Epigenetic memory of coronavirus infection in innate immune cells and their progenitors

Cell, Journal Year: 2023, Volume and Issue: 186(18), P. 3882 - 3902.e24

Published: Aug. 1, 2023

Language: Английский

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Decoding Toll-like receptors: Recent insights and perspectives in innate immunity

Immunity, Journal Year: 2024, Volume and Issue: 57(4), P. 649 - 673

Published: April 1, 2024

Language: Английский

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Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung

The Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 221(6)

Published: April 10, 2024

Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects SARS-CoV-2 virus by productively infecting healthy human lung tissue using scRNA-seq reconstruct the transcriptional program “infection pseudotime” for individual cell types. predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands viral RNA molecules, taking over 60% transcriptome forming dense bodies while inducing host profibrotic (TGFB1, SPP1) inflammatory (early interferon response, CCL2/7/8/13, CXCL10, IL6/10) programs destroying architecture. Infected alveolar (AMs) showed none these extreme responses. Spike-dependent entry into AMs used ACE2 Sialoadhesin/CD169, whereas IM DC-SIGN/CD209. These results identify IMs as a prominent site takeover, focus inflammation fibrosis, suggest targeting CD209 prevent early pathology pneumonia. This approach be generalized any infection evaluate therapeutics.

Language: Английский

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TLR8 escapes X chromosome inactivation in human monocytes and CD4+ T cells

Biology of Sex Differences, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 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.

Language: Английский

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Macrophage phagocytosis of SARS-CoV-2-infected cells mediates potent plasmacytoid dendritic cell activation

Cellular and Molecular Immunology, Journal Year: 2023, Volume and Issue: 20(7), P. 835 - 849

Published: May 30, 2023

Abstract Early and strong interferon type I (IFN-I) responses are usually associated with mild COVID-19 disease, whereas persistent or unregulated proinflammatory cytokine severe disease outcomes. Previous work suggested that monocyte-derived macrophages (MDMs) resistant unresponsive to SARS-CoV-2 infection. Here, we demonstrate upon phagocytosis of SARS-CoV-2-infected cells, MDMs activated secrete IL-6 TNF. Importantly, in turn mediate activation plasmacytoid dendritic cells (pDCs), leading the secretion high levels IFN-α Furthermore, pDC promoted production by MDMs. This kind was dependent on direct integrin-mediated cell‒cell contacts involved stimulation TLR7 STING signaling pathways. Overall, present study describes a novel potent pathway is linked macrophage-mediated clearance infected cells. These findings suggest infection rate may lead exaggerated responses, which contribute tissue damage disease.

Language: Английский

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The role of plasmacytoid dendritic cells (pDCs) in immunity during viral infections and beyond

Cellular and Molecular Immunology, Journal Year: 2024, Volume and Issue: 21(9), P. 1008 - 1035

Published: May 22, 2024

Abstract Type I and III interferons (IFNs) are essential for antiviral immunity act through two different but complimentary pathways. First, IFNs activate intracellular antimicrobial programs by triggering the upregulation of a broad repertoire viral restriction factors. Second, innate adaptive immunity. Dysregulation IFN production can lead to severe immune system dysfunction. It is thus crucial identify characterize cellular sources IFNs, their effects, regulation promote beneficial effects limit detrimental which depend on nature infected or diseased tissues, as we will discuss. Plasmacytoid dendritic cells (pDCs) produce large amounts all subtypes during infection. pDCs resistant infection many viruses, inhibiting evasion mechanisms viruses that target downstream responses. Therefore, considered control infections establishment protective A thorough bibliographical survey showed that, in most infections, despite being major producers, actually dispensable host resistance, achieved multiple depending tissue. Moreover, primary responses only transiently affected absence pDCs. More surprisingly, be some autoimmune diseases. This makes conservation vertebrate evolution an enigma raises outstanding questions about role not also other diseases under physiological conditions.

Language: Английский

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Interferons and epigenetic mechanisms in training, priming and tolerance of monocytes and hematopoietic progenitors

Immunological Reviews, Journal Year: 2024, Volume and Issue: 323(1), P. 257 - 275

Published: April 3, 2024

Training and priming of innate immune cells involve preconditioning by PAMPs, DAMPs, and/or cytokines that elicits stronger induction inflammatory genes upon secondary challenge. Previous models distinguish training based whether activation returns to baseline prior Tolerance is a protective mechanism whereby potent stimuli induce refractoriness are important for memory responses protect against infection, efficacy vaccines, maintaining in state readiness; tolerance prevents toxicity from excessive activation. Dysregulation these processes can contribute pathogenesis autoimmune/inflammatory conditions, post-COVID-19 hyperinflammatory states, or sepsis-associated immunoparalysis. Training, priming, regulate similar "signature" such as TNF, IL6, IL1B utilize overlapping epigenetic mechanisms. We review how interferons (IFNs), best known activating JAK-STAT signaling interferon-stimulated genes, also play key role regulating training, via chromatin-mediated present new data on monocyte-to-macrophage differentiation modulates IFN-γ-mediated affects regulation AP-1 CEBP activity, attenuates superinduction genes. "training-priming continuum" model integrates IFN-mediated into current concepts about proposes central STAT1 IRF1.

Language: Английский

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Regulation of type I and type III interferon induction in response to pathogen sensing

Current Opinion in Immunology, Journal Year: 2024, Volume and Issue: 87, P. 102424 - 102424

Published: April 1, 2024

Type I and III interferons (IFN-I IFN-III) have a central role in the early antimicrobial response against invading pathogens. Induction of IFN-Is IFN-IIIs arises due to sensing by pattern recognition receptors pathogen-associated molecular patterns (from micro-organisms) or damage-associated (DAMPs; produced host cells). Here, we review recent developments on how IFN-I IFN-III expression is stimulated different pathogens signalling pathways leading IFN induction are tightly regulated. We also summarise growing knowledge that lead severe acute respiratory syndrome coronavirus 2.

Language: Английский

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Cyclophilin–CD147 interaction enables SARS-CoV-2 infection of human monocytes and their activation via Toll-like receptors 7 and 8

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 3, 2025

Monocytes and macrophages, as important constituents of the innate immune system, are equipped with multiple Toll-like-receptors (TLRs) to recognize invading pathogens, such SARS-CoV-2, mount an antiviral response. Nevertheless, their uncontrolled activation can lead hyperinflammation seen in severe COVID-19. Surprisingly, we observed that recombinant SARS-CoV-2 Spike (S) Nucleocapsid (N) proteins triggered only a weak proinflammatory response human peripheral blood monocytes. By employing THP-1 Jurkat NF-κB::eGFP reporter cell lines expressing specific TLRs, various TLR ligands blocking antibodies, determined surface including TLR2/1, TLR2/6 TLR4 do not play major role sensing. However, monocytes potently activated by replication-competent correlates viral uptake is monocytes, but lymphocytes. We show monocyte involves two distinct steps. Firstly, infects process independent S protein prime receptor angiotensin-converting enzyme 2. Instead, alternative CD147, which highly expressed on recognizes its well-known interaction partners cyclophilins A B incorporated into virions. Secondly, upon via cyclophilin-CD147 interaction, be inhibited CD147 antibodies or competition cyclophilin B, RNA recognized TLR7/8 endosomes, leading upregulation tumor necrosis factor (TNF), interleukin (IL)-1β IL-6, comprising core hyperinflammatory signature. Taken together, our data reveal novel mechanism how sense suggest targeting axis might beneficial alleviate overt myeloid-driven inflammation infection.

Language: Английский

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Immunologic and inflammatory consequences of SARS-CoV-2 infection and its implications in renal disease

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Feb. 12, 2025

The emergence of the COVID-19 pandemic made it critical to understand immune and inflammatory responses SARS-CoV-2 virus. It became increasingly recognized that response was a key mediator illness severity its mechanisms needed be better understood. Early infection both tissue cells, such as macrophages, leading pyroptosis-mediated inflammasome production in an organ system for systemic oxygenation likely plays central role morbidity wrought by SARS-CoV-2. Delayed transcription Type I III interferons may lead early disinhibition viral replication. Cytokines interleukin-1 (IL-1), IL-6, IL-12, tumor necrosis factor α (TNFα), some which produced through involving nuclear kappa B (NF-κB), contribute hyperinflammatory state patients with severe COVID-19. Lymphopenia, more apparent among natural killer (NK) CD8+ T-cells, B-cells, can disease reflect direct cytopathic effects or end-organ sequestration. Direct activation endothelial cells mechanism systems are impacted. In this context, endovascular neutrophil extracellular trap (NET) formation microthrombi development seen lungs other organs throughout body, heart, gut, brain. kidney most impacted extrapulmonary owing high concentration ACE2 exposure kidney, acute tubular injury, myofibroblast activation, collapsing glomerulopathy select populations account COVID-19-related AKI CKD development. COVID-19-associated nephropathy (COVAN), particular, mediated IL-6 signal transducer activator 3 (STAT3) signaling, suggesting connection between chronic disease. Chronic manifestations also include conditions like Multisystem Inflammatory Syndrome Children (MIS-C) Adults (MIS-A) post-acute sequelae (PASC), spectrum clinical presentations persistent dysregulation. lessons learned those undergoing continued study have broad implications understanding infections’ immunologic consequences beyond coronaviruses.

Language: Английский

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