Distinct SARS-CoV-2 RNA fragments activate Toll-like receptors 7 and 8 and induce cytokine release from human macrophages and microglia DOI Creative Commons
Thomas Wallach, Martin Raden,

Lukas Hinkelmann

и другие.

Frontiers in Immunology, Год журнала: 2023, Номер 13

Опубликована: Янв. 13, 2023

The pandemic coronavirus disease 19 (COVID-19) is caused by severe acute respiratory syndrome 2 (SARS-CoV-2) and marked thromboembolic events an inflammatory response throughout the body, including brain. Employing machine learning approach BrainDead we systematically screened for SARS-CoV-2 genome-derived single-stranded (ss) RNA fragments with high potential to activate viral RNA-sensing innate immune receptors Toll-like receptor (TLR)7 and/or TLR8. Analyzing HEK TLR7/8 reporter cells tested such respect their induce activation of human TLR7 TLR8 macrophages, as well iPSC-derived microglia, resident in We experimentally validated several sequence-specific fragment candidates out predicted silico activators Moreover, these ssRNAs induced cytokine release from macrophages microglia a sequence- species-specific fashion. Our findings determine key sensors SARS-CoV-2-derived may deepen our understanding mechanisms how this virus triggers, but also modulates through signaling.

Язык: Английский

Sensing of SARS-CoV-2 by pDCs and their subsequent production of IFN-I contribute to macrophage-induced cytokine storm during COVID-19 DOI Creative Commons
Paôline Laurent, Chao Yang, André F. Rendeiro

и другие.

Science Immunology, Год журнала: 2022, Номер 7(75)

Опубликована: Сен. 9, 2022

Lung-infiltrating macrophages create a marked inflammatory milieu in subset of patients with COVID-19 by producing cytokine storm, which correlates increased lethality. However, these are largely not infected SARS-CoV-2, so the mechanism underlying their activation lung is unclear. Type I interferons (IFN-I) contribute to protecting host against SARS-CoV-2 but may also have some deleterious effect, and source IFN-I lungs well defined. Plasmacytoid dendritic cells (pDCs), key cell type involved antiviral responses, can produce response SARS-CoV-2. We observed infiltration pDCs SARS-CoV-2–infected patients, correlated strong signaling macrophages. In severe COVID-19, expressed robust signature, persistent at single-cell level. Hence, we uncoupling kinetics associated storm that were dominant IFN-α–producing virus blood, whereas produced IFN-α only when physical contact epithelial cells. showed pDCs, after sensing TLR7, mediated changes both transcriptional epigenetic levels, favored hyperactivation environmental stimuli. Together, data indicate priming result from leading macrophage COVID-19.

Язык: Английский

Процитировано

64
The pathogenesis of coronavirus-19 disease DOI Creative Commons
Alain Borczuk, Rhonda K. Yantiss

Journal of Biomedical Science, Год журнала: 2022, Номер 29(1)

Опубликована: Окт. 26, 2022

Abstract Severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) is the causal agent of coronavirus disease-2019 (COVID-19), a systemic illness characterized by variably severe pulmonary symptoms, cardiac conduction abnormalities, diarrhea, and gastrointestinal bleeding, as well neurologic deficits, renal insufficiency, myalgias, endocrine other perturbations that reflect widespread microvascular injury pro-inflammatory state. The mechanisms underlying various manifestations viral infection are incompletely understood but most data suggest COVID-19 results from virus-driven in immune system resultant tissue injury. Aberrant interferon-related responses lead to alterations cytokine elaboration deplete resident cells while simultaneously recruiting hyperactive macrophages functionally altered neutrophils, thereby tipping balance adaptive immunity innate immunity. Disproportionate activation these neutrophils further depletes normal activity B-cells, T-cells, natural killer (NK) cells. In addition, this state stimulates uncontrolled complement development neutrophil extracellular traps (NETS), both which promote coagulation cascade induce “thrombo-inflammation”. These have similar multiple organ systems, frequently show pathologic findings related thrombosis large small vessels. However, patients with generally more pronounced than those organs. Not only do they feature inflammatory thromboses endothelial injury, much parenchymal damage stems failed maturation alveolar pneumocytes, interactions between type 2 pneumocytes non-resident macrophages, greater degree NET formation. purpose review discuss pathogenesis can occur SARS-CoV-2 infection. Understanding important future therapies for COVID-19, many will likely target specific components system, particularly induction, cytokines, subpopulations

Язык: Английский

Процитировано

57
Toll-like receptor (TLRs) agonists and antagonists for COVID-19 treatments DOI Creative Commons
Zhimei Liu, Minghui Yang, Kun Yu

и другие.

Frontiers in Pharmacology, Год журнала: 2022, Номер 13

Опубликована: Сен. 7, 2022

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) rapidly infects humans and animals which make disease 2019 (COVID-19) a grievous epidemic worldwide broke out in 2020. According to data analysis of the other family, for instance severe SARS (SARS-CoV), can provide experience mutation SARS-CoV-2 prevention treatment COVID-19. Toll-like receptors (TLRs) as pattern recognition receptor (PRRs), have an indispensable function identifying invader even activate innate immune system. It is possible organism different TLR pathways leads secretion proinflammatory cytokines such Interleukin 1 (IL-1), 6 (IL-6), Tumor necrosis factor α (TNFα) Ⅰ interferon. As component non-specific immunity, TLRs pathway may participate pathogenic processes, due previous works proved that are involved invasion infection SARS-CoV MERS varying degrees. Different TLR, TLR2, TLR4, TLR7, TLR8 TLR9 probably double-sided COVID-19 infection. Therefore, it great significance correctly acknowledging how take part will be development strategies.

Язык: Английский

Процитировано

49
Inflammatory pathways in COVID‐19: Mechanism and therapeutic interventions DOI
Yujie Jiang, Tingmei Zhao, Xueyan Zhou

и другие.

MedComm, Год журнала: 2022, Номер 3(3)

Опубликована: Авг. 1, 2022

The 2019 coronavirus disease (COVID-19) pandemic has become a global crisis. In the immunopathogenesis of COVID-19, SARS-CoV-2 infection induces an excessive inflammatory response in patients, causing cytokine storm severe cases. Cytokine leads to acute respiratory distress syndrome, pulmonary and other multiorgan failure, which is important cause COVID-19 progression even death. Among them, activation pathways major factor generating storms dysregulated immune responses, closely related severity viral infection. Therefore, elucidation signaling pathway providing otential therapeutic targets treatment strategies against COVID-19. Here, we discuss pathogenesis including induction, function, downstream signaling, as well existing potential interventions targeting these cytokines or pathways. We believe that comprehensive understanding regulatory dysregulation inflammation will help develop better clinical therapy effectively control diseases, such

Язык: Английский

Процитировано

48
Tissue factor in COVID-19-associated coagulopathy DOI Creative Commons
Saravanan Subramaniam, Hema Kothari, Markus Bosmann

и другие.

Thrombosis Research, Год журнала: 2022, Номер 220, С. 35 - 47

Опубликована: Окт. 1, 2022

Язык: Английский

Процитировано

41
Platelets and SARS-CoV-2 During COVID-19: Immunity, Thrombosis, and Beyond DOI Open Access

Anthony R. Sciaudone,

Heather A. Corkrey,

Fiachra Humphries

и другие.

Circulation Research, Год журнала: 2023, Номер 132(10), С. 1272 - 1289

Опубликована: Май 11, 2023

COVID-19 is characterized by dysregulated thrombosis and coagulation that can increase mortality in patients. Platelets are fast responders to pathogen presence, alerting the surrounding immune cells contributing intravascular coagulation. The SARS-CoV-2 genome has been found platelets from patients with COVID-19, its coverage varies according method of detection, suggesting direct interaction virus these cells. Antibodies against Spike Nucleocapsid have confirmed this platelet-viral interaction. This review discusses immune, prothrombotic, procoagulant characteristics observed COVID-19. We outline indirect SARS-CoV-2, contribution programmed cell death pathway activation consequent extracellular vesicle release. discuss platelet immunothrombosis effect on platelets, possible classical triggers as well complement activation. As COVID-19-mediated still not understood vivo, we available murine models mouse adaptable strains.

Язык: Английский

Процитировано

41
Fighting the SARS-CoV-2 pandemic requires a global approach to understanding the heterogeneity of vaccine responses DOI Open Access

Jeffrey Tomalka,

Mehul S. Suthar, Steven G. Deeks

и другие.

Nature Immunology, Год журнала: 2022, Номер 23(3), С. 360 - 370

Опубликована: Фев. 24, 2022

Язык: Английский

Процитировано

40
TLR8 escapes X chromosome inactivation in human monocytes and CD4+ T cells DOI Creative Commons
Ali Youness, Claire Cénac, Bérénice Faz-Lopez

и другие.

Biology of Sex Differences, Год журнала: 2023, Номер 14(1)

Опубликована: Сен. 18, 2023

Human endosomal Toll-like receptors TLR7 and TLR8 recognize self non-self RNA ligands, are important mediators of innate immunity autoimmune pathogenesis. are, respectively, encoded by adjacent X-linked genes. We previously established that evades X chromosome inactivation (XCI) in female immune cells. Whether also XCI, however, has not yet been explored.

Язык: Английский

Процитировано

26
Components, Formulations, Deliveries, and Combinations of Tumor Vaccines DOI
Tengfei Liu,

Wenyan Yao,

Wenyu Sun

и другие.

ACS Nano, Год журнала: 2024, Номер 18(29), С. 18801 - 18833

Опубликована: Июль 9, 2024

Tumor vaccines, an important part of immunotherapy, prevent cancer or kill existing tumor cells by activating restoring the body's own immune system. Currently, various formulations vaccines have been developed, including cell membrane DNA mRNA polypeptide virus-vectored and tumor-in-situ vaccines. There are also multiple delivery systems for such as liposomes, vesicles, viruses, exosomes, emulsions. In addition, to decrease risk escape tolerance that may exist with a single vaccine, combination therapy radiotherapy, chemotherapy, checkpoint inhibitors, cytokines, CAR-T therapy, photoimmunotherapy is effective strategy. Given critical role in here, we look back history discuss antigens, adjuvants, formulations, systems, mechanisms, future directions

Язык: Английский

Процитировано

16
Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19 DOI Creative Commons
Rebeka Fekete, Alba Simats, Eduárd Bíró

и другие.

Nature Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Март 6, 2025

COVID-19 is associated with diverse neurological abnormalities, but the underlying mechanisms are unclear. We hypothesized that microglia, resident immune cells of brain, centrally involved in this process. To study this, we developed an autopsy platform allowing integration molecular anatomy, protein and mRNA datasets postmortem mirror blocks brain peripheral organ samples from cases COVID-19. observed focal loss microglial P2Y12R, CX3CR1-CX3CL1 axis deficits metabolic failure at sites virus-associated vascular inflammation severely affected medullary autonomic nuclei other areas. Microglial dysfunction linked to mitochondrial injury excessive synapse myelin phagocytosis glutamatergic terminals, line proteomic changes assembly, metabolism neuronal injury. Furthermore, regionally heterogeneous viral load central systemic related interleukin (IL)-1 or IL-6 via virus-sensing pattern recognition receptors inflammasomes. Thus, SARS-CoV-2-induced might lead a primarily gliovascular which could be common contributor COVID-19-related neuropathologies.

Язык: Английский

Процитировано

2