuropsychiatric disorders, thrive under long COVID. How much the neuropsychiatric disorders reported in long COVID are stress related in nature, due to prolonged quarantine and social isolation, would also be important to study. Patients with diabetes are already known to have a higher risk of mortality and morbidity in COVID-19. How brain glucose metabolism may contribute to the neuropsychiatric symptoms in long COVID is an important area for COVID-19 research. Patients on psychotropics often asked their clinicians about potential conflicts of their medications with anti-COVID 19 vaccinations, or whether it would increase their vulnerability to COVID-19 viral infection. Thus, early reports of protective effects of psychotropics against COVID-19 need to be validated. Some antidepressant and antipsychotic agents indeed possess significant affinities for the sigma-1 and histamine receptors. This, with the earlier reports of reduced number of sigma-1 receptors in post- mortem schizophrenic brains and the reported roles of sigma and histamine receptors in neuroinflammation and viral infections, may point to an important and novel direction for drug discovery against COVID-19. Literature and data in all these areas are accumulating at a fast rate. We reviewed and discussed the relevant and important literature.

Tang, S., Leonard, B., & Helmeste, D. (2022). Long covid, neuropsychiatric disorders, psychotropics, present and future. Acta Neuropsychiatrica, 1-43. doi:10.1017/neu.2022.6 Published online by Cambridge University Press: 11 February 2022, pp. 1-43


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Welberg, L. Strong evidence that Epstein–Barr virus infection triggers multiple sclerosis. Nat Neurosci 25, 131 (2022). https://doi.org/10.1038/s41593-022-01017-5

https://doi.org/10.1126/science.abj8222 (2022)

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Abbrev. Abstract: Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system (CNS). B lymphocytes in the cerebrospinal fluid (CSF) of MS patients contribute to inflammation and secrete oligoclonal immunoglobulinsEpstein-Barr virus (EBV) infection has been linked to MS epidemiologically, but its pathological role remains unclearHere Lanz and colleagues demonstrate high-affinity molecular mimicry between the EBV transcription factor EBNA1 and the CNS protein GlialCAM, and provide structural and in-vivo functional evidence for its relevance. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates the mouse model of MS and anti-EBNA1/GlialCAM antibodies are prevalent in MS patients. The results provide a mechanistic link for the association between MS and EBV, and could guide the development of novel MS therapies.

Lanz TV, Brewer RC, Ho PP, Moon JS, Jude KM, Fernandez D, Fernandes RA, Gomez AM, Nadj GS, Bartley CM, Schubert RD, Hawes IA, Vazquez SE, Iyer M, Zuchero JB, Teegen B, Dunn JE, Lock CB, Kipp LB, Cotham VC, Ueberheide BM, Aftab BT, Anderson MS, DeRisi JL, Wilson MR, Bashford-Rogers RJM, Platten M, Garcia KC, Steinman L, Robinson WH. Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM. Nature. 2022 Jan 24. doi: 10.1038/s41586-022-04432-7. Epub ahead of print. PMID: 35073561.

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