Voltage-gated T-type calcium channel blockers reduce apoptotic body mediated SARS-CoV-2 cell-to-cell spread and subsequent cytokine storm DOI Creative Commons
Thanh Kha Phan, Dylan Sheerin, Bo Shi

et al.

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

Published: Nov. 6, 2023

ABSTRACT SARS-CoV-2 typically utilises host angiotensin-converting enzyme 2 (ACE2) as a cellular surface receptor and serine protease TMPRSS2 for the proteolytic activation of viral spike protein enabling entry. Although macrophages express low levels ACE2, they are often found positive in autopsied lungs from COVID-19 patients. As viral-induced macrophage inflammation overwhelming cytokine release key immunopathological events that drives exacerbated tissue damage severe patients, insights into entry therefore critical to understand pathogenesis devise novel therapies. Mounting evidence suggest is associated with apoptosis, type programmed cell death leads numerous large extracellular vesicles (EVs) called apoptotic bodies (ApoBDs). Here, we showed ApoBDs derived SARS-CoV-2-infected cells carry antigens infectious virions. Human monocyte-derived readily efferocytosed SARS-CoV-2-induced ApoBDs, resulting pro-inflammatory responses. To target this ApoBD-mediated process, screened ApoBD formation inhibitors discovered T-type voltage-gated calcium channel (T-channel) blockers can inhibit formation. Mechanistically, T-channel impaired influxes required biogenesis. Importantly, blockade by were able limit dissemination virus-induced vitro pre-clinical mouse model COVID-19. Our discovery ApoBD-efferocytosis-mediated reveals route infection storm induction, expanding our understanding offering new therapeutic avenues diseases.

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 omicron BA.5 and XBB variants have increased neurotropic potential over BA.1 in K18-hACE2 mice and human brain organoids DOI Creative Commons
Romal Stewart, Kexin Yan, Sevannah A. Ellis

et al.

Frontiers in Microbiology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 23, 2023

The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described, although whether such attenuation retained for later like BA.5 and XBB remains controversial. We show that isolates were significantly more pathogenic in K18-hACE2 mice than a isolate, showing increased neurotropic potential, resulting fulminant brain infection mortality, similar seen original ancestral isolates. also infected human cortical organoids greater extent In brains mice, neurons main target infection, neuronal progenitor cells immature infected. results herein suggest evolving may have increasing potential.

Language: Английский

Citations

25
Role of the gut microbiota in hematologic cancer DOI Creative Commons
Patricia Guevara-Ramí­rez, Santiago Cadena-Ullauri, Elius Paz‐Cruz

et al.

Frontiers in Microbiology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 25, 2023

Hematologic neoplasms represent 6.5% of all cancers worldwide. They are characterized by the uncontrolled growth hematopoietic and lymphoid cells a decreased immune system efficacy. Pathological conditions in hematologic cancer could disrupt balance gut microbiota, potentially promoting proliferation opportunistic pathogens. In this review, we highlight studies that analyzed described role microbiota different types diseases. For instance, myeloma is often associated with Pseudomonas aeruginosa Clostridium leptum , while leukemias, Streptococcus most common genus, Lachnospiraceae Ruminococcaceae less prevalent. Lymphoma exhibits moderate reduction diversity. Moreover, certain factors such as delivery mode, diet, other environmental can alter diversity leading to dysbiosis. This dysbiosis may inhibit response increase susceptibility cancer. A comprehensive analysis microbiota-cancer interactions be useful for disease management provide valuable information on host-microbiota dynamics, well possible use distinguishable marker progression.

Language: Английский

Citations

21
iPSC-derived three-dimensional brain organoid models and neurotropic viral infections DOI Open Access

Michael Swingler,

Martina Donadoni, Anna Bellizzi

et al.

Journal of NeuroVirology, Journal Year: 2023, Volume and Issue: 29(2), P. 121 - 134

Published: April 1, 2023

Language: Английский

Citations

19
Chronic Opioid Treatment Arrests Neurodevelopment and Alters Synaptic Activity in Human Midbrain Organoids DOI Creative Commons
Hye Sung Kim, Yang Xiao, Xuejing Chen

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(21)

Published: March 28, 2024

Understanding the impact of long-term opioid exposure on embryonic brain is critical due to surging number pregnant mothers with dependency. However, this has been limited by human inaccessibility and cross-species differences in animal models. Here, a midbrain model established that uses hiPSC-derived organoids assess cell-type-specific responses acute chronic fentanyl treatment withdrawal. Single-cell mRNA sequencing 25,510 cells from different groups reveals arrests neuronal subtype specification during early development alters synaptic activity neuron projection. In contrast, increases dopamine release but does not significantly alter gene expression related cell lineage development. These results provide first examination effects at single-cell level.

Language: Английский

Citations

7
Orchestration of antiviral responses within the infected central nervous system DOI Creative Commons
Andreas Pavlou, Felix Mulenge, Olivia Luise Gern

et al.

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(9), P. 943 - 958

Published: July 12, 2024

Abstract Many newly emerging and re-emerging viruses have neuroinvasive potential, underscoring viral encephalitis as a global research priority. Upon entry of the virus into CNS, severe neurological life-threatening conditions may manifest that are associated with high morbidity mortality. The currently available therapeutic arsenal against is rather limited, emphasizing need to better understand local antiviral immunity within infected CNS. In this review, we discuss new insights pathophysiology encephalitis, focus on myeloid cells CD8 + T cells, which critically contribute protection CNS infection. By illuminating prerequisites cell activation, discussing discoveries regarding their transcriptional signatures, dissecting mechanisms recruitment sites replication aim further delineate complexity responses Moreover, summarize current knowledge in field infection neurodegeneration potential links some neurotropic certain pathological hallmarks observed neurodegeneration.

Language: Английский

Citations

6
Understanding neurotropic enteric viruses: routes of infection and mechanisms of attenuation DOI Creative Commons
Valeria Lulla, Adithya Sridhar

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: Oct. 4, 2024

Language: Английский

Citations

4
Organoid Models to Study Human Infectious Diseases DOI Creative Commons

Sijing Zhu,

Dan Chen,

Xinzhi Yang

et al.

Cell Proliferation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

ABSTRACT Infectious diseases have become significant events that threaten global public health and economic development. Since the 20th century, multiple outbreaks of infectious gradually deepened humanity's understanding viral infections, prevention treatment. Organoids possess a high degree similarity to human physiological states strong self‐organising capabilities. Research on based organoids offers advantages in terms availability, editability diversity. In this perspective, we briefly introduce development organoids, focusing historically caused fatal harm health, such as HIV, ZIKV, SARS‐CoV‐2 MPXV. We further summarise relevant research pathogenic mechanisms these viruses organoid models, host reactivity, therapeutic strategies. Finally, list latest techniques combined with discuss challenges faced look forward future prospects vaccine drug

Language: Английский

Citations

0
Component specific responses of the microbiomes to common chemical stressors in the human food chain DOI Creative Commons

Wasimuddin,

Aurea C. Chiaia‐Hernández,

Céline Terrettaz

et al.

Environmental Microbiome, Journal Year: 2025, Volume and Issue: 20(1)

Published: April 28, 2025

Language: Английский

Citations

0
Integrative network pharmacology and in silico analyses identify the anti-omicron SARS-CoV-2 potential of eugenol DOI Creative Commons
Yang Liu

Heliyon, Journal Year: 2023, Volume and Issue: 9(3), P. e13853 - e13853

Published: Feb. 18, 2023

Eugenol as a natural product is the source of isoniazid, and purified eugenol extensively used in cosmetics industry productive processes edible spices. Accumulating evidence suggested that exerted potent anti-microorganism anti-inflammation effects. Application effectively reduced risk atherosclerosis, arterial embolism, Type 2 diabetes. A previous study confirmed treatment with attenuated lung inflammation improved heart functions SARS-CoV-2 spike S1-intoxicated mice. In addition to study, based on series public datasets, computational analyses were conducted characterize acting targets functional roles these COVID-19. The binding capacities conservative sites like RNA-dependent RNA polymerase (RdRp) mutable site (S) protein, calculated by using molecular docking following dynamics simulation RMSD, RMSF, MM-GBSA methods. results network pharmacology indicated six targets, including PLAT, HMOX1, NUP88, CTSL, ITGB1 andTMPRSS2 eugenol-SARS-CoV-2 interacting proteins. omics in-silico further implicated increased expression SCARB1, HMOX1 GDF15, especially which potential between antigens. Enrichment extensive biological effects such regulating immune infiltration macrophage, lipid localization, monooxyenase activity, iron ion PPAR signaling. integrated analysis immunotranscription profile COVID-19 cases shows also plays an important role strengthen immunologic cytokine As complement analysis, interactions four proteins relating production/release function T type lymphocytes, human TLR-4, TCR, NF-κB, JNK AP-1. Furthermore, (100ns) simulations stimulated modification Omicron Spike-ACE2 complex, for ACE2, interaction RdRp, no less favorable than two positive controls, molnupiravir nilotinib. Dynamics (200ns) stabilities finger subdomain RdRp molnupiravir. However, simulated capacity wild RBD mutant was predicted have more favor LD50 value lower cytotoxicity can pass through blood-brain barrier (BBB). brief, helpful attenuating systemic induced infection, due direct bio-manipulation pro-inflammatory factors. This carefully suggests candidate compound developing drugs supplement agents against its variants.

Language: Английский

Citations

8