Translating animal models of SARS-CoV-2 infection to vascular, neurological and gastrointestinal manifestations of COVID-19

Disease Models & Mechanisms, Год журнала: 2025, Номер 18(9)

Опубликована: Апрель 8, 2025

ABSTRACT Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) initiated a global pandemic resulting in an estimated 775 million infections with over 7 deaths, it has become evident that COVID-19 is not solely pulmonary disease. Emerging evidence shown that, subset patients, certain symptoms − including chest pain, stroke, anosmia, dysgeusia, diarrhea and abdominal pain – all indicate role vascular, neurological gastrointestinal (GI) pathology disease process. Many these processes persist long after been resolved, ‘long COVID’ or post-acute sequelae (PASC). The molecular mechanisms underlying systemic conditions associated remain incompletely defined. Appropriate animal models provide method understanding at system level through study progression, tissue pathology, immune response to pathogen behavioral responses. However, very few studies have addressed PASC whether existing hold promise for studying this challenging problem. Here, we review current literature on cardiovascular, GI pathobiology caused by along established manifestations their prospects use studies. Our aim guidance selection appropriate order recapitulate aspects enhance translatability mechanistic

Язык: Английский

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SARS-CoV-2 (MA10) Infection Aggravates Cerebrovascular Pathology in Endothelial Nitric Oxide Synthase-Deficient Mice

Viruses, Год журнала: 2025, Номер 17(6), С. 784 - 784

Опубликована: Май 29, 2025

SARS-CoV-2 can cause neurological issues, including cognitive dysfunction in COVID-19 survivors. Endothelial dysfunction, a key mechanism COVID-19, is also risk factor for vascular dementia (VaD). Reduced nitric oxide (NO) bioavailability pathogenic of endothelial and platelet aggregation patients, NO synthase (eNOS) levels decline with advancing age, both morbidity VaD. induces cellular senescence senescence-associated secretory phenotype (SASP). We hypothesized that eNOS deficiency would worsen neuroinflammation, senescence, blood–brain barrier (BBB) permeability, hypercoagulability eNOS-deficient mice. Six-month-old eNOS+/− (pre-cognitively impaired experimental VaD) wild-type (WT) male mice were infected mouse-adapted (MA10) SARS-CoV-2. Mice evaluated weight loss, viral load, markers inflammation 3 days post-infection. showed more loss (~15%) compared to WT (~5%) increased inflammatory (Ccl2, Cxcl9, Cxcl10, IL-1β, IL-6) (p53 p21). They exhibited higher microglial activation (Iba1) plasma coagulation BBB despite comparable lung loads absence virus the brain. This first evidence demonstrating exacerbates SARS-CoV-2-induced morbidity, brain linking COVID-19-related neuropathology.

Язык: 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, Год журнала: 2023, Номер 24(22), С. 16394 - 16394

Опубликована: Ноя. 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.

Язык: 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, Год журнала: 2023, Номер 17

Опубликована: Ноя. 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.

Язык: 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, Год журнала: 2024, Номер 230, С. 105970 - 105970

Опубликована: Июль 26, 2024

Язык: Английский

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

Aging Cell, Год журнала: 2024, Номер unknown

Опубликована: Сен. 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.

Язык: Английский

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

Translational Stroke Research, Год журнала: 2024, Номер unknown

Опубликована: Окт. 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.

Язык: Английский

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

Brain Behavior & Immunity - Health, Год журнала: 2024, Номер 42, С. 100905 - 100905

Опубликована: Ноя. 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

Язык: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 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.

Язык: Английский

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

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Июль 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.

Язык: Английский

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