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1.
Frontiers in Neuroscience ; 2022.
Article in English | ProQuest Central | ID: covidwho-2022808

ABSTRACT

Editorial on the Research Topic Changes in metabolic processes affecting brain development The developing human brain has its own intrinsic chemistry and metabolic functions dictated by genetic factors and nutrient availability to provide the energy for vast proliferation, differentiation, and migration of neurons and glia, synapse formation, and circuitry establishment. Early life infections, including TORCH pathogens (toxoplasmosis, other- syphilis and parvovirus B19, rubella, cytomegalovirus CMV, and herpes simplex virus), bacteria, and other emerging pathogens such as Zika virus and SARS-CoV2, can also cause perinatal infection and lead to detrimental brain development through inflammatory pathways. [...]gut-derived short chain fatty acids can cross the blood brain barrier and activate microglia, the cannonical immune surveillance cells in the CNS, triggering a host inflammatory response through various signaling pathways such as the Jak3/STAT1 pathway (Erny et al., 2015).

2.
Frontiers in Immunology ; 13, 2022.
Article in English | EMBASE | ID: covidwho-2009862

ABSTRACT

Recent epidemiological studies show a noticeable correlation between chronic microbial infections and neurological disorders. However, the underlying mechanisms are still not clear due to the biological complexity of multicellular and multiorgan interactions upon microbial infections. In this review, we show the infection leading to neurodegeneration mediated by multiorgan interconnections and neuroinflammation. Firstly, we highlight three inter-organ communications as possible routes from infection sites to the brain: nose-brain axis, lung-brain axis, and gut-brain axis. Next, we described the biological crosstalk between microglia and astrocytes upon pathogenic infection. Finally, our study indicates how neuroinflammation is a critical player in pathogen-mediated neurodegeneration. Taken together, we envision that antibiotics targeting neuro-pathogens could be a potential therapeutic strategy for neurodegeneration.

3.
Brain Disord ; 4: 100021, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1426913

ABSTRACT

Coronaviruses have emerged as alarming pathogens owing to their inherent ability of genetic variation and cross-species transmission. Coronavirus infection burdens the endoplasmic reticulum (ER.), causes reactive oxygen species production and induces host stress responses, including unfolded protein response (UPR) and antioxidant system. In this study, we have employed a neurotropic murine ß-coronavirus (M-CoV) infection in the Central Nervous System (CNS) of experimental mice model to study the role of host stress responses mediated by interplay of DJ-1 and XBP1. DJ-1 is an antioxidant molecule with established functions in neurodegeneration. However, its regulation in virus-induced cellular stress response is less explored. Our study showed that M-CoV infection activated the glial cells and induced antioxidant and UPR genes during the acute stage when the viral titer peaks. As the virus particles decreased and acute neuroinflammation diminished at day ten p.i., a significant up-regulation in UPR responsive XBP1, antioxidant DJ-1, and downstream signaling molecules, including Nrf2, was recorded in the brain tissues. Additionally, preliminary in silico analysis of the binding between the DJ-1 promoter and a positively charged groove of XBP1 is also investigated, thus hinting at a mechanism behind the upregulation of DJ-1 during MHV-infection. The current study thus attempts to elucidate a novel interplay between the antioxidant system and UPR in the outcome of coronavirus infection.

4.
Journal of the Academy of Consultation-Liaison Psychiatry ; 63:S51, 2022.
Article in English | EMBASE | ID: covidwho-1966666

ABSTRACT

Background: The neurobiology of depression can be heterogeneous with multiple hypotheses proposed, including serotonin and neuroinflammatory pathways, each falling short of explaining the complete picture. Several reports describe the increased frequency of depression in the community following the COVID-19 pandemic and reports about neuropsychiatric sequela of the virus are emerging and the possible role of neuroinflammation. We present a patient who developed severe depression with psychotic features subsequent to his COVID-19 infection and was treated successfully with ECT following several failed medication trials. Case: A 49-year-old male with a past medical history of type II diabetes, hyperlipidemia, hypertension, chronic kidney disease, and gastroesophageal reflux disease was diagnosed with COVID-19 in January 2021. Upon initial diagnosis, neither admission nor treatment with steroids was required. He presented to the emergency department four days later with sepsis, pneumonia, and AKI secondary to COVID-19 along with the new onset of suicidal ideations with plans to cut himself and significant psychomotor features despite no previous history of mental illness or treatment. His EEG showed diffuse slow waves, consistent with encephalopathy, but no delirium was noted. He exhibited irritability, anger, anhedonia, negativism, and isolated himself in his room. He demonstrated delusional fear about his apartment exploding due to electricity disconnected for not paying his bills. He misinterpreted the blood draws as someone suspecting he has HIV. Treatment started on the medical floor and he was later transferred to the psychiatric floor. Several psychotropic medications were tried separately including citalopram 20mg, escitalopram 20mg, and bupropion (titrated to 300mg) with the addition of aripiprazole 5 mg without improvement. ECT was considered and his depression and psychosis improved following 6 treatments of bilateral ECT. He was discharged following completion of 10 ECT treatments on 300 mg of bupropion daily and 5mg olanzapine at night. Discussion: Viral infections such as HIV, Hepatitis C, and Influenza are associated with neuropsychiatric sequelae, including depression. COVID-19 infection is occasionally associated with ‘cytokine storm’ which may exacerbate neuroinflammation via increases in cytokines and possible activation of mast cells and microglia.[1] The role of elevated pro-inflammatory cytokines and glucocorticoid receptor resistance is widely studied. Interleukin-6 and CRP are the most strongly linked to depression with a high correlation for anhedonia and psychomotor retardation, prominent features of depression in our case, hinting at a possible role of neuroinflammation. [2] Psychotic features and psychomotor retardation are predictors of ECT response which matched the response to ECT in this case. References: 1. Kempuraj, Duraisamy, et al. COVID-19, mast cells, cytokine storm, psychological stress, and neuroinflammation. The Neuroscientist 2020: 402-414. 2. Tiemeier, Henning, et al. Inflammatory proteins and depression in the elderly. Epidemiology 2003: 103-107.

5.
Pathogens ; 11(7)2022 Jul 21.
Article in English | MEDLINE | ID: covidwho-1938938

ABSTRACT

The small ubiquitin-like modifier (SUMO) system regulates numerous biological processes, including protein localization, stability and/or activity, transcription, and DNA repair. SUMO also plays critical roles in innate immunity and antiviral defense by mediating interferon (IFN) synthesis and signaling, as well as the expression and function of IFN-stimulated gene products. Viruses including human immunodeficiency virus-1, Zika virus, herpesviruses, and coronaviruses have evolved to exploit the host SUMOylation system to counteract the antiviral activities of SUMO proteins and to modify their own proteins for viral persistence and pathogenesis. Understanding the exploitation of SUMO is necessary for the development of effective antiviral therapies. This review summarizes the interplay between viruses and the host SUMOylation system, with a special emphasis on viruses with neuro-invasive properties that have pathogenic consequences on the central nervous system.

6.
J Neuropathol Exp Neurol ; 2022 Jul 11.
Article in English | MEDLINE | ID: covidwho-1931851

ABSTRACT

Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.

7.
Internal Medicine Journal ; 52(SUPPL 1):13, 2022.
Article in English | EMBASE | ID: covidwho-1916176

ABSTRACT

Background: Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) has been associated to Epstein Bar Virus (EBV), Coxsakie virus and Ross River virus infections. Recently a similar condition to ME/CFS has been described as 'Long Covid' associated to SARS-CoV-2. Patients with positive EBV serology and ME/CFS may be carriers of a chronic latent infection that translates in a chronic systemic inflammation with neuroinflammation. The activation of the immunologic cascade after a viral infection or vaccination can trigger the formation of Anti-idiotype antibodies (Ab2) and an activation of pyrin domain containing protein3 (NRLP3) inflammasome. The NRLP3 inflammasome is the pattern of activation for interleukin (IL1-beta) cytokine complex which is activated in inflammatory conditions (1). Colchicine is postulated to work by inhibiting tubulin polymerization and microtubule formation blocking inflammasome activation (2). Spironolactone increased the activity and number of macrophage angiotensin converting enzyme 2 (ACE2) receptors. In the microglia this effect may represent a reduction of neuro-inflammation (3). In this we present ME/CFS patients treated with the synergetic effect of Colchicine and Spironolactone to inhibit Inflammasome and decrease inflammation. Population and Method: 23 patients (19 females) with positive serology for EBV infection and ME/CFS were included. All the patients were treated with multivitamins. Patients were educated about benefit and adverse effects of spironolactone and colchicine before treatment. The starting dose of Spironolactone was 12.5 mg a day increased to 25 mg a day (during years 2019 to 2021). The introduction of Colchicine 0.5 mg/day on treatment plan was during year 2021. Patient follow-up was in the outpatient clinic and GP clinic. Results: Total 23 Patients 19 were Females age 37.3+28 and 4 were Males age 61+9. Two patients stop colchicine after 4 weeks. Improvement in cognitive skills was the early manifestation of spironolactone benefit. Patients reported to be less brain foggy, more alert, and they found it easier to focus when doing normal everyday activities. They were also less irritable by noise and light and described themselves to be able to multi-task again. There was an improvement in general condition and everyday activities four weeks after Colchicine started. Conclusion: Patients with ME/CFS improve their cognitive skills and everyday physical activity tolerance when treated with Colchicine and Spironolactone.

8.
Internal Medicine Journal ; 52(SUPPL 1):13-14, 2022.
Article in English | EMBASE | ID: covidwho-1916175

ABSTRACT

Introduction: Since the SARS-CoV-2 (severe acute respiratory syndrome coronavirus2) vaccination started there have been multiple reports of different off target adverse effects related to the vaccination, such as myocarditis, immune mediated thrombosis, thrombocytopenia and allergic reactions. W Murphy and Dan Longo in the NEJM November 2021 reported these adverse effects associated with Anti-idiotype antibodies (Ab2) in SARS-CoV-2 vaccination. The pathologic cascade of Ab2 is described in several ways as the antibodies can bind to the protective normal antibodies (Ab1) resulting in immune complex formation and clearance thus impairing Ab1 efficacy. Another action of the Ab2 could be inhibiting normal ligands affecting interaction with angiotensin converting enzyme 2 (ACE2) receptors or stimulating the ACE2 receptor and downregulating the ACE2 function. There is also a description of complementmediated and immune cell attack on ACE2 expressing cells (1). The case reported in this manuscript is related to a severe deterioration in a male with previous diagnose of ME/CFS with worsening lethargy and cognitive skills after SARS-CoV-2 vaccination. The outstanding clinical improvement after starting oral Colchicine is the reason for this paper. Case Report: A 46-year-old male with a previous history of Sarcoidosis and Haemochromatosis had ME/CFS since 2016. He was followed up at Noosa Hospital clinic related to his ME/CFS. His general symptoms related to this condition were under control and he was able to work and study at the University. After the second dose of his SARS-CoV-2 (Pfizer -BioNTech COVID-19) vaccination in August 2021 his general condition deteriorated. During September-October 2021 his cognitive skills declined and he had to stop his university studies. The patient also stopped driving his car because of lethargy and could not do any sport recreational activity. Because of ME/CFS he was on treatment with multivitamins and low dose Naltrexone and Spironolactone before vaccination. After the ME/CFS clinical deterioration the decision was to start Colchicine 0.5 mg a day (November 2021). After four weeks of Colchicine plus his previous medication, his level of energy and cognitive skills recovered to pre vaccination status. Discussion: The immunologic cascade after SARS-CoV-2 vaccination triggered by Ab2 ended in activation of pyrin domain containing protein3 (NRLP3 Inflammasome). This is the pattern of activation for interleukin (IL-1beta). This may determine a general increase in the systemic and microglia inflammation as described in ME/CFS. The clinical manifestation in the present case was worsening in the symptoms of the ME/CFS. The patient was already on Spironolactone targeting the increase on number of macrophages ACE2 receptors as immune modulation. An anti-inflammatory synergy between Colchicine and Spironolactone is currently the focus of research in atherosclerosis. Colchicine has a direct effect on phagocytes leading to inflammasome inhibition and impaired production of IL-1 beta. Conclusion: The Colchicine had a beneficial effect in recovering this patient from an exacerbation of his ME/CFS induced by SARS-CoV-2 vaccination.

9.
Italian Journal of Medicine ; 16(SUPPL 1):24, 2022.
Article in English | EMBASE | ID: covidwho-1912950

ABSTRACT

Case Report: A 62-year-old previously healthy male presented to the ED for confusion and single episode of epilepsy. A week earlier he received influenza vaccine. At admission, he had fever and agitation without meningeal irritation or neurological focal signs. Diagnostic tests including brain contrast-enhanced CT scan, MRI, nasopharyngeal SARS-CoV-2 swabs and lumbar puncture resulted unremarkable except for slightly increased CRP and increase of CSF and serum IL-6. On the 3°day, after hydration, steroids and antibiotic therapy, the patient presented a normal mental status, though amnesic for the previous 72 hours. A EEG on the 5°day and serum levels of IL-6 on the 8°day were normal. The patient was discharged at 10°day in good clinical conditions. Discussion: The acute onset after vaccination in absence of other documented etiologies, the overproduction of intrathecal neuroinflammatory mediators, the downward trend of cytokines and the prompt recovery after corticosteroid therapy, seem the typical picture of a brain dysfunction associated to cytokine storm. Recently, a unifying definition of cytokine storm-associated encephalopathy (CySE) was proposed. CySE origins from the massive release of cytokines promoting blood-brain barrier disruption and microglia/ astrocyte activation which support neuroinflammation in a synergistic act. Conclusions: We documented the first hyperacute reversible encephalopathy following influenza vaccination, suggesting cytokine storm as its causative mechanism, and highlighting the need to deepen our knowledge on this immune-mediated phenomenon.

10.
Virologie ; 26(2):120, 2022.
Article in English | EMBASE | ID: covidwho-1912931

ABSTRACT

Establishment of the interferon (IFN)-mediated antiviral state provides a crucial initial line of defense against viral infection. Numerous genes that contribute to this antiviral state remain to be identified. Using a loss-of-function strategy, we screened an original library of 1156 siRNAs targeting 386 individual curated human genes in stimulated microglial cells infected with Zika virus (ZIKV), an emerging RNA virus that belongs to the flavivirus genus. The screen recovered twenty-one potential host proteins that modulate ZIKV replication in an IFN-dependent manner, including the previously known IFITM3 and LY6E. Further characterization contributed to delineate the spectrum of action of these genes towards other pathogenic RNA viruses, including Hepatitis C virus and SARS-CoV-2. Our data revealed that APOL3 acts as a proviral factor for ZIKV and several other related and unrelated RNA viruses. In addition, we showed that MTA2, a chromatin remodeling factor, possesses potent flavivirus-specific antiviral functions. We are currently investigating the molecular mechanisms behind IFN-dependent flaviviral restriction of MTA2. Our work identified previously unrecognized genes that modulate the replication of RNA viruses in an IFN-dependent way, opening new perspectives to target weakness points in the life cycle of these viruses.

11.
Front Cell Neurosci ; 16: 918883, 2022.
Article in English | MEDLINE | ID: covidwho-1911070

ABSTRACT

Prion diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep, are infectious and chronic neurodegenerative diseases to which there are no cures. Infection with prions in the central nervous system (CNS) ultimately causes extensive neurodegeneration, and this is accompanied by prominent microglial and astrocytic activation in affected regions. The microglia are the CNS macrophages and help maintain neuronal homeostasis, clear dead or dying cells and provide defense against pathogens. The microglia also provide neuroprotection during CNS prion disease, but their pro-inflammatory activation may exacerbate the development of the neuropathology. Innate immune tolerance induced by consecutive systemic bacterial lipopolysaccharide (LPS) treatment can induce long-term epigenetic changes in the microglia in the brain that several months later can dampen their responsiveness to subsequent LPS treatment and impede the development of neuritic damage in a transgenic mouse model of Alzheimer's disease-like pathology. We therefore reasoned that innate immune tolerance in microglia might similarly impede the subsequent development of CNS prion disease. To test this hypothesis groups of mice were first infected with prions by intracerebral injection, and 35 days later given four consecutive systemic injections with LPS to induce innate immune tolerance. Our data show that consecutive systemic LPS treatment did not affect the subsequent development of CNS prion disease. Our data suggests innate immune tolerance in microglia does not influence the subsequent onset of prion disease-induced neuropathology in mice, despite previously published evidence of this effect in an Alzheimer's disease mouse model.

12.
Free Neuropathology ; 3, 2022.
Article in English | Scopus | ID: covidwho-1904016

ABSTRACT

Here, we review a collection of recent manuscripts and research trends on the neuropathology of neurodegen-eration that are considered by the author to be among the potentially most impactful. To the greatest extent possible, we chose to focus on histopathological studies that are most relevant to experimental and diagnostic neuropathology. While there has been an abundance of important recent discoveries and developments in neu-rodegenerative disease research, there was a deliberate effort here to provide balance to prevent disease categories and experimental approaches from overshadowing the others. The result is a diverse series of outstanding studies, together showing the landscape of progress across neurodegenerative disorders. One is a stereological study examining dystrophic microglia in aging. We highlight the first large genetic study of primary age-related tauopathy, showing convergence and divergence from classical Alzheimer’s disease. There were further advances in the neuropathological criteria and staging of chronic traumatic encephalopathy. Links suggesting a causal role for TMEM106B in TDP-43 proteinopathy emerged. Attempts to subtype Alzheimer’s disease on the molecular level were made. Evidence for a role for the VEGF family in cognitive impairment was advanced. Comparison of gene expression profiles from myeloid cells in peripheral blood and brain tissues from Parkinson’s disease patients revealed pathways that may lead to new mechanistic insights and biomarkers. A large autopsy series identified an increased frequency of central nervous system developmental malformations in Huntington’s disease. A robust and reliable system for assessing Lewy body pathology was proposed. Finally, we continue to be plagued by the COVID-19 pandemic, with lingering concerns of a long-term link with neurodegeneration. © 2022 The author(s).

13.
The Lancet Infectious Diseases ; 20(5):549, 2020.
Article in English | ProQuest Central | ID: covidwho-1900300

ABSTRACT

The researchers then showed that APN01 could inhibit viral replication in human blood vessel and kidney organoids (three-dimensional cell cultures derived from stem cells). An electron microscopy study in brain tissue samples from people who had been infected showed that the chronic infection causes a loss of inhibitory synapses and an unsheathing of other neurons by microglia, with similar histological patterns seen in other psychiatric disorders. Sickle cell and HIV Findings from a new study have added weight to previous suggestions that people with sickle-cell anaemia have a lower risk of HIV infection than otherwise healthy people—but it was unable to pin down the mechanistic explanation as to why.

14.
Adv Gerontol ; 35(2):263-273, 2022.
Article in Russian | PubMed | ID: covidwho-1897968

ABSTRACT

The role of neuronal inflammation developing during the formation of amyloid plaques and Lewy bodies has been investigated. The influence of various exogenous and endogenous factors on the development of neuroinflammation has been established, but the role of various infectious agents in the development of this process has been much less studied. Today, the existence of a universal trigger mechanism of the neurodegenerative process is obvious: a specific pathogen of a bacterial or viral nature (including a long-term persistent in the nervous tissue in a latent state), reactivating, penetrates into certain cerebral structures, where it is influenced by either Aβ or resident macrophages of the central nervous system, which, in turn, are activated and induce the release of pro-inflammatory cytokines, leading to the development of neuronal inflammation, autophagy and neurodegeneration. Reactivation of latent, such as herpes, infection in individuals who are carriers of APOE4 significantly increases the risk of developing Alzheimer's disease. Class II genes of the HLA locus (HLA II) may be related to the progression of neurodegenerative diseases. The increase in iron levels in the glia is induced by inflammation, which leads to neurodegeneration. Disruption of the homeostasis of redox-active metals, iron and copper, is an integral part of the pathogenesis of Alzheimer's disease and Parkinson's disease. The developing neuroinflammation leads to the intensification of the processes of peroxidation, oxidation of metals and the development of ferroptosis.

15.
Med Drug Discov ; 15: 100136, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1885989

ABSTRACT

The emergence of new SARS-CoV-2 variants continues to pose an enormous public health concern. The SARS-CoV-2 infection disrupted host immune response accounting for cytokine storm has been linked to multiorgan failure and mortality in a significant portion of positive cases. Abruptly activated macrophages have been identified as the key pathogenic determinant of cytokine storm in COVID-19. Besides, reactive microglia have been known to discharge a surplus amount of proinflammatory factors leading to neuropathogenic events in the brains of SARS-CoV-2 infected individuals. Considering the fact, depletion of activated macrophages and microglia could be proposed to eradicate the life-threatening cytokine storm in COVID-19. Clodronate, a non-nitrogenous bisphosphonate drug has been identified as a potent macrophage and microglial depleting agent. While recent advancement in the field of liposome encapsulation technology offers the most promising biological tool for drug delivery, liposome encapsulated clodronate has been reported to effectively target and induce prominent phagocytic cell death in activated macrophages and microglia compared to free clodronate molecules. Thus, in this review article, we emphasize that depletion of activated macrophages and microglial cells by administration of liposome encapsulated clodronate can be a potential therapeutic strategy to diminish the pathogenic cytokine storm and alleviate multiorgan failure in COVID-19. Moreover, recently developed COVID-19 vaccines appear to render the chronic activation of macrophages accounting for immunological dysregulation in some cases. Therefore, the use of liposome encapsulated clodronate can also be extended to the clinical management of unforeseen immunogenic reactions resulting from activated macrophages associated adverse effects of COVID-19 vaccines.

16.
Int Immunopharmacol ; 109: 108903, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1885844

ABSTRACT

With the widespread use of volatile anesthetic agents in the prolonged sedation for COVID-19 pneumonia and ARDS, there is an urgent need to investigate the effects and treatments of lengthy low-concentration inhaled anesthetics exposure on cognitive function in adults. Previous studies showed that general anesthetics dose- and exposure length-dependently induced neuroinflammatory response and cognitive decline in neonatal and aging animals. The anti-diabetes drug metformin has anti-neuroinflammation effects by modulating microglial polarization and inhibiting astrocyte activation. In this study, we demonstrated that the inhalation of 1.3% isoflurane (a sub-minimal alveolar concentration, sub-MAC) for 6 h impaired recognition of novel objects from Day 1 to Day3 in adult mice. Prolonged sub-MAC isoflurane exposure also triggered typically reactive microglia and A1-like astrocytes in the hippocampus of adult mice on Day 3 after anesthesia. In addition, prolonged isoflurane inhalation switched microglia into a proinflammatory M1 phenotype characterized by elevated CD68 and iNOS as well as decreased arginase-1 and IL-10. Metformin pretreatment before anesthesia enhanced cognitive performance in the novel object test. The positive cellular modifications promoted by metformin pretreatment included the inhibition of reactive microglia and A1-like astrocytes and the polarization of microglia into M2 phenotype in the hippocampus of adult mice. In conclusion, prolonged sub-MAC isoflurane exposure triggered significant hippocampal neuroinflammation and cognitive decline in adult mice which can be alleviated by metformin pretreatment via inhibiting reactive microglia and A1-like astrocytes and promoting microglia polarization toward anti-inflammatory phenotype in the hippocampus.


Subject(s)
Anesthetics , COVID-19 , Cognitive Dysfunction , Isoflurane , Metformin , Animals , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/drug therapy , Isoflurane/pharmacology , Isoflurane/therapeutic use , Metformin/pharmacology , Metformin/therapeutic use , Mice , Microglia , Neuroinflammatory Diseases
17.
Cell ; 185(14): 2452-2468.e16, 2022 07 07.
Article in English | MEDLINE | ID: covidwho-1885669

ABSTRACT

COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.


Subject(s)
COVID-19 , Influenza, Human , Neoplasms , Animals , Humans , Influenza, Human/pathology , Mice , Microglia/pathology , Myelin Sheath , Neoplasms/pathology , SARS-CoV-2
18.
Journal of Urology ; 207(SUPPL 5):e415, 2022.
Article in English | EMBASE | ID: covidwho-1886501

ABSTRACT

INTRODUCTION AND OBJECTIVE: Neurodegenerative diseases, such as multiple sclerosis (MS), often lead to the development of neurogenic lower urinary tract symptoms (LUTS). We previously characterized neurogenic bladder dysfunction in a mouse model of MS induced by a coronavirus, mouse hepatitis virus (MHV). The objective of this study was to identify genes and pathways linking neuroinflammation in the central nervous system with urinary bladder dysfunction to enhance our understanding of the mechanisms underlying LUTS in demyelinating diseases. METHODS: Adult C57BL/6 male mice (N=12) received either an intracranial injection of MHV (6,000 PFU) or sterile saline (control). The lumbosacral (L6-S2) spinal cord (SC) segments and urinary bladders were collected during acute infection stage (week 1) and at the first peak of demyelination (week 4) after inoculation with the virus. Total RNA was isolated and analyzed using Nanostring nCounter Neuroinflammation panel. The expression levels of 770 genes associated with neuroinflammation were assessed and compared between the specimens. RESULTS: Transcriptome analysis of SC specimens confirmed a significantly increased expression of 132 genes in MHV mice (tens to hundreds fold change) involved in the regulation of astrocyte, microglia and oligodendrocyte functions, neuroinflammation and immune responses. Out of 132 genes up-regulated in the SC, only 2 genes (siglec1, 46-fold in the SC, 2.6-fold at 1 week and 1.8-fold at 4 weeks in the bladder;and zbp1, 568-fold in the SC, 2.8-fold at 1 week and 2.2-fold at 4 weeks in the bladder) were up-regulated in the urinary bladders of MHV-infected mice. Additionally, two genes were significantly up-regulated (ttr, 2.2-fold at 1week and 1.7-fold at 4 weeks;and ms4a4a, 2.3-fold at 1week and 1.6-fold at 4 weeks), and two were down-regulated (asb2, -1.8-fold at 1 week and -1.6-fold at 4 weeks, and myct1, -1.7-fold at 1week and -1.6-fold at 4 weeks) exclusively in the urinary bladders of MHV mice. CONCLUSIONS: Two genes, siglec1 (encodes type 1 transmembrane protein, expressed in microglia and macrophages, promotes neuroinflammation) and zbp1 (encodes a Z-DNA binding protein, plays role in the innate immune response) link the development of neuroinflammation in the central nervous system with neurogenic changes in the urinary bladders of MHV-infected mice. Further research is needed to establish a functional relationship between expression of these genes and neurogenic LUTS.

19.
Viruses ; 14(6)2022 06 03.
Article in English | MEDLINE | ID: covidwho-1884379

ABSTRACT

The numerous neurological syndromes associated with COVID-19 implicate an effect of viral pathogenesis on neuronal function, yet reports of direct SARS-CoV-2 infection in the brain are conflicting. We used a well-established organotypic brain slice culture to determine the permissivity of hamster brain tissues to SARS-CoV-2 infection. We found levels of live virus waned after inoculation and observed no evidence of cell-to-cell spread, indicating that SARS-CoV-2 infection was non-productive. Nonetheless, we identified a small number of infected cells with glial phenotypes; however, no evidence of viral infection or replication was observed in neurons. Our data corroborate several clinical studies that have assessed patients with COVID-19 and their association with neurological involvement.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Brain , Cricetinae , Humans , Neuroglia , Neurons
20.
Topics in Antiviral Medicine ; 30(1 SUPPL), 2022.
Article in English | EMBASE | ID: covidwho-1879890

ABSTRACT

The proceedings contain 936 papers. The topics discussed include: vaccine strategies for HIV-1 and COVID-19;we?re still here: HIV, aging, and the invisible generation;HIV prevention in vulnerable populations: generating evidence to reduce inequalities;liver steatosis in persons living with HIV;deep mutational scanning to interpret viral evolution;the original delta virus or D like the devil;assessing vaccine effectiveness in the real world;studying covid treatment outcomes: why disparate results?;analysis approaches to correlates of vaccine efficacy;HIV nonhuman primate models for studies of virus pathogenesis, persistence, and cure;children exposed to HIV, but uninfected: evidence for action;macrophages are the primary source of virus in semen in acutely infected macaques;HIV infection of brain organoid microglia induces inflammation and neuronal death;and Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2.

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