Induction of antiviral gene expression by cyclosporine A, but not inhibition of cyclophilin A or B, contributes to its restriction of human coronavirus 229E infection in a lung epithelial cell line DOI Creative Commons

John E. Mamatis,

Carla E. Gallardo-Flores,

Taylor Walsh

et al.

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

Published: July 20, 2023

Abstract The development of antivirals with an extended spectrum activity is attractive possibility to protect against future emerging coronaviruses (CoVs). Cyclosporine A (CsA), a clinically approved immunosuppressive drug, has established antiviral diverse unrelated viruses, including several CoVs. However, its mechanisms action CoV infection have remained elusive, precluding the rational design non-immunosuppressive derivatives improved activities. In this study, we evaluated CsA HCoV-229E in human lung epithelial cell line. We demonstrate that independent classical target proteins, cyclophilin or B, which are not required host factors for A549 cells. Instead, treatment induces expression genes manner dependent on interferon regulatory factor 1, but responses, contributes inhibitory effect infection. Our results also point role nucleoprotein antagonizing activation type I interferon, show does affect evasion innate immune signaling pathways by HCoV-229E. Overall, our findings further understanding and highlight novel immunomodulatory strategy inhibit may inform drug efforts.

Language: Английский

iPSC‐derived human cortical organoids display profound alterations of cellular homeostasis following SARS‐CoV‐2 infection and Spike protein exposure DOI Creative Commons
Gioia Cappelletti,

Lorenzo Brambilla,

Sergio Strizzi

et al.

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(4)

Published: Feb. 14, 2025

Abstract COVID‐19 commonly leads to respiratory issues, yet numerous patients also exhibit a diverse range of neurological conditions, suggesting detrimental impact SARS‐CoV‐2 or the viral Spike protein on central nervous system. Nonetheless, molecular pathway behind pathology and presumed neurotropism remains largely unexplored. We generated human cortical organoids (HCOs) derived from induced pluripotent stem cells (hiPSC) assess: (1) expression main entry factors; (2) their vulnerability infection; (3) infection exposure transcriptome. Results proved that HCOs express receptors co‐receptors; may be productively infected by SARS‐CoV‐2; particles released SARS‐CoV‐2‐infected are able re‐infect another cellular line; (4) resulted in activation apoptotic stress pathways, along with inflammatory processes. Notably, these effects were recapitulated when exposed alone. The data obtained demonstrate likely infects probably through binding ACE2, CD147, NRP1 factors. Furthermore, alone sufficient disrupt homeostasis induce neurotoxic effects, potentially contributing onset long‐COVID symptoms.

Language: Английский

Citations

2
SARS-CoV-2 mitochondrial metabolic and epigenomic reprogramming in COVID-19 DOI Creative Commons
Joseph W. Guarnieri, Jeffrey Haltom, Yentli E. Soto Albrecht

et al.

Pharmacological Research, Journal Year: 2024, Volume and Issue: 204, P. 107170 - 107170

Published: April 12, 2024

To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey metabolic pathways modulated by and confirmed their importance for propagation cataloging specific pathway inhibitors. This revealed that strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased reactive oxygen species (mROS) production. The elevated mROS stabilizes HIF-1α which redirects carbon molecules from oxidation through glycolysis pentose phosphate (PPP) to provide substrates viral biogenesis. also induces release DNA (mtDNA) activates innate immunity. restructuring energy metabolism is mediated part Orf8 Orf10 whose expression restructures nuclear (nDNA) mtDNA OXPHOS gene expression. These proteins likely alter epigenome, either directly altering histone modifications or modulating metabolite epigenome modification enzymes, potentially silencing contributing long-COVID.

Language: Английский

Citations

13
Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics DOI Creative Commons
Yash Gupta, Oleksandr V. Savytskyi, Matt Coban

et al.

Molecular Aspects of Medicine, Journal Year: 2022, Volume and Issue: 91, P. 101151 - 101151

Published: Oct. 28, 2022

With more than 5 million fatalities and close to 300 reported cases, COVID-19 is the first documented pandemic due a coronavirus that continues be major health challenge. Despite being rapid, uncontrollable, highly infectious in its spread, it also created incentives for technology development redefined public needs research agendas fast-track innovations translated. Breakthroughs computational biology peaked during with renewed attention making all cutting-edge deliver agents combat disease. The demand develop effective treatments yielded surprising collaborations from previously segregated fields of science technology. long-standing pharmaceutical industry's aversion repurposing existing drugs lack exponential financial gain was overrun by crisis pressures front-line researchers providers. Effective vaccine even at an unprecedented pace took year commence trials. Now emergence variants waning protections booster shots resulting breakthrough infections continue strain care systems. As now, every protein SARS-CoV-2 has been structurally characterized related host pathways have extensively mapped out. community addressed druggability multitude possible targets. This made virtual computer-assisted drug as well new tools technologies such artificial intelligence leads. Here this article, we are discussing advances discovery field target-based exploring implications known target-specific on therapeutic management. current scenario calls personalized medicine efforts stratifying patient populations early their need different combinations prognosis-specific therapeutics. We intend highlight target hotspots potential agents, ultimate goal using rational design therapeutics not only end but uncover generalizable platform use future pandemics.

Language: Английский

Citations

30
Host-targeted antivirals against SARS-CoV-2 in clinical development - prospect or disappointment? DOI Creative Commons
André Schreiber, Stephan Ludwig

Antiviral Research, Journal Year: 2025, Volume and Issue: 235, P. 106101 - 106101

Published: Feb. 7, 2025

The global response to the COVID-19 pandemic, caused by novel SARS-CoV-2 virus, has seen an unprecedented increase in development of antiviral therapies. Traditional strategies have primarily focused on direct-acting antivirals (DAAs), which specifically target viral components. In recent years, increasing attention was given alternative approach aiming exploit host cellular pathways or immune responses inhibit replication, led so-called host-targeted (HTAs). emergence and promoted a boost this field. Numerous HTAs been tested demonstrated their potential against through vitro vivo studies. However, striking contrast, only limited number successfully progressed advanced clinical trial phases (2-4), even less entered practice. This review aims explore current landscape targeting that reached phase 2-4 trials. Additionally, it will challenges faced gaining regulatory approval market availability.

Language: Английский

Citations

0
PROTAC targeting cyclophilin A controls virus-induced cytokine storm DOI Creative Commons

Heqiao Li,

Wenxian Yang, Huizi Li

et al.

iScience, Journal Year: 2023, Volume and Issue: 26(9), P. 107535 - 107535

Published: Aug. 3, 2023

Cytokine storms caused by viruses are associated with elevated cytokine levels and uncontrolled inflammatory responses that can lead to acute respiratory distress syndrome. Current antiviral therapies not sufficient prevent or treat these complications. Cyclophilin A (CypA) is a key factor regulates the production of multiple cytokines could be potential therapeutic target for storms. Here, three proteolysis targeting chimeras (PROTACs) CypA were designed. These PROTACs bind CypA, enhance its ubiquitination, promote degradation in both cell lines mouse organs. During influenza B virus (IBV) infection, PROTAC-mediated depletion reduces P65 phosphorylation NF-κB-mediated proinflammatory A549 cells. Moreover, Comp-K suppresses excessive secretion bronchoalveolar lavage fluid, lung injury, enhances survival rates IBV-infected mice. Collectively, we provide which candidates control

Language: Английский

Citations

9
A review of immune modulators and immunotherapy in infectious diseases DOI

P. Vijayan,

J.G. Xavier,

Mohanan Parayanthala Valappil

et al.

Molecular and Cellular Biochemistry, Journal Year: 2023, Volume and Issue: 479(8), P. 1937 - 1955

Published: Sept. 8, 2023

Language: Английский

Citations

8
Innate immunity and immunotherapy for hemorrhagic shock DOI Creative Commons
Qingxia Huang, Song Gao, Yao Yao

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Aug. 25, 2022

Hemorrhagic shock (HS) is a result of hypovolemic injury, in which the innate immune response plays central role pathophysiology ofthe severe complications and organ injury surviving patients. During development HS, immunity acts as first line defense, mediating rapid to pathogens or danger signals through pattern recognition receptors. The early exaggerated activation immunity, widespread patients with results systemic inflammation, cytokine storm, excessive complement factors cells, comprised type II lymphoid CD4 + T natural killer eosinophils, basophils, macrophages, neutrophils, dendritic cells. Recently, compelling evidence focusing on regulation preclinical clinical studies promises new treatment avenues reverse minimize HS-induced tissue dysfunction, ultimately mortality. In this review, we discuss involved HS then systematically detail cutting-edge therapeutic strategies past decade regarding field; these include use mesenchymal stem exosomes, genetic approaches, antibody therapy, small molecule inhibitors, medicine, mesenteric lymph drainage, vagus nerve stimulation, hormones, glycoproteins, others. We also reviewed available for treating assessed potential concerning translation from basic research practice. Combining an improved understanding how system responds could help identify develop targeted modalities that mitigate improve patient outcomes, reduce mortality due injury.

Language: Английский

Citations

13
Human motor neurons derived from induced pluripotent stem cells are susceptible to SARS-CoV-2 infection DOI Creative Commons
Gioia Cappelletti, Claudia Colombrita, Fiona Limanaqi

et al.

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

Published: Dec. 5, 2023

COVID-19 typically causes Q7 respiratory disorders, but a high proportion of patients also reports neurological and neuromuscular symptoms during after SARSCoV-2 infection. Despite number studies documenting SARS-CoV-2 infection various neuronal cell populations, the impact exposure on motor cells specifically has not been investigated so far.Thus, by using human iPSC-derived neurons (iPSC-MNs) we assessed: (i) expression main receptors; (ii) iPSC-MN infectability SARS-CoV-2; (iii) effect transcriptome.Gene profiling immunofluorescence (IF) analysis host receptors recognized revealed that all them are expressed in iPSC-MNs, with CD147 NRP1 being most represented ones. By analyzing N1 N2 gene over time, observed iPSC-MNs were productively infected absence cytopathic effect. Supernatants collected from SARS-CoV-2-infected able to re-infect VeroE6 cells. Image analyses nucleocapsid proteins IF confirmed infectability. Furthermore, iPSCMNs significantly altered genes (IL-6, ANG, S1PR1, BCL2, BAX, Casp8, HLA-A, ERAP1, CD147, MX1) associated survival metabolism, as well antiviral inflammatory response.These results suggest for very first time can infect MNs probably binding receptors. Such information will be important unveil biological bases disorders characterizing called long-COVID symptoms.

Language: Английский

Citations

7
Cyclosporine A-Induced Systemic Metabolic Perturbations in Rats: A Comprehensive Metabolome Analysis DOI
Nguyen Thi Hai Yen,

Nguyen Tran Nam Tien,

Nguyễn Thị Vân Anh

et al.

Toxicology Letters, Journal Year: 2024, Volume and Issue: 395, P. 50 - 59

Published: March 28, 2024

Language: Английский

Citations

2
The critical impacts of cytokine storms in respiratory disorders DOI Creative Commons

Shahana Riyaz Tramboo,

Ahmed M. E. Elkhalifa,

Syed Quibtiya

et al.

Heliyon, Journal Year: 2024, Volume and Issue: 10(9), P. e29769 - e29769

Published: April 17, 2024

Cytokine storm (CS) refers to the spontaneous dysregulated and hyper-activated inflammatory reaction occurring in various clinical conditions, ranging from microbial infection end-stage organ failure. Recently novel coronavirus involved COVID-19 (Coronavirus disease-19) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) has been associated with pathological phenomenon of CS critically ill patients. Furthermore, patients suffering are likely have a grave prognosis higher case fatality rate. Pathologically is manifested as hyper-immune activation clinically multiple An in-depth understanding etiology will enable discovery not just disease risk factors but also therapeutic approaches modulate immune response improve outcomes respiratory diseases having pathogenic pathway. Owing consequences diseases, this attracted attention researchers clinicians throughout globe. So present manuscript, we attempted discuss its ramifications other well prospective treatment biomarkers cytokine storm. provide insight into both prophylactic point view. In addition, included recent findings reported different parts world, which based on expert opinion, case-control research, experimental case-controlled cohort approach.

Language: Английский

Citations

2