Mouse Adapted SARS-CoV-2 Model Induces “Long-COVID” Neuropathology in BALB/c Mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 20, 2023

Abstract The novel coronavirus SARS-CoV-2 has caused significant global morbidity and mortality continues to burden patients with persisting neurological dysfunction. COVID-19 survivors develop debilitating symptoms include neuro-psychological dysfunction, termed “Long COVID”, which can cause reduction of quality life. Despite vigorous model development, the possible these underlying pathophysiology this devastating disease remains elusive. Mouse adapted (MA10) is a mouse-based simulates clinical respiratory distress associated infection in mice. In study, we evaluated long-term effects MA10 on brain pathology neuroinflammation. 10-week 1-year old female BALB/cAnNHsd mice were infected intranasally 10 4 plaque-forming units (PFU) 3 PFU MA10, respectively, was examined 60 days post-infection (dpi). Immunohistochemical analysis showed decrease neuronal nuclear protein NeuN an increase Iba-1 positive amoeboid microglia hippocampus after infection, indicating changes area critical for memory consolidation processing. Importantly, seen 40-50% mice, correlates prevalence LC clinically. Our data shows first time that induces neuropathological outcomes several weeks at similar rates observed COVID”. These observations strengthen as viable study humans. Establishing viability key step towards rapid development therapeutic strategies ameliorate neuroinflammation restore function those suffering from persistent cognitive dysfunction “Long-COVID”.

Language: Английский

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SARS-CoV-2 Spike Protein Intensifies Cerebrovascular Complications in Diabetic hACE2 Mice through RAAS and TLR Signaling Activation

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(22), P. 16394 - 16394

Published: Nov. 16, 2023

Diabetics are more vulnerable to SARS-CoV-2 neurological manifestations. The molecular mechanisms of SARS-CoV-2-induced cerebrovascular dysfunction in diabetes unclear. We hypothesize that exacerbates diabetes-induced oxidative stress and inflammation via activation the destructive arm renin–angiotensin-aldosterone system (RAAS) Toll-like receptor (TLR) signaling. spike protein was injected humanized ACE2 transgenic knock-in mice. Cognitive functions, cerebral blood flow, architecture, RAAS, TLR signaling were used determine effect diabetes. Studies mirrored vitro using human brain microvascular endothelial cells treated with high glucose-conditioned media mimic diabetic conditions. Spike exacerbated stress, inflammation, cell death resulting an increase vascular rarefaction diminished flow. worsened cognitive compared control enhanced RAAS at expense protective arm. In parallel, significantly diabetes, aggravating cellular apoptosis vicious circle. Our study illustrated SAR-CoV-2 intensified increasing damage dysfunction.

Language: Английский

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Nirmatrelvir and Molnupiravir maintain potent in vitro and in vivo antiviral activity against circulating SARS-CoV-2 Omicron subvariants

Antiviral Research, Journal Year: 2024, Volume and Issue: 230, P. 105970 - 105970

Published: July 26, 2024

Language: Английский

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Emerging signs of Alzheimer‐like tau hyperphosphorylation and neuroinflammation in the brain post recovery from COVID‐19

Aging Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 29, 2024

Abstract Coronavirus disease 2019 (COVID‐19) has been suggested to increase the risk of memory decline and Alzheimer's (AD), main cause dementia in elderly. However, direct evidence about whether COVID‐19 induces AD‐like neuropathological changes brain, especially post recovery from acute infection, is still lacking. Here, using postmortem human brain samples, we found abnormal accumulation hyperphosphorylated tau protein hippocampus medial entorhinal cortex within 4–13 months clinically COVID‐19, together with prolonged activation glia cells increases inflammatory factors, even though no SARS‐COV‐2 invasion was detected these regions. By contrast, did not change beta‐amyloid deposition hippocampal neuron number, had limited effects on AD‐related pathological phenotypes olfactory circuits including bulb, anterior nucleus, tubercle, piriform lateral cortex. These results provide evidences linking prognostic for AD.

Language: Английский

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Microglia influence immune responses and restrict neurologic disease in response to central nervous system infection by a neurotropic murine coronavirus

Frontiers in Cellular Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Nov. 30, 2023

Intracranial (i.c.) inoculation of susceptible mice with a glial-tropic strain mouse hepatitis virus (JHMV), murine coronavirus, results in an acute encephalomyelitis followed by viral persistence white matter tracts accompanied chronic neuroinflammation and demyelination. Microglia serve numerous functions including maintenance the healthy central nervous system (CNS) are among first responders to injury or infection. More recently, studies have demonstrated that microglia aid tailoring innate adaptive immune responses following infection neurotropic viruses flaviviruses, herpesviruses, picornaviruses. These findings emphasized important role for host defense against these pathogens. In addition, also critical optimizing immune-mediated control JHMV replication within CNS while restricting severity demyelination enhancing remyelination. This review will highlight our current understanding molecular cellular mechanisms which defense, limit neurologic disease, promote repair coronavirus.

Language: Английский

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Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 19, 2023

Abstract Leukocyte infiltration of the CNS can contribute to neuroinflammation and cognitive impairment. Brain endothelial cells regulate adhesion, activation, diapedesis T across blood-brain barrier (BBB) in inflammatory diseases. The integral membrane protein Caveolin-1 (Cav-1) critically regulates BBB permeability, but its influence on cell respiratory viral infections is unknown. In this study, we sought determine role Cav-1 at a COVID-19 mouse model. We used mice genetically deficient test found that SARS-CoV-2 infection upregulated brain Cav-1. Moreover, increased vascular adhesion molecule-1 (VCAM-1) CD3+ hippocampus, region important for short term learning memory. Concordantly, observed memory deficits. Importantly, genetic deficiency attenuated VCAM-1 expression hippocampus with infection. KO were protected from deficits caused by These results indicate importance permeability suggest potential therapeutic value targeting improve disease outcomes.

Language: Английский

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SARS-CoV-2 Spike Protein Exacerbates Thromboembolic Cerebrovascular Complications in Humanized ACE2 Mouse Model

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: July 25, 2024

COVID-19 increases the risk for acute ischemic stroke, yet molecular mechanisms are unclear and remain unresolved medical challenges. We hypothesize that SARS-CoV-2 spike protein exacerbates stroke cerebrovascular complications by increasing coagulation decreasing fibrinolysis disrupting renin-angiotensin-aldosterone system (RAAS). A thromboembolic model was induced in humanized ACE2 knock-in mice after one week of injection. hACE2 were treated with Losartan, an angiotensin receptor (AT₁R) blocker, immediately Cerebral blood flow infarct size compared between groups. Vascular-contributes to cognitive impairments dementia assessed using a Novel object recognition test. Tissue factor-III plasminogen activator inhibitor-1 measured immunoblotting assess fibrinolysis. Human brain microvascular endothelial cells (HBMEC) exposed hypoxia with/without mimic conditions inflammation, RAAS balance, coagulation, Our results showed caused imbalance increased inflammatory signal decreased protective arm. when coincident insult, which accompanied decrease cerebral flow, increase neuronal death, decline function. Losartan treatment restored balance reduced protein-induced effects. inflammation hypercoagulation, leading neurovascular damage dysfunction. However, AT₁R COVID-19-induced complications.

Language: Английский

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SARS-CoV-2 Spike Protein Exacerbates Thromboembolic Cerebrovascular Complications in Humanized ACE2 Mouse Model

Translational Stroke Research, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 2, 2024

Abstract COVID-19 increases the risk for acute ischemic stroke, yet molecular mechanisms are unclear and remain unresolved medical challenges. We hypothesize that SARS-CoV-2 spike protein exacerbates stroke cerebrovascular complications by increasing coagulation decreasing fibrinolysis disrupting renin-angiotensin-aldosterone system (RAAS). A thromboembolic model was induced in humanized ACE2 knock-in mice after one week of injection. hACE2 were treated with Losartan, an angiotensin receptor (AT 1 R) blocker, immediately Cerebral blood flow infarct size compared between groups. Vascular-contributes to cognitive impairments dementia assessed using a Novel object recognition test. Tissue factor-III plasminogen activator inhibitor-1 measured immunoblotting assess fibrinolysis. Human brain microvascular endothelial cells (HBMEC) exposed hypoxia with/without mimic conditions inflammation, RAAS balance, coagulation, Our results showed caused imbalance increased inflammatory signal decreased protective arm. when coincident insult, which accompanied decrease cerebral flow, increase neuronal death, decline function. Losartan treatment restored balance reduced protein-induced effects. inflammation hypercoagulation, leading neurovascular damage dysfunction. However, AT R COVID-19-induced complications.

Language: Английский

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BALB/c mice challenged with SARS-CoV-2 B.1.351 β variant cause pathophysiological and neurological changes within the lungs and brains

Journal of General Virology, Journal Year: 2024, Volume and Issue: 105(10)

Published: Oct. 30, 2024

Up to one-third of individuals suffering from acute SARS-CoV-2 infection with the onset severe-to-mild diseases could develop several symptoms neurological disorders, which last long after resolving infection, known as neuro-COVID. Effective therapeutic treatments for neuro-COVID remain unavailable, in part, due absence animal models studying its underlying mechanisms and developing medical countermeasures against it. Here, we explored impact on well-being respiratory functions BALB/c mice by using a clinical isolate β-variant, i.e. B.1.351. We found that this β-variant primarily infected lungs, causing tissue damage, profound inflammatory responses, altered transient but significant hypoxia. Although live progeny viruses not be isolated, viral RNAs were detected across many anatomical regions brains most challenged triggered activation genes encoding NF -kB , IL-6 IP-10 RANTES microglial cells. noted significantly activated -encoded gene persisted at 4 weeks infection. Together, these results suggest B.1.351/BALB/c model warrants further studies establish it desirable neuropathogenesis development effective therapeutics

Language: Английский

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Utilizing HCoV-OC43 to better understand the neurological impact of COVID-19

Brain Behavior & Immunity - Health, Journal Year: 2024, Volume and Issue: 42, P. 100905 - 100905

Published: Nov. 9, 2024

As the COVID-19 pandemic enters its fifth year, research tools to study SARS-CoV-2 (CoV-2) virus are critical, and many researchers have turned another beta coronavirus: HCoV-OC43 (OC43). OC43 is a ubiquitous pathogen that now causes common cold, but emergence in 1890 closely coincided with likely produced catastrophic Russian Flu pandemic. Beyond their historical parallels, CoV-2 share similar genetics disease sequelae. Both viruses induce respiratory symptoms. Additionally, infection can result acute neurological dysfunction children, exposure has been linked long-term disorders adults. Similarly, produce neuropathology phenomenon of prolonged symptoms known as Long-COVID typically impacts brain. Mouse models developed pathogenesis both CoV-2, thereby facilitating on sequelae associated either infection. These further utilized test therapeutic interventions against viruses, seek establish potential for using proxy CoV-2. Further, because mouse two betacoronaviruses exhibit sequelae, could provide insight into impact requires lower biosafety level than which makes it accessible more resulting expeditious scientific progress ongoing

Language: Английский

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