Cyclophilin–CD147 interaction enables SARS-CoV-2 infection of human monocytes and their activation via Toll-like receptors 7 and 8

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Фев. 3, 2025

Monocytes and macrophages, as important constituents of the innate immune system, are equipped with multiple Toll-like-receptors (TLRs) to recognize invading pathogens, such SARS-CoV-2, mount an antiviral response. Nevertheless, their uncontrolled activation can lead hyperinflammation seen in severe COVID-19. Surprisingly, we observed that recombinant SARS-CoV-2 Spike (S) Nucleocapsid (N) proteins triggered only a weak proinflammatory response human peripheral blood monocytes. By employing THP-1 Jurkat NF-κB::eGFP reporter cell lines expressing specific TLRs, various TLR ligands blocking antibodies, determined surface including TLR2/1, TLR2/6 TLR4 do not play major role sensing. However, monocytes potently activated by replication-competent correlates viral uptake is monocytes, but lymphocytes. We show monocyte involves two distinct steps. Firstly, infects process independent S protein prime receptor angiotensin-converting enzyme 2. Instead, alternative CD147, which highly expressed on recognizes its well-known interaction partners cyclophilins A B incorporated into virions. Secondly, upon via cyclophilin-CD147 interaction, be inhibited CD147 antibodies or competition cyclophilin B, RNA recognized TLR7/8 endosomes, leading upregulation tumor necrosis factor (TNF), interleukin (IL)-1β IL-6, comprising core hyperinflammatory signature. Taken together, our data reveal novel mechanism how sense suggest targeting axis might beneficial alleviate overt myeloid-driven inflammation infection.

Язык: Английский

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RAGE pathway activation and function in chronic kidney disease and COVID-19

Frontiers in Medicine, Год журнала: 2022, Номер 9

Опубликована: Авг. 9, 2022

The multi-ligand receptor for advanced glycation end-products (RAGE) and its ligands are contributing factors in autoimmunity, cancers, infectious disease. RAGE activation is increased chronic kidney disease (CKD) coronavirus 2019 (COVID-19). CKD may increase the risk of COVID-19 severity also develop form long COVID. expressed essentially all cell types. Increased production isoforms during promotes activity. downstream effects include cellular dysfunction, tissue injury, fibrosis, inflammation, which turn contribute to a decline function, hypertension, thrombotic disorders, cognitive impairment. In this review, we discuss forms mechanisms COVID-19. Because various small molecules antagonize activity animal models, targeting RAGE, co-receptors, or offer novel therapeutic approaches slowing halting progressive disease, current therapies often inadequate.

Язык: Английский

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Single-Cell Transcriptomics Reveals Evidence of Endothelial Dysfunction in the Brains of COVID-19 Patients with Implications for Glioblastoma Progression

Brain Sciences, Год журнала: 2023, Номер 13(5), С. 762 - 762

Опубликована: Май 5, 2023

Endothelial dysfunction is implicated in various inflammatory diseases such as ischemic stroke, heart attack, organ failure, and COVID-19. Recent studies have shown that endothelial the brain attributed to excessive responses caused by SARS-CoV-2 infection, leading increased permeability of blood-brain barrier consequently neurological damage. Here, we aim examine single-cell transcriptomic landscape COVID-19 its implications for glioblastoma (GBM) progression.Single-cell transcriptome data GSE131928 GSE159812 were obtained from gene expression omnibus (GEO) analyze profiles key players innate immunity inflammation between GBM analysis patients revealed cells had undergone significant changes, with several genes involved immune upregulated. Moreover, transcription factors observed modulate this inflammation, including interferon-regulated genes.The results indicate a overlap context dysfunction, suggesting there may be an link connecting severe infection progression.

Язык: Английский

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Assessing the Potential Contribution of in Silico Studies in Discovering Drug Candidates that Interact with Various SARS-CoV-2 Receptors

Опубликована: Авг. 4, 2023

COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly search candidates that interact with various SARS-CoV-2 receptors. These involve use of computer simulations and computational algorithms predict potential interaction target The primary receptors targeted by include RNA polymerase, main protease, spike protein, ACE2 receptor, TMPRSS2, AP2-associated protein kinase 1. identified several promising candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, Camostat mesylate, among others. offers advantages, ability screen large number relatively short amount time, thereby reducing time cost involved traditional methods. Additionally, allow prediction binding affinity receptors, providing insight into their efficacy. However, it is crucial consider both advantages limitations these complement them experimental validation ensure efficacy safety candidates.

Язык: Английский

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Human-derived air–liquid interface cultures decipher Alzheimer’s disease–SARS-CoV-2 crosstalk in the olfactory mucosa

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Дек. 14, 2023

Abstract Background The neurological effects of the coronavirus disease 2019 (COVID-19) raise concerns about potential long-term consequences, such as an increased risk Alzheimer's (AD). Neuroinflammation and other AD-associated pathologies are also suggested to increase serious SARS-CoV-2 infection. Anosmia is a common symptom reported in COVID-19 early AD. olfactory mucosa (OM) important for perception smell proposed site viral entry brain. However, little known infection at OM individuals with Methods To address this gap, we established 3D vitro model from primary cells derived cognitively healthy AD individuals. We cultured air–liquid interface (ALI) study under controlled experimental conditions. Primary ALI expressed angiotensin-converting enzyme 2 (ACE-2), neuropilin-1 (NRP-1), several receptor were highly vulnerable Infection was determined by secreted RNA content confirmed nucleocapsid protein (NP) infected immunocytochemistry. Differential responses individuals-derived sequencing. Results indicate that donors do not differ susceptibility wild-type virus. transcriptomic signatures distinct. Specifically, patients virus showed levels oxidative stress, desensitized inflammation immune responses, alterations genes associated olfaction. These results imply may be greater experiencing severe outcomes infection, potentially driven pre-existing neuroinflammation. Conclusions sheds light on interplay between pathology Altered contribute unique symptoms more course, notable involvement Furthermore, research emphasizes need targeted interventions enhance crucial better comprehend relationship AD, COVID-19, anosmia. It highlights importance ongoing develop effective treatments those high Graphical

Язык: Английский

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SARS-CoV-2 infection activates inflammatory macrophages in vascular immune organoids

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Апрель 16, 2024

Abstract SARS-CoV-2 provokes devastating tissue damage by cytokine release syndrome and leads to multi-organ failure. Modeling the process of immune cell activation subsequent is a significant task. Organoids from human tissues advanced our understanding infection mechanisms though, they are missing crucial components: cells endothelial cells. This study aims generate organoids with these components. We established vascular pluripotent stem examined effect infection. demonstrated that infections activated inflammatory macrophages. Notably, upregulation interferon signaling supports macrophages’ role in syndrome. propose useful platform model discover factors ameliorate SARS-CoV-2-mediated

Язык: Английский

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Repurposing Niclosamide as a Novel Anti-SARS-CoV-2 Drug by Restricting Entry Protein CD147

Biomedicines, Год журнала: 2023, Номер 11(7), С. 2019 - 2019

Опубликована: Июль 18, 2023

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the global disease 2019 (COVID-19) pandemic, and search for effective treatments been limited. Furthermore, rapid mutations SARS-CoV-2 have posed challenges existing vaccines neutralizing antibodies, as they struggle keep up with increased viral transmissibility immune evasion. However, there is hope in targeting CD147-spike protein, which serves an alternative point entry into host cells. This protein emerged a promising therapeutic target development drugs against COVID-19. Here, we demonstrate that RNA-binding Human-antigen R (HuR) plays crucial role post-transcriptional regulation CD147 by directly binding its 3'-untranslated region (UTR). We observed decrease levels across multiple cell lines upon HuR depletion. identified niclosamide can reduce lowering cytoplasmic translocation reducing glycosylation. Moreover, our investigation revealed infection induces upregulation ACE2-expressing A549 cells, be effectively neutralized dose-dependent manner. Overall, study unveils novel regulatory mechanism regulating through suggests option

Язык: Английский

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Potential Alternative Receptors for SARS-CoV-2-Induced Kidney Damage: TLR-4, KIM-1/TIM-1, and CD147

Frontiers in Bioscience-Landmark, Год журнала: 2024, Номер 29(1), С. 8 - 8

Опубликована: Янв. 12, 2024

Kidney damage in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can occur even patients with no underlying kidney disease. Signs of problems progress to a state that demands dialysis and hampering recovery. Although not without controversy, emerging evidence implicates direct infectivity SARS-CoV-2 the kidney. At early stage pandemic, consideration was mainly on well-recognized angiotensin-converting enzyme (ACE2) receptor as being site for viral interaction subsequent cellular internalization. Despite abundance ACE2 receptors kidneys, researchers have expanded beyond identified novel entry pathways could be advantageously explored therapeutic targets. This review presents potential involvement toll-like 4 (TLR-4), injury molecule-1/T cell immunoglobulin mucin domain 1 (KIM-1/TIM-1), cluster differentiation 147 (CD147) SARS-CoV-2-associated renal damage. In this context, we address unresolved issues surrounding infectivity.

Язык: Английский

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Development of a novel human CD147 knock-in NSG mouse model to test SARS-CoV-2 viral infection

Cell & Bioscience, Год журнала: 2022, Номер 12(1)

Опубликована: Июнь 11, 2022

An animal model that can mimic the SARS-CoV-2 infection in humans is critical to understanding rapidly evolving virus and for development of prophylactic therapeutic strategies combat emerging mutants. Studies show spike proteins SARS-CoV bind human angiotensin-converting enzyme 2 (hACE2, a well-recognized, functional receptor SARS-CoV-2) mediate viral entry. Several hACE2 transgenic (hACE2Tg) mouse models are being widely used, which clearly invaluable. However, hACE2Tg cannot fully explain: (1) low expression ACE2 observed lung heart, but or heart failure occurs frequently severe COVID-19 patients; (2) on immune cells, lymphocytopenia (3) mice do not natural course humans. Moreover, one most outstanding features coronavirus diversity usage, includes newly proposed CD147 (hCD147) as possible co-receptor It still debatable whether serve Here we successfully generated hCD147 knock-in (hCD147KI) NOD-scid IL2Rgammanull (NSG) background. In this hCD147KI-NSG model, genetic sequence was placed downstream endogenous promoter (mCD147), creates an vivo may better recapitulate physiological at molecular level compared existing well-studied K18-hACE2-B6 (JAX) model. addition, allows further study immunodeficiency condition assist our context high-risk populations immunosuppressed states. Our data protein expressed various organs (including bronchiolar epithelial cells) by immunohistochemical staining flow cytometry; marginally sensitive WT-NSG littermates characterized increased copies qRT-PCR moderate body weight decline baseline; significant increase leukocytes lungs mice, infected mice. more The additional interrogation independent accessory entry responses.

Язык: Английский

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Utilizing the codon adaptation index to evaluate the susceptibility to HIV-1 and SARS-CoV-2 related coronaviruses in possible target cells in humans

Frontiers in Cellular and Infection Microbiology, Год журнала: 2023, Номер 12

Опубликована: Янв. 25, 2023

Comprehensive identification of possible target cells for viruses is crucial understanding the pathological mechanism virosis. The susceptibility to depends on many factors. Besides existence receptors at cell surface, effective expression viral genes also pivotal infection. regulation gene a multilevel process including transcription, translational initiation and elongation. At elongation level, efficiency mRNAs mainly match between their codon composition cellular machinery (usually referred as adaptation). Thus, adaptation ORFs in different types may be related viruses. In this study, we selected index (CAI) which common adaptation-based indicator assessing level evaluate two-pandemic (HIV-1 SARS-CoV-2) human types. Compared with previous studies that evaluated infectivity based adaptation, main advantage our study analysis refined cell-type level. first, verified positive correlation CAI strengthened rationality research method. Then calculated two various We found compared high-expression endogenous genes, CAIs are relatively low. This phenomenon implied kinds have not been well adapted regulatory cells. Also, indicated presumptive according usually consistent results experimental research. However, there still some exceptions. Finally, effects mechanisms. HIV-1 decouples host SARS-CoV-2 exhibits increased its infected Our least cases SARS-CoV-2, can regarded an auxiliary assess cells’ but cannot used only evidence identify

Язык: Английский

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