SARS-CoV-2 ORF3a Protein as a Therapeutic Target against COVID-19 and Long-Term Post-Infection Effects

Pathogens, Год журнала: 2024, Номер 13(1), С. 75 - 75

Опубликована: Янв. 14, 2024

The COVID-19 pandemic caused by SARS-CoV-2 has posed unparalleled challenges due to its rapid transmission, ability mutate, high mortality and morbidity, enduring health complications. Vaccines have exhibited effectiveness, but their efficacy diminishes over time while new variants continue emerge. Antiviral medications offer a viable alternative, success been inconsistent. Therefore, there remains an ongoing need identify innovative antiviral drugs for treating post-infection ORF3a (open reading frame 3a) protein found in SARS-CoV-2, represents promising target treatment multifaceted role viral pathogenesis, cytokine storms, disease severity, mortality. contributes significantly pathogenesis facilitating assembly release, essential processes the life cycle, also suppressing body’s responses, thus aiding replication. implicated triggering excessive inflammation, characterized NF-κB-mediated production, ultimately leading apoptotic cell death tissue damage lungs, kidneys, central nervous system. Additionally, triggers activation of NLRP3 inflammasome, inciting storm, which is major contributor severity subsequent As with spike protein, undergoes mutations, certain mutant correlate heightened COVID-19. These mutations may influence replication host cellular inflammatory responses. While establishing direct link between difficult, involvement promoting inflammation exacerbating likely higher rates severe cases. This review offers comprehensive detailed exploration ORF3a’s potential as drug target. we outline strategies discovering developing inhibitor counteract harmful effects, alleviate damage, reduce lingering

Язык: Английский

---

Severe Acute Respiratory Syndrome Coronavirus 2 Variant Infection Dynamics and Pathogenesis in Transgenic K18-hACE2 and Inbred Immunocompetent C57BL/6J Mice

Viruses, Год журнала: 2025, Номер 17(4), С. 500 - 500

Опубликована: Март 30, 2025

The global impact of the COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), persists in part due to emergence new variants. Understanding variant-specific infection dynamics and pathogenesis murine models is crucial for identifying phenotypic changes guiding development countermeasures. To address limitations earlier studies that investigated only a few variants or used small sample sizes, we evaluated clinical disease, kinetics, viral titers, cellular localization, histopathologic lungs brains transgenic B6.Cg-Tg(K18-ACE2)2Prlmn/J (“K18”) corresponding genetic control (C57BL/6J) mice expressing human angiotensin-converting enzyme (hACE2). Six SARS-CoV-2 were assessed: B.1 (WA1-like), alpha, beta, delta, omicron, omicron XBB.1.5, using cohorts ≥18 mice. Following intranasal inoculation with B.1, delta variants, K18 experienced rapid weight loss reached euthanasia criteria 5–6 days post-inoculation (dpi). In contrast, inoculated both recovered their starting within 4–6 dpi. Infectious was detected oropharynx at 1 and2 dpi, 2, 4, 6 brain 4 dpi all except omicron. nucleoprotein detected, interstitial pneumonia varying severity observed infected Brain lesions identified As express hACE2 brain—a feature not present humans—we also compared three those mouse-adapted WA1 strain C57BL/6J lacking ACE2 gene. did experience lethal exhibited milder pneumonia, had no evidence neuroinvasion despite similar kinetics These findings demonstrate contrasting phenotypes across two reduced tropism pathology models. This comprehensive analysis mouse provides valuable insights model variant selection future studies.

Язык: Английский

---

Multicomponent intranasal adjuvant for mucosal and durable systemic SARS-CoV-2 immunity in young and aged mice

npj Vaccines, Год журнала: 2023, Номер 8(1)

Опубликована: Июнь 29, 2023

Abstract Multiple FDA-approved SARS-CoV-2 vaccines currently provide excellent protection against severe disease. Despite this, immunity can wane relatively fast, particularly in the elderly and novel viral variants capable of evading infection- vaccination-induced continue to emerge. Intranasal (IN) vaccination more effectively induces mucosal immune responses than parenteral vaccines, which would improve reduce transmission. Here, we developed a rationally designed IN adjuvant consisting combined nanoemulsion (NE)-based an RNA-based RIG-I agonist (IVT DI) drive robust, broadly protective antibody T cell responses. We previously demonstrated this combination (NE/IVT) potently through synergistic activation array innate receptors. now demonstrate that NE/IVT with receptor binding domain (RBD), robust durable humoral, mucosal, cellular equivalent magnitude quality young aged mice. This contrasted MF59-like intramuscular adjuvant, Addavax, showed decrease immunogenicity age. Robust antigen-specific IFN-γ/IL-2/TNF-α was induced both NE/IVT-immunized animals, is significant as their reduced production associated suboptimal elderly. These findings highlight potential adjuvanted for improving COVID-19.

Язык: Английский

---

A cell-adapted SARS-CoV-2 mutant, showing a deletion in the spike protein spanning the furin cleavage site, has reduced virulence at the lung level in K18-hACE2 mice.

Virology, Год журнала: 2024, Номер 592, С. 109997 - 109997

Опубликована: Янв. 28, 2024

Here we investigated the virulence properties of a unique cell-adapted SARS-CoV-2 mutant showing ten-amino acid deletion encompassing furin cleavage site spike protein (Δ

Язык: Английский

---

Inflammatory Response and Defects on Myelin Integrity in the Olfactory System of K18hACE2 Mice Infected with SARS-CoV-2

eNeuro, Год журнала: 2024, Номер 11(6), С. ENEURO.0106 - 24.2024

Опубликована: Июнь 1, 2024

Viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), use epithelial cells an entry point for infection. Within the nasal cavity, olfactory epithelium (OE) is particularly sensitive to infections which may lead dysfunction. In patients suffering from disease 2019, deficits in olfaction have been characterized a distinctive symptom. Here, we used K18hACE2 mice study spread of SARS-CoV-2 infection and inflammation system (OS) after 7 d OE, found that selectively targeted supporting/sustentacular (SCs) macrophages lamina propria. brain, infected some microglial bulb (OB), there was widespread projection neurons OB, piriform cortex (PC), tubular striatum (TuS). Inflammation, indicated by both elevated numbers morphologically activated IBA1 + (monocyte/macrophage lineages), preferentially increased OE septum, while it homogeneously distributed throughout layers PC, TuS. Myelinated OS axonal tracts, lateral tract, anterior commissure, exhibited decreased levels 2′,3′-cyclic-nucleotide 3′-phosphodiesterase, indicative myelin defects. Collectively, our work supports hypothesis SC and, centrally, microglia subpopulations neurons. The observed areas central defects account long-lasting deficit.

Язык: Английский

---

Advances in Molecular Genetics Enabling Studies of Highly Pathogenic RNA Viruses

Viruses, Год журнала: 2022, Номер 14(12), С. 2682 - 2682

Опубликована: Ноя. 30, 2022

Experimental work with viruses that are highly pathogenic for humans and animals requires specialized Biosafety Level 3 or 4 facilities. Such pathogens include some spectacular but also rather seldomly studied examples such as Ebola virus (requiring BSL-4), more wide-spread commonly HIV, the most recent example, SARS-CoV-2, which causes COVID-19. A common characteristic of these is their genomes consist single-stranded RNA, conversion into a DNA copy easy manipulation; this can be performed to study viral life cycle in detail, develop novel therapies vaccines, monitor disease course over time chronic infections. We summarize advances new genetic applications RNA Switzerland last 25 years, from early days HIV/AIDS epidemic developments research on SARS-CoV-2 coronavirus. highlight game-changing collaborative efforts between clinical molecular disciplines HIV path optimal management. Moreover, we how modern technical evolution enabled studies emerging viruses, confirming at forefront potentially other newly viruses.

Язык: Английский

---

Proof-of-Concept Study of Liposomes with a Set of SARS-CoV-2 Viral Peptidic T-Cell Epitopes as a Vaccine

Russian Journal of Bioorganic Chemistry, Год журнала: 2022, Номер 48(S1), С. S23 - S37

Опубликована: Дек. 1, 2022

Язык: Английский

---

Measuring the replicability of our own research

Journal of Neuroscience Methods, Год журнала: 2024, Номер 406, С. 110111 - 110111

Опубликована: Март 21, 2024

In the study of transgenic mouse models neurodevelopmental and neurodegenerative disorders, we use batteries tests to measure deficits in behaviour from results these tests, make inferences about mental states mice that interpret as "learning", "memory", "anxiety", "depression", etc. This paper discusses problems determining whether a particular is valid model disease X, problem background strains, question our behavioural are measuring what say they are. The reliability then discussed: replicable between labs can replicate own lab? involves intra- inter- experimenter reliability. variables influence replicability importance conducting complete phenotype: sensory, motor, cognitive social emotional discussed. Then thorny failure examined: Is it curse or blessing? Finally, role research tells us paradigms examined.

Язык: Английский

---

Premature aging effects on COVID-19 pathogenesis: new insights from mouse models

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

Опубликована: Авг. 24, 2024

Aging is identified as a significant risk factor for severe coronavirus disease-2019 (COVID-19), often resulting in profound lung damage and mortality. Yet, the biological relationship between aging, aging-related comorbidities, COVID-19 remains incompletely understood. This study aimed to elucidate age-related COVID19 pathogenesis using an Hutchinson-Gilford progeria syndrome (HGPS) mouse model, premature aging disease with humanized ACE2 receptors. Pathological features were compared young, aged, HGPS hACE2 mice following SARS-CoV-2 challenge. We demonstrated that young display robust interferon response antiviral activity, whereas this attenuated aged mice. Viral infection results respiratory tract hemorrhage, likely contributing higher mortality rate. In contrast, exhibit milder manifestations characterized by minor immune cell infiltration dysregulation of multiple metabolic processes. Comprehensive transcriptome analysis revealed both shared unique gene expression dynamics among different groups. Collectively, our studies evaluated impact on progeroid syndromes which holds promise useful tool investigating individuals aging.

Язык: Английский

---

Productive infection of the retinal pigment epithelium by SARS-CoV-2: Initial effects and consideration of long-term consequences

PNAS Nexus, Год журнала: 2024, Номер 3(12)

Опубликована: Ноя. 28, 2024

Abstract As the SARS-CoV-2 coronavirus continues to evolve and infect global population, many individuals are likely suffer from post-acute sequelae of infection (PASC). Manifestations PASC include vision symptoms, but little is known about ability impact retinal cells. Here, we demonstrate that can perturb pigment epithelium (RPE) in vivo, after intranasal inoculation a transgenic mouse model infection, cell culture. Separate lentiviral studies showed Spike protein mediates viral entry replication RPE cells, while Envelope ORF3a proteins induce morphological changes. Infection with major variants compromised barrier function phagocytic capacity. It also caused complement activation production cytokines chemokines, resulting an inflammatory response spread across layer. This signature has similarities associated onset age-related macular degeneration (AMD), cause human blindness, pathology eventually leads photoreceptor loss. Thus, our findings suggest may have long-term implications for vision, perhaps comparable increased occurrence AMD found among infected by HIV, greater public health consequences due much larger number infections.

Язык: Английский

---