Tag: blood-brain barrier

Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model

Abstract:

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, is known to infect people of all ages and both sexes. Senior populations have the greatest risk of severe COVID-19, and sexual dimorphism in clinical outcomes has been reported. Neurological symptoms are widely observed in COVID-19 patients, with many survivors exhibiting persistent neurological and cognitive impairment. The present study aims to investigate the impact of age and sex on the neuroinflammatory response to SARS-CoV-2 infection using a mouse model. Wild-type C57BL/6J mice were intranasally inoculated with SARS-CoV-2 lineage B.1.351, a variant known to infect mice.

Older male mice exhibited a significantly greater weight loss and higher viral loads in the lung at 3 days post infection. Notably, no viral RNA was detected in the brains of infected mice. Nevertheless, expression of IL-6, TNF-α, and CCL-2 in the lung and brain increased with viral infection. RNA-seq transcriptomic analysis of brains showed that SARS-CoV-2 infection caused significant changes in gene expression profiles, implicating innate immunity, defense response to virus, and cerebrovascular and neuronal functions.

These findings demonstrate that SARS-CoV-2 infection triggers a neuroinflammatory response, despite the lack of detectable virus in the brain. Aberrant activation of innate immune response, disruption of blood-brain barrier and endothelial cell integrity, and suppression of neuronal activity and axonogenesis underlie the impact of SARS-CoV-2 infection on the brain. Understanding the role of these affected pathways in SARS-CoV-2 pathogenesis helps identify appropriate points of therapeutic interventions to alleviate neurological dysfunction observed during COVID-19.

Source: Krishna VD, Chang A, Korthas H, Var SR, Low WC, Li L, Cheeran MC. Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model. bioRxiv [Preprint]. 2023 Aug 14:2023.08.11.552998. doi: 10.1101/2023.08.11.552998. Update in: Front Microbiol. 2024 Jul 15;15:1404312. doi: 10.3389/fmicb.2024.1404312. PMID: 37645925; PMCID: PMC10462071. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10462071/ (Full text)

Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment

Abstract:

Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood–brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog.

Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog.

Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers.

Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.

Source: Greene C, Connolly R, Brennan D, Laffan A, O’Keeffe E, Zaporojan L, O’Callaghan J, Thomson B, Connolly E, Argue R, Martin-Loeches I, Long A, Cheallaigh CN, Conlon N, Doherty CP, Campbell M. Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci. 2024 Mar;27(3):421-432. doi: 10.1038/s41593-024-01576-9. Epub 2024 Feb 22. PMID: 38388736; PMCID: PMC10917679. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917679/ (Full text)

Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment

Abstract:

Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood–brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog.

Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.

Source: Greene, C., Connolly, R., Brennan, D. et al. Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci (2024). https://doi.org/10.1038/s41593-024-01576-9 https://www.nature.com/articles/s41593-024-01576-9 (Full text)

Long-Term cognitive dysfunction after the COVID-19 pandemic: a narrative review

Abstract:

Introduction: SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has brought a conglomerate of novel chronic disabling conditions described as ‘Long COVID/Post-COVID-19 Syndrome’. Recent evidence suggests that the multifaceted nature of this syndrome results in both pulmonary and extrapulmonary sequelae, chronic dyspnoea, persistent fatigue, and cognitive dysfunction being the most common, debilitating symptoms. Several mechanisms engender or exacerbate cognitive impairment, including central nervous system (CNS) and extra-CNS causes, although the exact mechanism remains unclear. Both hospitalized and non-hospitalized patients may suffer varying degrees of cognitive impairment, ranging from fatigue and brain fog to prolonged deficits in memory and attention, detrimental to the quality-of-life years post-recovery. The aim of this review is to understand the underlying mechanisms, associations, and attempts for prevention with early intervention of long-term cognitive impairment post-COVID-19.

Methodology: A systematic search was conducted through multiple databases such as Medline, National Library of Medicine, Ovid, Scopus database to retrieve all the articles on the long term sequalae of cognitive dysfunction after Sars-Cov2 infection. The inclusion criteria included all articles pertinent to this specific topic and exclusion criteria subtracted studies pertaining to other aetiologies of cognitive dysfunction. This search was carefully screened for duplicates and the relevant information was extracted and analysed.

Results/discussion: To date, the exact pathogenesis, and underlying mechanisms behind cognitive dysfunction in COVID-19, remain unclear, hindering the development of adequate management strategies. However, the proposed mechanisms suggested by various studies include direct damage to the blood-brain barrier, systemic inflammation, prolonged hypoxia, and extended intensive care admissions. However, no clear-cut guidelines for management are apparent.

Conclusion: This review of the COVID-19 pandemic has elucidated a new global challenge which is affecting individuals’ quality of life by inducing long-term impaired cognitive function. We have found that comprehensive evaluations and interventions are crucial to address the cognitive sequelae in all COVID-19 patients, especially in patients with pre-existing cognitive impairment. Nevertheless, the authors recommend further research for the development of relevant, timely neurocognitive assessments and treatment plans.

Source: Shariff, Sanobar; Uwishema, Olivier; Mizero, Jocelyn; Devi Thambi, Vimala; Nazir, Abubakar; Mahmoud, Ashraf; Kaushik, Ikshwaki; Khayat, Saadeddine; Yusif Maigoro, Abdulkadir; Awde, Sara; Al Maaz, Zeina; Alwan, Iktimal; Hijazi, Mahdi; Wellington, Jack MSc (LSHTM) FGMS; Soojin, Lee. Long-Term cognitive dysfunction after the COVID-19 pandemic: a narrative review. Annals of Medicine & Surgery ():10.1097/MS9.0000000000001265, September 8, 2023. | DOI: 10.1097/MS9.0000000000001265 https://journals.lww.com/annals-of-medicine-and-surgery/abstract/9900/long_term_cognitive_dysfunction_after_the_covid_19.1011.aspx

COVID-19 and Long COVID: Disruption of the Neurovascular Unit, Blood-Brain Barrier, and Tight Junctions

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), could affect brain structure and function. SARS-CoV-2 can enter the brain through different routes, including the olfactory, trigeminal, and vagus nerves, and through blood and immunocytes. SARS-CoV-2 may also enter the brain from the peripheral blood through a disrupted blood-brain barrier (BBB).
The neurovascular unit in the brain, composed of neurons, astrocytes, endothelial cells, and pericytes, protects brain parenchyma by regulating the entry of substances from the blood. The endothelial cells, pericytes, and astrocytes highly express angiotensin converting enzyme 2 (ACE2), indicating that the BBB can be disturbed by SARS-CoV-2 and lead to derangements of tight junction and adherens junction proteins. This leads to increased BBB permeability, leakage of blood components, and movement of immune cells into the brain parenchyma. SARS-CoV-2 may also cross microvascular endothelial cells through an ACE2 receptor–associated pathway.
The exact mechanism of BBB dysregulation in COVID-19/neuro-COVID is not clearly known, nor is the development of long COVID. Various blood biomarkers could indicate disease severity and neurologic complications in COVID-19 and help objectively diagnose those developing long COVID. This review highlights the importance of neurovascular and BBB disruption, as well as some potentially useful biomarkers in COVID-19, and long COVID/neuro-COVID.
Source: Kempuraj D, Aenlle KK, Cohen J, Mathew A, Isler D, Pangeni RP, Nathanson L, Theoharides TC, Klimas NG. COVID-19 and Long COVID: Disruption of the Neurovascular Unit, Blood-Brain Barrier, and Tight Junctions. Neuroscientist. 2023 Sep 11:10738584231194927. doi: 10.1177/10738584231194927. Epub ahead of print. PMID: 37694571. https://pubmed.ncbi.nlm.nih.gov/37694571/

Differential effects of SARS-CoV-2 variants on central nervous system cells and blood–brain barrier functions

Abstract:

Background: Although mainly causing a respiratory syndrome, numerous neurological symptoms have been identified following of SARS-CoV-2 infection. However, how the virus affects the brain and how the mutations carried by the different variants modulate those neurological symptoms remain unclear.

Methods: We used primary human pericytes, foetal astrocytes, endothelial cells and a microglial cell line to investigate the effect of several SARS-CoV-2 variants of concern or interest on their functional activities. Cells and a 3D blood-brain barrier model were infected with the wild-type form of SARS-CoV-2, Alpha, Beta, Delta, Eta, or Omicron (BA.1) variants at various MOI. Cells and supernatant were used to evaluate cell susceptibility to the virus using a microscopic assay as well as effects of infection on (i) cell metabolic activity using a colorimetric MTS assay; (ii) viral cytopathogenicity using the xCELLigence system; (iii) extracellular glutamate concentration by fluorometric assay; and (iv) modulation of blood-brain barrier permeability.

Results: We demonstrate that productive infection of brain cells is SARS-CoV-2 variant dependent and that all the variants induce stress to CNS cells. The wild-type virus was cytopathic to all cell types except astrocytes, whilst Alpha and Beta variants were only cytopathic for pericytes, and the Omicron variant cytopathic for endothelial cells and pericytes. Lastly wild-type virus increases blood-brain barrier permeability and all variants, except Beta, modulate extracellular glutamate concentration, which can lead to excitotoxicity or altered neurotransmission.

Conclusions: These results suggest that SARS-CoV-2 is neurotropic, with deleterious consequences for the blood-brain barrier integrity and central nervous system cells, which could underlie neurological disorders following SARS-CoV-2 infection.

Source: Proust A, Queval CJ, Harvey R, Adams L, Bennett M, Wilkinson RJ. Differential effects of SARS-CoV-2 variants on central nervous system cells and blood-brain barrier functions. J Neuroinflammation. 2023 Aug 3;20(1):184. doi: 10.1186/s12974-023-02861-3. PMID: 37537664; PMCID: PMC10398935. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10398935/ (Full text)

LC, POTS, and ME/CFS: Lifting the Fog

Abstract:

These three syndromes – long covid (LC), postural orthostatic tachycardia syndrome (POTS), and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) – have many symptoms in common. The common denominator remains elusive.
The blood brain barrier (BBB) has been a barrier not only to microbes and toxins but also to understanding pathogenetic links. There are several areas within the brain that have no BBB. These are known as circumventricular organs (CVOs) and their location relative to CNS nuclei that direct autonomic and neuroendocrine functions is provocative in the quest for pathogenesis.
In addition the majority afflicted with LC and ME/CFS appear to be those with two MTHFR polymorphisms, present in over 50% of Americans. These polymorphisms elevate homocysteine. When homocysteine is combined with CVOs, the fog of POTS and its paradox are lifted. POTS may represent the intersection of LC and ME/CFS in those with the MTHFR gene (hypermethylation or 677TT).
The gut microbiomes of LC and ME/CFS, deficient in butyrates, GABA, and diversity, are then linked with MTHFR genotype 677TT. Reactivation of neurotropic EBV and VZV, due to loss of surveillance by CD4+/CD8+ T cells, is seen as secondary. The oxidative stress generated by homocysteine, loss of glutathione, low fiber diet, and persistent chronic inflammation exhaust available mitochondria and, assisted by BKN and estrogen, exacerbate all the elements of these post viral fatigue syndromes.
Source: Chambers, P. LC, POTS, and ME/CFS: Lifting the Fog. Preprints.org 2023, 2023030418. https://doi.org/10.20944/preprints202303.0418.v1 (Full text available as PDF file)

Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics

Abstract:

The development of long-term symptoms of coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed “long COVID” or post-acute sequela of COVID-19 (PASC), can implicate persistent neurological complications in up to one third of patients and present as fatigue, “brain fog”, headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, and peripheral neuropathy. Pathogenic mechanisms of these symptoms of long COVID remain largely unclear; however, several hypotheses implicate both nervous system and systemic pathogenic mechanisms such as SARS-CoV2 viral persistence and neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, and endotheliopathy.
Outside of the CNS, SARS-CoV-2 can invade the support and stem cells of the olfactory epithelium leading to persistent alterations to olfactory function. SARS-CoV-2 infection may induce abnormalities in innate and adaptive immunity including monocyte expansion, T-cell exhaustion, and prolonged cytokine release, which may cause neuroinflammatory responses and microglia activation, white matter abnormalities, and microvascular changes. Additionally, microvascular clot formation can occlude capillaries and endotheliopathy, due to SARS-CoV-2 protease activity and complement activation, can contribute to hypoxic neuronal injury and blood–brain barrier dysfunction, respectively.
Current therapeutics target pathological mechanisms by employing antivirals, decreasing inflammation, and promoting olfactory epithelium regeneration. Thus, from laboratory evidence and clinical trials in the literature, we sought to synthesize the pathophysiological pathways underlying neurological symptoms of long COVID and potential therapeutics.
Source: Leng A, Shah M, Ahmad SA, Premraj L, Wildi K, Li Bassi G, Pardo CA, Choi A, Cho S-M. Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics. Cells. 2023; 12(5):816. https://doi.org/10.3390/cells12050816 (Full text)

Blood-brain barrier penetration of non-replicating SARS-CoV-2 and S1 variants of concern induce neuroinflammation which is accentuated in a mouse model of Alzheimer’s disease

Highlights:

• Two models of SARS-CoV-2 and all S1 protein Variants of Concern readily cross the BBB.
• The SARS-CoV-2 pseudovirus is taken up by microglia and induce neuroinflammation.
• The S1-induced neuroinflammation is exacerbated in a mouse model of Alzheimer’s disease.

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 BB B 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.

Source: Erickson MA, Logsdon AF, Rhea EM, Hansen KM, Holden SJ, Banks WA, Smith JL, German C, Farr SA, Morley JE, Weaver RR, Hirsch AJ, Kovac A, Kontsekova E, Baumann KK, Omer MA, Raber J. Blood-brain barrier penetration of non-replicating SARS-CoV-2 and S1 variants of concern induce neuroinflammation which is accentuated in a mouse model of Alzheimer’s disease. Brain Behav Immun. 2023 Jan 20;109:251-268. doi: 10.1016/j.bbi.2023.01.010. Epub ahead of print. PMID: 36682515; PMCID: PMC9867649. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9867649/ (Full text)

Molecular and cellular similarities in the brain of SARS-CoV-2 and Alzheimer’s disease individuals

Abstract:

Infection with the etiological agent of COVID-19, SARS-CoV-2, appears capable of impacting cognition, which some patients with Post-acute Sequelae of SARS-CoV-2 (PASC). To evaluate neuro-pathophysiological consequences of SARS-CoV-2 infection, we examine transcriptional and cellular signatures in the Broadman area 9 (BA9) of the frontal cortex and the hippocampal formation (HF) in SARS-CoV-2, Alzheimer’s disease (AD) and SARS-CoV-2 infected AD individuals, compared to age- and gender-matched neurological cases. Here we show similar alterations of neuroinflammation and blood-brain barrier integrity in SARS-CoV-2, AD, and SARS-CoV-2 infected AD individuals. ‘

Distribution of microglial changes reflected by the increase of Iba-1 reveal nodular morphological alterations in SARS-CoV-2 infected AD individuals. Similarly, HIF-1α is significantly upregulated in the context of SARS-CoV-2 infection in the same brain regions regardless of AD status. The finding may help to inform decision-making regarding therapeutic treatments in patients with neuro-PASC, especially those at increased risk of developing AD.

Source: Griggs E, Trageser K, Naughton S, Yang EJ, Mathew B, Van Hyfte G, Hellmers L, Jette N, Estill M, Shen L, Fischer T, Pasinetti GM. Molecular and cellular similarities in the brain of SARS-CoV-2 and Alzheimer’s disease individuals. bioRxiv [Preprint]. 2022 Nov 23:2022.11.23.517706. doi: 10.1101/2022.11.23.517706. PMID: 36451886; PMCID: PMC9709800. https://www.biorxiv.org/content/10.1101/2022.11.23.517706v1.full (Full text)