Respiratory long COVID in aged hamsters features impaired lung function post-exercise with bronchiolization and fibrosis DOI Creative Commons
L. Heydemann, Małgorzata Ciurkiewicz, Theresa Störk

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 28, 2025

Abstract Long-term consequences of SARS-CoV-2 infection affect millions people and strain public health systems. The underlying pathomechanisms remain unclear, necessitating further research in appropriate animal models. This study aimed to characterize the trajectory lung regeneration over 112 days male hamster model by combining morphological, transcriptomic functional readouts. We demonstrate that acute phase, Delta-infected, male, aged hamsters show a severe impairment function at rest. In chronic similar impairments persisted up 7 weeks post-infection but were only evident after exercise on rodent treadmill. recapitulates pulmonary fibrotic changes observed many patients with respiratory long COVID, lacks extra-pulmonary long-term lesions. sub-pleural interstitial fibrosis as well alveolar bronchiolization persist until dpi. Interestingly, CK8 + differentiation intermediate (ADI) cells are becoming less prominent proliferation areas from 28 dpi on. Instead, CK14 airway basal SCGB1A1 club cells, expressing cell markers, mainly populate later time-points. postulate cell-rich represent potential risk factors for other diseases long-COVID survivors.

Language: Английский

Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung DOI Creative Commons
Ting-Hsuan Wu, Kyle J. Travaglini, Arjun Rustagi

et al.

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

Citations

20
Comparative single-cell analysis reveals IFN-γ as a driver of respiratory sequelae after acute COVID-19 DOI
Chaofan Li, Wei Qian, Xiaoqin Wei

et al.

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(756)

Published: July 17, 2024

Postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) represent an urgent public health challenge and are estimated to affect more than 60 million individuals globally. Although a growing body evidence suggests that dysregulated immune reactions may be linked with PASC symptoms, most investigations have primarily centered around blood-based studies, few focusing on samples derived from affected tissues. Furthermore, clinical studies alone often provide correlative insights rather causal mechanisms. Thus, it is essential compare relevant animal models conduct functional experiments understand the etiology PASC. In this study, we comprehensively compared bronchoalveolar lavage fluid single-cell RNA sequencing data mouse model This revealed pro-fibrotic monocyte-derived macrophage response in PASC, as well abnormal interactions between pulmonary macrophages resident T cells, both humans mice. Interferon-γ (IFN-γ) emerged key node mediating anomalies Neutralizing IFN-γ after resolution SARS-CoV-2 reduced lung inflammation tissue fibrosis Together, our study underscores importance performing comparative analysis cause signaling axis might therapeutic target.

Language: Английский

Citations

15
Systems analysis of innate and adaptive immunity in Long COVID DOI
Michael J. Peluso, Mohamed Abdel‐Mohsen, Timothy J. Henrich

et al.

Seminars in Immunology, Journal Year: 2024, Volume and Issue: 72, P. 101873 - 101873

Published: March 1, 2024

Language: Английский

Citations

14
Cardiac tissue model of immune-induced dysfunction reveals the role of free mitochondrial DNA and the therapeutic effects of exosomes DOI Creative Commons
Rick Xing Ze Lu, Naimeh Rafatian, Yimu Zhao

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(13)

Published: March 27, 2024

Despite tremendous progress in the development of mature heart-on-a-chip models, human cell-based models myocardial inflammation are lacking. Here, we bioengineered a vascularized with circulating immune cells to model severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced myocarditis. We observed hallmarks disease (COVID-19)-induced inflammation, as presence augmented secretion proinflammatory cytokines, triggered progressive impairment contractile function, and altered intracellular calcium transients. An elevation cell-free mitochondrial DNA (ccf-mtDNA) was measured first then validated COVID-19 patients low left ventricular ejection fraction, demonstrating that damage is an important pathophysiological hallmark inflammation-induced cardiac dysfunction. Leveraging this platform context SARS-CoV-2-induced established administration endothelial cell-derived exosomes effectively rescued deficit, normalized handling, elevated contraction force, reduced ccf-mtDNA cytokine release via Toll-like receptor-nuclear factor κB signaling axis.

Language: Английский

Citations

12
Targeting the SARS-CoV-2 reservoir in long COVID DOI
Amy D. Proal, Soo Aleman, Morgane Bomsel

et al.

The Lancet Infectious Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

2
Dual-Locked Fluorescence Probe for Monitoring the Dynamic Transition of Pulmonary Macrophages DOI
Yuxuan Hu, Jing Liu,

Mengke Xu

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 13, 2025

Pulmonary macrophages undergo dynamic changes in population, proportion, and polarization during respiratory diseases. Monitoring these is critical for understanding their roles pathology, improving the diagnosis, guiding drug development. However, current analytic methods based on tissue biopsy are invasive static, limiting ability to provide such information. Herein, we report a dual-locked macrophage-specific renal-clearable probe (DMRPNOCas) monitoring of pulmonary influenza A virus (IAV) infection. DMRPNOCas activates fluorescence presence two biomarkers (caspase-1 NO) only coexpressed by M1 macrophages. To optimize NO reactivity, scaffold screened from hemicyanine derivatives with an o-phenylenediamine group positioned differently indole ring. Notably, para-substituted demonstrates higher NO-activated compared its meta-substituted counterpart. This enhancement, as revealed quantum chemical calculations, attributed differential inhibition twisted intramolecular charge transfer induced reaction. specifically distinguishes other leukocytes including T cells, neutrophils, M2 macrophages, capability unmatched single-locked control probes reported probes. Consequently, enables vivo uncovering extensive recruitment monocyte-derived within 48 h IAV process accompanied significant reduction alveolar These findings new insights into macrophage-mediated inflammation underscore potential precise diagnosis pathological processes.

Language: Английский

Citations

2
Lung commensal bacteria promote lung cancer progression through NK cell-mediated immunosuppressive microenvironment DOI Creative Commons
Haiyang Wang, Jiayi Hu,

Yuchen Ma

et al.

International Journal of Medical Sciences, Journal Year: 2025, Volume and Issue: 22(5), P. 1039 - 1051

Published: Feb. 3, 2025

Symbiotic microbiota pervades the majority of human body's organs and tissues, functioning as crucial regulators both health maintenance disease progression. Pertinently, lung adenocarcinoma has been indisputably linked to chronic inflammation. However, precipitators that instigate such inflammation, along with particular immune mediators involved, remain enigmatic warrant extensive exploration. This research revealed a significant variance exists in commensal bacteria between cancer tissues their normal counterparts. holds true for clinical patients mice, where diversity abundance tumor significantly surpass those tissues. It demonstrated disturbances pulmonary can stimulate proliferation cells. Mechanistically, we suggest may promote expression NK cell immunosuppressive molecule TIGIT secretion IL-2 IFN-γ. consequently mediates alterations microenvironment, thereby fostering proliferation.

Language: Английский

Citations

2
Nerve- and airway-associated interstitial macrophages mitigate SARS-CoV-2 pathogenesis via type I interferon signaling DOI
Stephen T. Yeung, Payal Damani‐Yokota, Sara A. Thannickal

et al.

Immunity, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

2
Induction of protective immune responses at respiratory mucosal sites DOI Creative Commons
Seok‐Chan Park,

Matthew J. Wiest,

Vivian Yan

et al.

Human Vaccines & Immunotherapeutics, Journal Year: 2024, Volume and Issue: 20(1)

Published: July 2, 2024

Many pathogens enter the host through mucosal sites. Thus, interfering with pathogen entry local neutralization at sites therefore is an effective strategy for preventing disease. Mucosally administered vaccines have potential to induce protective immune responses This manuscript delves into some of latest developments in vaccination, particularly focusing on advancements adjuvant technologies and role these adjuvants enhancing vaccine efficacy against respiratory pathogens. It highlights anatomical immunological complexities system, emphasizing significance secretory IgA tissue-resident memory T cells responses. We further discuss differences between induced traditional parenteral vaccination approaches vs. administration strategies, explore advantages offered by immunization routes.

Language: Английский

Citations

9
Emerging SARS-CoV-2 Resistance After Antiviral Treatment DOI Creative Commons

Trevor J M Tamura,

Manish C. Choudhary,

Rinki Deo

et al.

JAMA Network Open, Journal Year: 2024, Volume and Issue: 7(9), P. e2435431 - e2435431

Published: Sept. 25, 2024

Importance Previous studies have identified mutations in SARS-CoV-2 strains that confer resistance to nirmatrelvir, yet how often this arises and its association with posttreatment virologic rebound is not well understood. Objective To examine the prevalence of emergent antiviral after nirmatrelvir treatment rebound. Design, Setting, Participants This cohort study enrolled outpatient adults acute COVID-19 infection from May 2021 October 2023. were divided into those who received therapy did not. The was conducted at a multicenter health care system Boston, Massachusetts. Exposure Treatment regimen, including none, remdesivir. Main Outcomes Measures primary outcome resistance, defined as detection mutations, which present baseline, previously associated decreased efficacy, emerged during or completion participant’s treatment. Next-generation sequencing used detect low frequency down 1% total viral population. Results Overall, 156 participants (114 female [73.1%]; median [IQR] age, 56 [38-69] years) included. Compared 63 untreated individuals, 79 older more commonly immunosuppressed. After RNA participants’ anterior nasal swabs, detected 9 individuals (11.4%) compared 2 (3.2%) ( P = .09). Among treated immunosuppressed had highest emergence (5 22 [22.7%]), significantly greater than (2 [3.1%]) .01). Similar rates found (3 23 [13.0%]) vs (6 [10.7%]) .86). Most these (10 11 [90.9%]) frequencies (<20% population) reverted wild type subsequent time points. Emerging remdesivir only 14 [14.3%]) but similarly transient. Global Initiative on Sharing All Influenza Data analysis showed no evidence increased United States authorization nirmatrelvir. Conclusions Relevance In participants, treatment-emergent detected, especially However, generally transient nature, suggesting risk for spread community current variants drug usage patterns.

Language: Английский

Citations

9