Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 14, 2023

While immunologic correlates of COVID-19 have been widely reported, their associations with post-acute sequelae (PASC) remain less clear. Due to the wide array PASC presentations, understanding if specific disease features associate discrete immune processes and therapeutic opportunities is important. Here we profile patients in recovery phase via proteomics screening machine learning find signatures ongoing antiviral B cell development, immune-mediated fibrosis, markers death but not controls uncomplicated recovery. Plasma profiling further allow stratification into inflammatory non-inflammatory types. Inflammatory PASC, identifiable through a refined set 12 blood markers, displays evidence neutrophil activity, memory alterations, building autoreactivity more than year post COVID-19. Our work thus helps refine categorization aid both targeting epidemiological investigation PASC.

Language: Английский

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Autoantibodies against type I IFNs in patients with critical influenza pneumonia

The Journal of Experimental Medicine, Journal Year: 2022, Volume and Issue: 219(11)

Published: Sept. 16, 2022

Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies IFN-α2 alone (five patients) or with IFN-ω (eight from a cohort of 279 (4.7%) aged 6–73 yr influenza pneumonia. Nine four had antibodies high low concentrations, respectively, IFN-α2, six two IFN-ω. The patients’ increased A virus replication in both A549 cells reconstituted human airway epithelia. prevalence these was significantly higher than that the general population for <70 age (5.7 vs. 1.1%, P = 2.2 × 10−5), but not >70 (3.1 4.4%, 0.68). risk highest concentrations (OR 11.7, 1.3 especially those old 139.9, 3.1 10−10). also identified 10 additional patient cohorts. IFNs account ∼5% cases life-threatening old.

Language: Английский

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Innate immunity, cytokine storm, and inflammatory cell death in COVID-19

Journal of Translational Medicine, Journal Year: 2022, Volume and Issue: 20(1)

Published: Nov. 22, 2022

Abstract The innate immune system serves as the first line of defense against invading pathogens; however, dysregulated responses can induce aberrant inflammation that is detrimental to host. Therefore, careful regulation critical during infections. coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome 2 (SARS-CoV-2) and has resulted in global morbidity mortality well socio-economic stresses. Innate sensing SARS-CoV-2 multiple host cell pattern recognition receptors leads production various pro-inflammatory cytokines induction inflammatory death. These processes contribute cytokine storm, tissue damage, distress syndrome. Here, we discuss activation contribution this signaling development severity COVID-19. In addition, provide a conceptual framework for immunity driving storm organ damage patients with A better understanding molecular mechanisms regulated needed targeted modalities improve patient outcomes mitigating disease.

Language: Английский

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Recent developments in the immunopathology of COVID‐19

Allergy, Journal Year: 2022, Volume and Issue: 78(2), P. 369 - 388

Published: Nov. 24, 2022

Abstract There has been an important change in the clinical characteristics and immune profile of Coronavirus disease 2019 (COVID‐19) patients during pandemic thanks to extensive vaccination programs. Here, we highlight recent studies on COVID‐19, from immunological protective risk factors for severity mortality COVID‐19. The efficacy COVID‐19 vaccines potential allergic reactions after administration are also discussed. occurrence new variants concerns such as Omicron BA.2, BA.4, BA.5 global have changed scenario Multisystem inflammatory syndrome children (MIS‐C) may cause severe heterogeneous but with a lower rate. Perturbations immunity T cells, B mast well autoantibodies metabolic reprogramming contribute long‐term symptoms is conflicting evidence about whether atopic diseases, asthma rhinitis, associated susceptibility better outcomes At beginning pandemic, European Academy Allergy Clinical Immunology (EAACI) developed guidelines that provided timely information management diseases preventive measures reduce transmission clinics. distribution emerging acute respiratory coronavirus 2 (SARS‐CoV‐2) reduced pathogenic dramatically decreased morbidity, severity, Nevertheless, breakthrough infection remains challenge control. Hypersensitivity (HSR) low compared other vaccines, these were addressed EAACI statements indications reactions, including anaphylaxis vaccines. We gained depth knowledge experience over years since start yet full eradication SARS‐CoV‐2 not horizon. Novel strategies warranted prevent high‐risk groups, development MIS‐C long

Language: Английский

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Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Cell, Journal Year: 2023, Volume and Issue: 186(3), P. 621 - 645.e33

Published: Feb. 1, 2023

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn IFN-α/β-dependent intrinsic viral diseases. Both types IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria related intramacrophagic pathogens. These have no history severe disease, despite exposure to many viruses, including SARS-CoV-2, which is in individuals impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated vitro, IRF1-dependent responses IFN-γ are, both quantitatively qualitatively, much stronger than those IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control pathogens normally when IFN-γ. By contrast, nine almost normal fibroblasts. Human essential for mycobacteria, but largely redundant antiviral

Language: Английский

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Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency

Nature, Journal Year: 2023, Volume and Issue: 623(7988), P. 803 - 813

Published: Nov. 8, 2023

Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report patients NIK or RELB deficiency, specific of autosomal-dominant NF-κB2 also have neutralizing against IFNs and are at higher risk getting pneumonia. In these found only in individuals who heterozygous for variants associated both transcription (p52 activity) loss function (LOF) due impaired p100 processing generate p52, regulatory (IκBδ gain (GOF) the accumulation unprocessed p100, therefore increasing inhibitory activity IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, not NFKB2 causing haploinsufficiency p52 p52LOF/IκBδLOF) gain-of-function p52GOF/IκBδLOF). contrast APS-1, disorders NIK, very few tissue-specific autoantibodies. However, their thymuses an abnormal structure, AIRE-expressing medullary thymic epithelial cells. Human inborn errors alternative NF-κB pathway impair development cells, thereby underlying production viral diseases.

Language: Английский

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Immune mechanisms underlying COVID-19 pathology and post-acute sequelae of SARS-CoV-2 infection (PASC)

eLife, Journal Year: 2023, Volume and Issue: 12

Published: May 26, 2023

With a global tally of more than 500 million cases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections to date, there are growing concerns about the post-acute sequelae SARS-CoV-2 infection (PASC), also known as long COVID. Recent studies suggest that exaggerated immune responses key determinants severity and outcomes initial well subsequent PASC. The complexity innate adaptive in period requires in-depth mechanistic analyses identify specific molecular signals cell populations which promote PASC pathogenesis. In this review, we examine current literature on mechanisms dysregulation COVID-19 limited emerging data immunopathology While phases may share some parallel immunopathology, it is likely quite distinct heterogeneous, thus requiring large-scale longitudinal patients with without after an infection. By outlining knowledge gaps PASC, hope provide avenues for novel research directions will ultimately lead precision therapies restore healthy function patients.

Language: Английский

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Autoantibodies neutralizing type I IFNs underlie West Nile virus encephalitis in ∼40% of patients

The Journal of Experimental Medicine, Journal Year: 2023, Volume and Issue: 220(9)

Published: June 22, 2023

Mosquito-borne West Nile virus (WNV) infection is benign in most individuals but can cause encephalitis <1% of infected individuals. We show that ∼35% patients hospitalized for WNV disease (WNVD) six independent cohorts from the EU and USA carry auto-Abs neutralizing IFN-α and/or -ω. The prevalence these antibodies highest with (∼40%), silent as low general population. odds ratios WNVD relative to those without them population range 19.0 (95% CI 15.0–24.0, P value <10–15) only 100 pg/ml IFN-ω 127.4 (CI 87.1–186.4, both at a concentration 10 ng/ml. These block protective effect Vero cells vitro. Auto-Abs underlie ∼40% cases encephalitis.

Language: Английский

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Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 13, 2023

Abstract Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as capacity preserve and/or rapidly restore functions that promote disease resistance (immunocompetence) and control inflammation infectious diseases well other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics quantify balance between (i) CD8 + CD4 T-cell (ii) gene expression signatures tracking longevity-associated immunocompetence mortality-associated inflammation. Profiles ~48,500 individuals collectively indicate some persons resist degradation both during aging when challenged varied stressors. With resistance, preservation tracked a lower risk HIV acquisition, AIDS development, symptomatic influenza infection, recurrent skin cancer; survival COVID-19 sepsis; (iii) longevity. potentially reversible by decreasing Overall, show trait observed across age spectrum, more common females, aligned specific immunocompetence-inflammation linked favorable immunity-dependent health outcomes. mechanisms have utility biomarkers for measuring improving

Language: Английский

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Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Genome Medicine, Journal Year: 2023, Volume and Issue: 15(1)

Published: April 5, 2023

Abstract Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent interferon (IFN) immunity or autoantibodies against IFN, account for 15–20% cases life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants remain be identified ~ 80% cases. Methods report here a genome-wide rare variant burden association analysis 3269 patients with COVID-19, 1373 SARS-CoV-2-infected individuals without pneumonia. Among 928 tested quarter (234) were positive excluded. Results No gene reached significance. Under recessive model, most significant at-risk variants was TLR7 , an OR 27.68 (95%CI 1.5–528.7, P = 1.1 × 10 −4 ) biochemically loss-of-function (bLOF) variants. replicated enrichment predicted LOF (pLOF) at 13 influenza susceptibility loci involved TLR3-dependent (OR 3.70[95%CI 1.3–8.2], 2.1 ). This further strengthened by (1) adding recently TYK2 loci, particularly under model 19.65[95%CI 2.1–2635.4], 3.4 −3 ), (2) considering as pLOF branchpoint potentially strong impacts on splicing among 15 4.40[9%CI 2.3–8.4], 7.7 −8 Finally, pLOF/bLOF these significantly younger (mean age [SD] 43.3 [20.3] years) than other (56.0 [17.3] years; 1.68 −5 Conclusions Rare genes can underlie inheritance, 60 years old.

Language: Английский

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