SARS-CoV-2 ORF3a induces COVID-19-associated kidney injury through HMGB1-mediated cytokine production DOI Creative Commons
Chen‐Yu Zhang,

Volodymyr Gerzanich,

Ruth Cruz‐Cosme

и другие.

mBio, Год журнала: 2024, Номер 15(11)

Опубликована: Сен. 30, 2024

ABSTRACT The primary challenge posed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is COVID-19-related mortality, often exacerbated additional medical complications, such as COVID-19-associated kidney injuries (CAKIs). Up to half of COVID-19 patients experience with those facing failure and injury having the worst overall prognosis. Despite significant impact CAKI on mortality its enduring effects in long COVID, underlying causes molecular mechanisms remain elusive. In this study, we identified a functional relationship between expression SARS-CoV-2 ORF3a protein inflammation-driven apoptotic death renal tubular epithelial cells CAKI. We demonstrate vitro that independently induces cell-specific cell death, evidenced elevation molecule-1 (KIM-1) activation NF-kB-mediated proinflammatory cytokine (TNFα IL-6) production. By examining tissues SARS-CoV-2-infected K18-ACE2 transgenic mice, observed similar correlation ORF3a-induced cytopathic changes injury. This was further validated through reconstitution via direct adenoviral injection into mouse kidneys. Through medicinal analysis, natural compound, glycyrrhizin (GL4419), which not only blocks viral replication cells, but also mitigates inhibiting high mobility group box 1 (HMGB1) protein, leading reduction KIM-1. Moreover, interacts HMGB1. Overproduction or downregulation hmgb1 results correlative cellular KIM-1 response respective production, implicating crucial role HMGB1 ORF3a-inflicted injuries. Our data suggest link injury, highlighting unique therapeutic target contributing IMPORTANCE major during pandemic has tragically claimed millions lives. morbidity are pre-existing conditions, chronic diseases (CKDs), development (AKI) due COVID-19, collectively known Patients who have poorest clinical outcomes, including increased mortality. these alarming findings, there critical gap our understanding study establishes induced linking initially studies AKI animal studies, either expressing alone context infection. elucidating mechanistic pathways, research deepens presents potential avenues address healthcare challenges faced individuals conditions.

Язык: Английский

Genetic Conservation and Diversity of SARS‐CoV‐2 Envelope Gene Across Variants of Concern DOI
Baoming Liu,

Qiaobin Yao,

Ruth Cruz‐Cosme

и другие.

Journal of Medical Virology, Год журнала: 2025, Номер 97(1)

Опубликована: Янв. 1, 2025

ABSTRACT SARS‐CoV‐2 Envelope (E) protein is critical in viral assembly, release, and virulence. E gene was considered highly conserved evolving slowly. Pan‐sarbecoviruses–conserved regions the have been used as targets for various RT‐PCR assays to detect SARS‐CoV‐2. It remains elusive whether variants of concern (VOCs) accumulated significant mutations that may affect stability diagnostic assays. Herein we aimed perform a comprehensive genetic analysis on conservation diversity its VOCs comparison with other human coronaviruses (HCoVs). In silico 20 326 HCoV sequences retrieved from GenBank GISAID suggests has multiple pan‐HCoVs– pan‐SARS‐CoV‐2–conserved positions but accumulates VOC B.1.351 Omicron strains. Mutations were often found 5′ 3′ variable regions, whereas central region conserved. Nucleotide changes C109U A114G lead potential failure first‐line diagnostic/screening change C212U concomitant amino acid substitution Pro71Leu (i.e., C212U/Pro71Leu) hallmark mutation variants, while C26U/Thr9Ile characteristic all variants. Later subvariants, such XBB.1.5 EG.5, additionally acquired A31G/Thr11Ala mutation, confirmed by whole genome sequencing 118 pediatric cases. Wild‐type exhibits cytotoxicity cells, Thr9Ile, Thr11Ala, Thr9Ile + or reduces cytotoxicity. The Thr11Ala stabilizes proteins alters cellular distribution protein, reducing colocalization Golgi body. Altogether, this study not only sheds light also informs improvement development pan‐HCoVs screening

Язык: Английский

Процитировано

11
Alteration of circulating ACE2-network related microRNAs in patients with COVID-19 DOI Creative Commons
Zofia Wicik, Ceren Eyileten, A Nowak

и другие.

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

Опубликована: Июнь 12, 2024

Abstract Angiotensin converting enzyme 2 (ACE2) serves as the primary receptor for SARS-CoV-2 virus and has implications functioning of cardiovascular system. Based on our previously published bioinformatic analysis, in this study we aimed to analyze diagnostic predictive utility miRNAs (miR-10b-5p, miR-124-3p, miR-200b-3p, miR-26b-5p, miR-302c-5p) identified top regulators ACE2 network with potential affect cardiomyocytes system patients COVID-19. The expression was determined through qRT-PCR a cohort 79 hospitalized COVID-19 well 32 healthy volunteers. Blood samples clinical data were collected at admission, 7-days 21-days after admission. We also performed SHAP analysis target predictions advanced enrichment analyses. Low miR-200b-3p seventh day admission is indicative value determining length hospital stay and/or likelihood mortality, shown ROC curve an AUC 0.730 p-value 0.002. MiR-26b-5p levels lower baseline, 7 compared controls (P < 0.0001). Similarly, miR-10b-5p baseline post = 0.001). opposite situation observed miR-124-3p miR-302c-5p. Enrichment showed influence analyzed IL-2 signaling pathway multiple diseases COVID-19-related targets. Moreover, genes regulated by linked T cell protein tyrosine phosphatase HIF-1 transcriptional activity hypoxia. Analysis focused associated that all are strongly affecting disease pathways related CVDs which could be explained their strong interaction network.

Язык: Английский

Процитировано

3
Novel Vaccines Targeting the Highly Conserved SARS-CoV-2 ORF3a Ectodomain Elicit Immunogenicity in Mouse Models DOI Creative Commons

Jacob Meza,

Elizabeth M. Glass,

Avinaash K. Sandhu

и другие.

Vaccines, Год журнала: 2025, Номер 13(3), С. 220 - 220

Опубликована: Фев. 22, 2025

Background: The majority of antigen-based SARS-CoV-2 (SCV2) vaccines utilized in the clinic have had Spike protein or domains thereof as immunogen. While is highly immunogenic, it also subject to genetic drift over time, which has led a series variants concern that continue evolve, requiring yearly updates vaccine formulations. In this study, we investigate potential N-terminal ectodomain ORF3a encoded by orf3a gene SCV2 be an evolution-resistant antigen. This domain conserved and, unlike many other proteins, present on exterior virion, making accessible antibodies. important for eliciting robust anti-SARS-CoV-2 T-cell responses. Methods: We designed DNA fusing macrophage-inflammatory 3α (MIP3α), chemokine our laboratory enhances immunogenicity targeting antigen its receptor CCR6 immature dendritic cells. was tested mouse studies, vaccinating intramuscular (IM) electroporation and intranasal (IN) with CpG adjuvant administrations. peptide amino acids 15–28 immunogenic carrier KLH, adjuvanted Addavax. Results: IM route able induce 3a-specific splenic responses, showing proof principle region can immunogenic. IN further showed could ORF3a-specific responses lung, are critical disease mitigation. elicited anti-ORF3a antibody response systemically, well mucosa lungs sinus cavity. Conclusions: These studies collectively show evolutionarily stable targeted vaccination strategies, future work will test if these vaccines, alone combination, result reduced burden animal challenge models.

Язык: Английский

Процитировано

0
Acute COVID-19 and LongCOVID syndrome – molecular implications for therapeutic strategies - review DOI Creative Commons
Katarzyna Michalak,

Alicja Michalak,

Alicja Brenk-Krakowska

и другие.

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Апрель 17, 2025

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been recognized not only for its acute effects but also ability to cause LongCOVID (LCS), a condition characterized by persistent symptoms affecting multiple organ systems. This review examines the molecular and immunological mechanisms underlying LCS, with particular focus on autophagy inhibition, chronic inflammation, oxidative, nitrosative calcium stress, viral persistence autoimmunology. Potential pathophysiological involved in LCS include (1) autoimmune activation, (2) latent persistence, where SARS-CoV-2 continues influence host metabolism, (3) reactivation of pathogens such as Epstein-Barr virus (EBV) or cytomegalovirus (CMV), exacerbating immune metabolic dysregulation, (4) possible inflammatory body fails restore post-infection homeostasis. The manipulation cellular pathways proteins is critical aspect virus' evade clearance establish long-term dysfunction. Viral NSP13, ORF3a ORF8 have shown disrupt autophagy, thereby impairing promoting evasion. In addition, mitochondrial dysfunction, dysregulated signaling, oxidative HIF-1α activation Nrf2 inhibition create self-sustaining feedback loop that contributes tissue damage symptoms. Therefore understanding basis development effective therapeutic strategies. Targeting glycolysis restoration homeostasis may provide novel strategies mitigate consequences infection. Future research should personalized interventions based dominant perturbations individual patients.

Язык: Английский

Процитировано

0
Development of viral infectious clones and their applications based on yeast and bacterial artificial chromosome platforms DOI Creative Commons
Yiyi Wu,

Shangqing Gao,

G. Liu

и другие.

Molecular Biomedicine, Год журнала: 2025, Номер 6(1)

Опубликована: Апрель 29, 2025

Abstract Infectious Clones represent a foundational technique in the field of reverse genetics, allowing for construction and manipulation full-length viral genomes. The main methods currently used constructing infectious clones include Transformation-associated recombination (TAR), which is based on Yeast Artificial Chromosome (YAC) Bacterial (BAC). YAC BAC systems are powerful tools that enable large DNA fragments, making them well-suited These have been successfully applied to construct wide range viruses, including coronaviruses, herpesviruses, flaviviruses baculoviruses. rescued recombinant viruses from these widely various research areas, such as vaccine development, antiviral drug screening, pathogenesis virulence studies, gene therapy vector design. However, different possess unique biological characteristics, challenge remains how rapidly obtain future research. In summary, this review introduced development applications clones, with focus YAC, combined YAC-BAC technologies. We emphasize importance platforms areas aim provide deeper insights can advance platform broaden its application horizons.

Язык: Английский

Процитировано

0
Advanced Protocol for Molecular Characterization of Viral Genome in Fission Yeast (Schizosaccharomyces pombe) DOI Creative Commons
Jiantao Zhang, Zsigmond Benkő, Chen‐Yu Zhang

и другие.

Pathogens, Год журнала: 2024, Номер 13(7), С. 566 - 566

Опубликована: Июль 4, 2024

Fission yeast, a single-cell eukaryotic organism, shares many fundamental cellular processes with higher eukaryotes, including gene transcription and regulation, cell cycle vesicular transport membrane trafficking, death resulting from the stress response. As result, fission yeast has proven to be versatile model organism for studying human physiology diseases such as dysregulation cancer, well autophagy neurodegenerative like Alzheimer’s, Parkinson’s, Huntington’s diseases. Given that viruses are obligate intracellular parasites rely on host machinery replicate produce, could serve surrogate identify viral proteins affect processes. This approach facilitate study of virus–host interactions help potential targets antiviral therapy. Using functional characterization genomes offers several advantages, well-characterized haploid genome, robustness, cost-effectiveness, ease maintenance, rapid doubling time. Therefore, emerges valuable system comprehensive proteins, aiding in identification therapeutic or impact highly conserved functions significant virologic implications. Importantly, this track record success various plant viruses. In protocol, we present streamlined scalable molecular cloning strategy tailored genome-wide yeast.

Язык: Английский

Процитировано

0
SARS-CoV-2 ORF3a induces COVID-19-associated kidney injury through HMGB1-mediated cytokine production DOI Creative Commons
Chen‐Yu Zhang,

Volodymyr Gerzanich,

Ruth Cruz‐Cosme

и другие.

mBio, Год журнала: 2024, Номер 15(11)

Опубликована: Сен. 30, 2024

ABSTRACT The primary challenge posed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is COVID-19-related mortality, often exacerbated additional medical complications, such as COVID-19-associated kidney injuries (CAKIs). Up to half of COVID-19 patients experience with those facing failure and injury having the worst overall prognosis. Despite significant impact CAKI on mortality its enduring effects in long COVID, underlying causes molecular mechanisms remain elusive. In this study, we identified a functional relationship between expression SARS-CoV-2 ORF3a protein inflammation-driven apoptotic death renal tubular epithelial cells CAKI. We demonstrate vitro that independently induces cell-specific cell death, evidenced elevation molecule-1 (KIM-1) activation NF-kB-mediated proinflammatory cytokine (TNFα IL-6) production. By examining tissues SARS-CoV-2-infected K18-ACE2 transgenic mice, observed similar correlation ORF3a-induced cytopathic changes injury. This was further validated through reconstitution via direct adenoviral injection into mouse kidneys. Through medicinal analysis, natural compound, glycyrrhizin (GL4419), which not only blocks viral replication cells, but also mitigates inhibiting high mobility group box 1 (HMGB1) protein, leading reduction KIM-1. Moreover, interacts HMGB1. Overproduction or downregulation hmgb1 results correlative cellular KIM-1 response respective production, implicating crucial role HMGB1 ORF3a-inflicted injuries. Our data suggest link injury, highlighting unique therapeutic target contributing IMPORTANCE major during pandemic has tragically claimed millions lives. morbidity are pre-existing conditions, chronic diseases (CKDs), development (AKI) due COVID-19, collectively known Patients who have poorest clinical outcomes, including increased mortality. these alarming findings, there critical gap our understanding study establishes induced linking initially studies AKI animal studies, either expressing alone context infection. elucidating mechanistic pathways, research deepens presents potential avenues address healthcare challenges faced individuals conditions.

Язык: Английский

Процитировано

0