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1.
Brain, Behavior, and Immunity ; 2023.
Article in English | ScienceDirect | ID: covidwho-2176735

ABSTRACT

COVID-19 and especially Long COVID are associated with severe CNS symptoms and may place persons at risk to develop long-term cognitive impairments. Here, we show that two non-infective models of SARS-CoV-2 can cross the blood-brain barrier (BBB) and induce neuroinflammation, a major mechanism underpinning CNS and cognitive impairments, even in the absence of productive infection. The viral models cross the BBB by the mechanism of adsorptive transcytosis with the sugar N-acetylglucosamine being key. The delta and omicron variants cross the BBB faster than the other variants of concern, with peripheral tissue uptake rates also differing for the variants. Neuroinflammation induced by icv injection of S1 protein was greatly enhanced in young and especially in aged SAMP8 mice, a model of Alzheimer's disease, whereas sex and obesity had little effect.

2.
International Journal of Molecular Sciences ; 23(24):16085, 2022.
Article in English | ProQuest Central | ID: covidwho-2200326

ABSTRACT

HSV-1 is a typical neurotropic virus that infects the brain and causes keratitis, cold sores, and occasionally, acute herpes simplex encephalitis (HSE). The large amount of proinflammatory cytokines induced by HSV-1 infection is an important cause of neurotoxicity in the central nervous system (CNS). Microglia, as resident macrophages in CNS, are the first line of defense against neurotropic virus infection. Inhibiting the excessive production of inflammatory cytokines in overactivated microglia is a crucial strategy for the treatment of HSE. In the present study, we investigated the effect of nicotinamide n-oxide (NAMO), a metabolite mainly produced by gut microbe, on HSV-1-induced microglial inflammation and HSE. We found that NAMO significantly inhibits the production of cytokines induced by HSV-1 infection of microglia, such as IL-1β, IL-6, and TNF-α. In addition, NAMO promotes the transition of microglia from the pro-inflammatory M1 type to the anti-inflammatory M2 type. More detailed studies revealed that NAMO enhances the expression of Sirtuin-1 and its deacetylase enzymatic activity, which in turn deacetylates the p65 subunit to inhibit NF-κB signaling, resulting in reduced inflammatory response and ameliorated HSE pathology. Therefore, Sirtuin-1/NF-κB axis may be promising therapeutic targets against HSV-1 infection-related diseases including HSE.

3.
Advances in Gerontology ; 12(4):386-395, 2022.
Article in English | Web of Science | ID: covidwho-2193602

ABSTRACT

The role of neuronal inflammation developing during the formation of amyloid plaques and Lewy bodies is investigated. The influence of various exogenous and endogenous factors on the development of neuroinflammation is established, but the role of various infectious agents in the development of this process is 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 long-term persistent in nervous tissue in a latent state), reactivating, penetrates into certain cerebral structures, where it is influenced by either A beta or resident macrophages of the central nervous system, which, in turn, are activated and induce the release of proinflammatory cytokines, leading to the development of neuronal inflammation, autophagy and neurodegeneration. The reactivation of latent infection, such as herpes, in APOE4 carriers significantly increases the risk of development of Alzheimer's disease. Class-II genes of the HLA locus (HLA II) may be related to the progression of neurodegenerative diseases. An 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 intensification of the processes of peroxidation, oxidation of metals and the development of ferroptosis.

4.
Journal of Affective Disorders Reports ; : 100463, 2023.
Article in English | ScienceDirect | ID: covidwho-2165468

ABSTRACT

This review summarizes the pharmacological properties of tetrahydrocannabinol (THC) and cannabidiol (CBD), cannabinoid components of several species of herbal cannabis. The pharmacological effects of the phytocannabinoids have been extensively investigated and the importance of the cannabinoid receptors (CB1 and CB2) on immune cells has provided important information on the intracellular targets for these molecules. In addition to the phytocannabinoids, endogenous cannabinoids also exist in the form of anadramide and 2-srodolylglycerol (2-AG). These, together with their synthesizing and metabolizing enzymes, form the cannabinoid system. Since the discovery of the endocannabinoid system and the role that neuroinflammation plays in neurological and psychiatric illness, the potential therapeutic importance of this system has been of growing interest. In addition, the need to develop drugs which specifically target the CB1 and CB2 receptors has been stimulated by the pharmacological complexity of both THC and CBD. This review briefly summarizes the therapeutic potential of the naturally occurring and the synthetic cannabinoids which will need to be developed, if such drugs are to fulfill the therapeutic promise which the cannabinoids offer.

5.
Int Immunopharmacol ; 113(Pt B): 109436, 2022 Nov 14.
Article in English | MEDLINE | ID: covidwho-2119471

ABSTRACT

Social behavior is essential for the well-being and survival of individuals. However, social isolation is a serious public health issue, especially during the COVID-19 pandemic, affecting a significant number of people worldwide, and can lead to serious psychological crises. Microglia, innate immune cells in the brain, are strongly implicated in the development of psychiatry. Although many microglial inhibitors have been used to treat depression, there is no literature report on pexidartinib (PLX3397) and social isolation. Herein, we adopted PLX3397 to investigate the role of microglia in the modulation of social isolation. Our results found that social isolation during adolescence caused depressive-like, but not anxiety-like behavior in mice in adulthood, with enhanced expression of the microglial marker Iba1 in the hippocampus. In addition, treatment with PLX3397 reduced the expression of the microglial marker Iba1, decreased the mRNA expression of IL-1ß, increased the mRNA expression of Arg1, elevated the protein levels of DCX and GluR1 and restored the dendritic spine branches and density, ultimately mitigating depressive-like behavior in mice. These findings suggest that inhibition of microglia in the hippocampus could ameliorate mood disorders in mice, providing a new perspective for the treatment of psychiatric disorders such as depression.

6.
Int J Mol Sci ; 23(22)2022 Nov 19.
Article in English | MEDLINE | ID: covidwho-2116228

ABSTRACT

Interferons (IFNs) are pleiotropic cytokines originally identified for their antiviral activity. IFN-α and IFN-ß are both type I IFNs that have been used to treat neurological diseases such as multiple sclerosis. Microglia, astrocytes, as well as neurons in the central and peripheral nervous systems, including spinal cord neurons and dorsal root ganglion neurons, express type I IFN receptors (IFNARs). Type I IFNs play an active role in regulating cognition, aging, depression, and neurodegenerative diseases. Notably, by suppressing neuronal activity and synaptic transmission, IFN-α and IFN-ß produced potent analgesia. In this article, we discuss the role of type I IFNs in cognition, neurodegenerative diseases, and pain with a focus on neuroinflammation and neuro-glial interactions and their effects on cognition, neurodegenerative diseases, and pain. The role of type I IFNs in long-haul COVID-associated neurological disorders is also discussed. Insights into type I IFN signaling in neurons and non-neuronal cells will improve our treatments of neurological disorders in various disease conditions.


Subject(s)
COVID-19 , Interferon Type I , Nervous System Diseases , Humans , Neuroinflammatory Diseases , Nervous System Diseases/drug therapy , Interferon-alpha , Interferon-beta , Pain
7.
Cell Rep ; 41(5): 111573, 2022 Nov 01.
Article in English | MEDLINE | ID: covidwho-2113996

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), can induce a plethora of neurological complications in some patients. However, it is still under debate whether SARS-CoV-2 directly infects the brain or whether CNS sequelae result from systemic inflammatory responses triggered in the periphery. By using high-resolution microscopy, we investigated whether SARS-CoV-2 reaches the brain and how viral neurotropism can be modulated by aging in a non-human primate model of COVID-19. Seven days after infection, SARS-CoV-2 was detected in the olfactory cortex and interconnected regions and was accompanied by robust neuroinflammation and neuronal damage exacerbated in aged, diabetic animals. Our study provides an initial framework for identifying the molecular and cellular mechanisms underlying SARS-CoV-2 neurological complications, which will be essential to reducing both the short- and long-term burden of COVID-19.


Subject(s)
COVID-19 , Nervous System Diseases , Animals , SARS-CoV-2 , Neuroinflammatory Diseases , Neurons , Primates
8.
PeerJ ; 10: e14227, 2022.
Article in English | MEDLINE | ID: covidwho-2110911

ABSTRACT

Persistence of symptoms beyond the initial 3 to 4 weeks after infection is defined as post-acute COVID-19 syndrome (PACS). A wide range of neuropsychiatric symptoms like anxiety, depression, post-traumatic stress disorder, sleep disorders and cognitive disturbances have been observed in PACS. The review was conducted based on PRISMA-S guidelines for literature search strategy for systematic reviews. A cytokine storm in COVID-19 may cause a breach in the blood brain barrier leading to cytokine and SARS-CoV-2 entry into the brain. This triggers an immune response in the brain by activating microglia, astrocytes, and other immune cells leading to neuroinflammation. Various inflammatory biomarkers like inflammatory cytokines, chemokines, acute phase proteins and adhesion molecules have been implicated in psychiatric disorders and play a major role in the precipitation of neuropsychiatric symptoms. Impaired adult neurogenesis has been linked with a variety of disorders like depression, anxiety, cognitive decline, and dementia. Persistence of neuroinflammation was observed in COVID-19 survivors 3 months after recovery. Chronic neuroinflammation alters adult neurogenesis with pro-inflammatory cytokines supressing anti-inflammatory cytokines and chemokines favouring adult neurogenesis. Based on the prevalence of neuropsychiatric symptoms/disorders in PACS, there is more possibility for a potential impairment in adult neurogenesis in COVID-19 survivors. This narrative review aims to discuss the various neuroinflammatory processes during PACS and its effect on adult neurogenesis.

9.
J Neuroinflammation ; 19(1): 267, 2022 Nov 04.
Article in English | MEDLINE | ID: covidwho-2108803

ABSTRACT

BACKGROUND: Triggering receptor expressed on myeloid cells 2 (Trem2) plays a protective role in neurodegenerative diseases. By contrast, Trem2 functions can exacerbate tissue damage during respiratory viral or liver infections. We, therefore, investigated the role of Trem2 in a viral encephalomyelitis model associated with prominent Th1 mediated antiviral immunity leading to demyelination. METHODS: Wild-type (WT) and Trem2 deficient (Trem2-/-) mice were infected with a sublethal glia tropic murine coronavirus (MHV-JHM) intracranially. Disease progression and survival were monitored daily. Leukocyte accumulation and pathological features including demyelination and axonal damage in spinal cords (SC) were determined by flow cytometry and tissue section immunofluorescence analysis. Expression of select inflammatory cytokines and chemokines was measured by RT-PCR and global myeloid cell gene expression in SC-derived microglia and infiltrated bone-marrow-derived macrophages (BMDM) were determined using the Nanostring nCounter platform. RESULTS: BMDM recruited to SCs in response to infection highly upregulated Trem2 mRNA compared to microglia coincident with viral control. Trem2 deficiency did not alter disease onset or severity, but impaired clinical recovery after onset of demyelination. Disease progression in Trem2-/- mice could not be attributed to altered virus control or an elevated proinflammatory response. A prominent difference was increased degenerated myelin not associated with the myeloid cell markers IBA1 and/or CD68. Gene expression profiles of SC-derived microglia and BMDM further revealed that Trem2 deficiency resulted in impaired upregulation of phagocytosis associated genes Lpl and Cd36 in microglia, but a more complex pattern in BMDM. CONCLUSIONS: Trem2 deficiency during viral-induced demyelination dysregulates expression of other select genes regulating phagocytic pathways and lipid metabolism, with distinct effects on microglia and BMDM. The ultimate failure to remove damaged myelin is reminiscent of toxin or autoimmune cell-induced demyelination models and supports that Trem2 function is regulated by sensing tissue damage including a dysregulated lipid environment in very distinct inflammatory environments.


Subject(s)
Brain , Demyelinating Diseases , Animals , Mice , Brain/metabolism , Phagocytosis/genetics , Microglia/metabolism , Demyelinating Diseases/chemically induced , Disease Progression , Gene Expression , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism
10.
Neuron ; 110(21): 3484-3496, 2022 Nov 02.
Article in English | MEDLINE | ID: covidwho-2061716

ABSTRACT

Persistent neurological and neuropsychiatric symptoms affect a substantial fraction of people after COVID-19 and represent a major component of the post-acute COVID-19 syndrome, also known as long COVID. Here, we review what is understood about the pathobiology of post-acute COVID-19 impact on the CNS and discuss possible neurobiological underpinnings of the cognitive symptoms affecting COVID-19 survivors. We propose the chief mechanisms that may contribute to this emerging neurological health crisis.


Subject(s)
COVID-19 , Mental Disorders , Nervous System Diseases , Humans , SARS-CoV-2
11.
Investigative Ophthalmology and Visual Science ; 63(7):2373-A0057, 2022.
Article in English | EMBASE | ID: covidwho-2057947

ABSTRACT

Purpose : With this research project we wanted to approach the question of whether SARS-CoV 2 can infect the eye. In order to infect ocular tissues, virus-specific receptors;coreceptors or proteases must be present in the eye tissue. SARS-CoV 2 uses the human angiotensin converting enzyme 2 (ACE2) receptor to enter cells. In addition, the mammalian serine protease TMPRSS2, the protease furin and the glycoprotein neuropilin are identified as relevant proteases for the interaction of the virus with ACE2. Last year, we were able to show that ACE2 is significantly more expressed in ocular tissue of covid patients. Here the expression level of the co-receptor and glia markers, as well as the present of virus was confirmed in this study. Methods : Seven eyes from donors without covid disease (COVID-) as well as ten fixed eyes from COVID-19 patients (COVID+) were analysed for their expression profile of ACE2, TMPRSS2, neuropilin and furin in the retina and cornea. The ocular tissues were examined for protein expression by immunohistochemical staining or for RNA expression by quantitative real-time PCR. In addition, viral spike protein was detected histologically in eyes, and expression profiles of GFAP and Iba-1 were assessed. Results : Similar to ACE2 and TMPRSS2, the two proteases neuropilin and furin were detected in the retina and cornea. Interestingly, the expression profile differed in terms of strength and localization, especially in the retina. The presence of the virus in both cornea and retina was also demonstrated by the detection of viral spike protein. In all COVID+ retinas, strong GFAP staining was observed as well as some Iba-1 positive cells, suggesting activation of macro- and microglia. Conclusions : Expression of ACE2, TMPRSS2, furin and neuropilin was demonstrated in COVID+ ocular tissues. In addition to the virus detection in retina and cornea, a glial reaction could also be observed. One can therefore assume an infection of the eye in these cases. However, in summary it can be said that an infection of the eye tissue is possible since all demanded receptors are present.

12.
Investigative Ophthalmology and Visual Science ; 63(7):975-F0372, 2022.
Article in English | EMBASE | ID: covidwho-2057457

ABSTRACT

Purpose : Different signs of inflammation have been described in the brains of COVID-19 patients. In the retina, the fundus eye exam of these patients shows cotton wool spots, microhemorrhages, and a decrease in vascular density. However, morphological alterations of retinal cells in these patients are unknown. Thus, the aim was to analyze the morphological changes of the retinal cells from human donors with COVID-19 to establish several stages of response to damage in these cells and to define correlations with clinical parameters. Methods : The retinas of human donors with COVID-19 (n = 16) and control subjects (n = 12) obtained from the General University Hospital Consortium of Valencia were analyzed. Immunohistochemical stainings were performed on transversal sections or flat-mount retinas to study photoreceptors, microglial cells, Müller cells, astrocytes, and the presence of ACE2. TUNEL assays and confocal microscopy imaging were carried out. Correlations were calculated between retinal and clinical parameters. Results : Mean age of COVID-19 and control group were 80±10 and 70±8 years respectively. Müller cells, outer segment of cones and retinal pigment epithelium presented ACE2 staining. Larger staining of ACE2 and CRALBP was observed in cell bodies of Müller cells in COVID group. Disorganization of honeycomb-like pattern formed by Müller cells in the outer nuclear layer and disruption of external limiting membrane was found in the 81.3% of COVID patients. The 56.3% of COVID patients showed gliosis compared to controls (40%). COVID-19 retinas also presented epiretinal membranes and astrocytes protruding to vitreous humor. The 93.8% of COVID-19 patients had activated or ameboid-shape microglia. Microglial nodules around vessels and a reduction of the area occupied by microglia in these retinas were observed. COVID-19 group showed a more severe degeneration of cones. Cone degeneration correlated with Müller cell activation. Age of COVID patients correlated inversely with total retinal degeneration. Conclusions : Morphological alterations in the cone photoreceptors as well as glial activation showing an inflammatory state of the retina were observed in COVID-19 patients.

13.
Acta Neuropathol Commun ; 10(1): 124, 2022 Sep 05.
Article in English | MEDLINE | ID: covidwho-2009477

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with various neurological complications. Although the mechanism is not fully understood, several studies have shown that neuroinflammation occurs in the acute and post-acute phase. As these studies have predominantly been performed with isolates from 2020, it is unknown if there are differences among SARS-CoV-2 variants in their ability to cause neuroinflammation. Here, we compared the neuroinvasiveness, neurotropism and neurovirulence of the SARS-CoV-2 ancestral strain D614G, the Delta (B.1.617.2) and Omicron BA.1 (B.1.1.529) variants using in vitro and in vivo models. The Omicron BA.1 variant showed reduced neurotropism and neurovirulence compared to Delta and D614G in human induced pluripotent stem cell (hiPSC)-derived cortical neurons co-cultured with astrocytes. Similar differences were obtained in Syrian hamsters inoculated with D614G, Delta and the Omicron BA.1 variant 5 days post infection. Replication in the olfactory mucosa was observed in all hamsters, but most prominently in D614G inoculated hamsters. Furthermore, neuroinvasion into the CNS via the olfactory nerve was observed in D614G, but not Delta or Omicron BA.1 inoculated hamsters. Furthermore, neuroinvasion was associated with neuroinflammation in the olfactory bulb of hamsters inoculated with D614G. Altogether, our findings suggest differences in the neuroinvasive, neurotropic and neurovirulent potential between SARS-CoV-2 variants using in vitro hiPSC-derived neural cultures and in vivo in hamsters during the acute phase of the infection.


Subject(s)
COVID-19 , Induced Pluripotent Stem Cells , Animals , Cricetinae , Humans , Mesocricetus , SARS-CoV-2
14.
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.

15.
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.

16.
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.

17.
J Neuropathol Exp Neurol ; 81(9): 666-695, 2022 08 16.
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.


Subject(s)
COVID-19 , SARS-CoV-2 , Brain , Gene Expression , Humans , Immunity
18.
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.

19.
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.

20.
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.

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