Human complement Factor H and Properdin act as soluble pattern recognition receptors and differentially modulate SARS-CoV-2 Infection DOI Open Access

Nazar Beirag,

Praveen M. Varghese, Chandan Kumar

et al.

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

Published: July 8, 2023

Abstract Severe cases of SARS-CoV-2 infection are characterised by an imbalanced immune response, excessive inflammation, and the development acute respiratory distress syndrome, which can lead to multiorgan failure death. Several studies have demonstrated dysregulated complement activity as indicator immunopathogenesis in infection. Notably, alternative pathway has been implicated driving inflammation during severe Reduced levels factor H (FH), a down-regulator pathway, increased properdin (Factor P/FP), only known up-regulator observed individuals with COVID-19 The present study investigated activation-independent, more direct role FH FP against Using ELISA, interactions spike (S) receptor binding domain (RBD) were assessed. S protein expressing lentiviral pseudotypes, cell luciferase-based virus entry assays employed assess potential modulatory effects FH, FP, recombinant thrombospondin repeats 4 5 (TSR4+5) on entry. We also evaluated immunomodulatory functions cytokine response triggered pseudotypes via RT-qPCR. RBD proteins found bind both FP. Treatment A549 cells human ACE2 TMPRSS2 or TSR4+5 resulted pseudotypes. In silico revealed that increases affinity between host ACE2. impact viral was reversed anti-FP antibody treatment A549-hACE2+TMPRSS2 cells. However, reduced Furthermore, challenged spike, envelope, nucleoprotein, membrane alphaviral pre-treated TSR4+5, exhibited upregulation transcripts pro-inflammatory cytokines, such IL-1β, IL-8, IL-6, TNF-α, IFN-α RANTES (as well NF-κB). Conversely, pre-treatment downregulated expression these cytokines. protein-mediated NF-κB activation, while it. These findings suggest may act inhibitor binding, thereby attenuating infection-associated inflammatory activation-independent manner. contribute entry, exacerbating response. That result potentially influencing severity

Language: Английский

The complement cascade in lung injury and disease DOI Creative Commons
Maria G. Detsika, Kostas Palamaris, Ioanna Dimopoulou

et al.

Respiratory Research, Journal Year: 2024, Volume and Issue: 25(1)

Published: Jan. 4, 2024

Abstract Background The complement system is an important arm of immune defense bringing innate and adaptive immunity. Although originally regarded as a major complementary mechanism against pathogens, continuously emerging evidence has uncovered central role this complex in several diseases including lung pathologies. Main body Complement factors such anaphylatoxins C3a C5a, their receptors C3aR, C5aR C5aR2 well inhibitory proteins CD55, CD46 CD59 have been implicated pathologies the acute respiratory distress syndrome, pneumonia, chronic obstructive pulmonary disease, asthma, interstitial diseases, cancer. However, exact mechanisms by which induce these remain unclear. Several complement-targeting monoclonal antibodies are reported to treat diseases. Conclusions contributes progression Better understanding underlying will provide groundwork develop new strategy target for treatment

Language: Английский

Citations

10
Emerging role of complement in COVID-19 and other respiratory virus diseases DOI Creative Commons
Mark Xiao, Calder Ellsworth, Xuebin Qin

et al.

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

Published: Feb. 18, 2024

Abstract The complement system, a key component of innate immunity, provides the first line defense against bacterial infection; however, COVID-19 pandemic has revealed that it may also engender severe complications in context viral respiratory disease. Here, we review mechanisms activation and regulation explore their roles both protecting infection exacerbating We discuss emerging evidence related to complement-targeted therapeutics compare role other diseases like influenza syncytial virus. recent mechanistic studies animal models can be used for further investigation. Novel knockout are proposed better understand nuances system diseases.

Language: Английский

Citations

8
Complement C1q is involved in the activation of membrane attack complexes, regulation of bacterial infectious inflammation, and apoptosis through overexpression in primary cells of silver pomfret (Pampus argenteus) in vitro DOI
Yuanbo Li, Jiabao Hu, Youyi Zhang

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 268, P. 131863 - 131863

Published: April 24, 2024

Language: Английский

Citations

4
Complement activity and autophagy are dysregulated in the lungs of patients with nonresolvable COVID-19 requiring lung transplantation DOI Creative Commons
Pooja Shivshankar,

Stacey L. Mueller‐Ortiz,

Aleksey Y. Domozhirov

et al.

Respiratory Research, Journal Year: 2025, Volume and Issue: 26(1)

Published: Feb. 27, 2025

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced disease 2019 (COVID-19) pandemic has challenged the current understanding of complement cascade mechanisms host immune responses during infection-induced nonresolvable lung disease. While system is involved in opsonization and phagocytosis invading pathogens, uncontrolled activation also leads to aberrant autophagic response tissue damage. Our recent study revealed unique pathologic fibrotic signature genes associated with epithelial bronchiolization tissues patients COVID-19 (NR-COVID-19) requiring transplantation. However, there a knowledge gap if components are modulated contribute damage phenotype NR-COVID-19. We, therefore, aimed role factors their corresponding regulatory proteins pathogenesis We further examined association mediators response. observed significant upregulation expression classical pathway factor C1qrs alternative C3 C5a, as well anaphylatoxin receptor C5aR1, NR-COVID-19 tissues. Of note, protein, decay accelerating (DAF; CD55) was significantly downregulated at both transcript protein levels lungs, indicating dampened protective Furthermore, we decreased autophagy PPARγ LC3a/b, which corroborated by P C3b CR1, impaired clearance damaged cells that may patients. Thus, our previously unrecognized dysregulation cell death cells, promote patients, ultimately necessitating identified network dysregulated activity indicates interplay receptor-mediated modulation potential therapeutic targets for treating

Language: Английский

Citations

0
Human Complement Inhibits Myophages against Pseudomonas aeruginosa DOI Creative Commons
Julia E. Egido,

S. Dekker,

Catherine Toner-Bartelds

et al.

Viruses, Journal Year: 2023, Volume and Issue: 15(11), P. 2211 - 2211

Published: Nov. 3, 2023

Therapeutic bacteriophages (phages) are primarily chosen based on their in vitro bacteriolytic activity. Although anti-phage antibodies known to inhibit phage infection, the influence of other immune system components is less well known. An important anti-bacterial and anti-viral innate that may interact with phages complement system, a cascade proteases recognizes targets invading microorganisms. In this research, we aimed study effects serum such as infectivity different targeting Pseudomonas aeruginosa. We used fluorescence-based assay monitor killing P. aeruginosa by morphotypes presence human serum. Our results reveal several myophages inhibited concentration-dependent way, while activity four podophages one siphophage tested not affected By using specific nanobodies blocking cascade, showed activation classical pathway driver inhibition. To determine mechanism inhibition, produced bioorthogonally labeled fluorescent binding means microscopy flow cytometry. show adsorption hampered active complement. indicate interactions affect vivo therapeutically administered phages. A better understanding phenomenon essential optimize design application therapeutic cocktails.

Language: Английский

Citations

6
The Complement System and C4b-Binding Protein: A Focus on the Promise of C4BPα as a Biomarker to Predict Clopidogrel Resistance DOI
Hong‐Guang Xie, Li‐Ping Jiang, Ting Tai

et al.

Molecular Diagnosis & Therapy, Journal Year: 2024, Volume and Issue: 28(2), P. 189 - 199

Published: Jan. 23, 2024

Language: Английский

Citations

2
Human Complement Inhibits Myophages against <em>Pseudomonas aeruginosa</em> DOI Open Access
Julia E. Egido,

S. Dekker,

Catherine Toner-Bartelds

et al.

Published: Sept. 30, 2023

Therapeutic phages are primarily chosen based on their in vitro bacteriolytic activity. Although anti-phage antibodies known to inhibit phage infection, the influence of other immune system components is less well known. An important anti-bacterial and anti-viral innate that may interact with complement system, a cascade proteases recognizes targets invading microorganisms. In this study, we aimed study effects serum such as infectivity different targeting Pseudomonas aeruginosa. We used fluorescence-based assay monitor killing P. aeruginosa by morphotypes presence human serum. Our results reveal several myophages inhibited concentration-dependent way, while activity four podophages one siphophage tested not affected By using specific nanobodies blocking cascade, show activation classical pathway driver inhibition. To determine mechanism inhibition, produced bioorthogonally labeled fluorescent binding means microscopy flow cytometry. adsorption hampered active complement. indicate interactions affect vivo therapeutically administered phages. A better understanding phenomenon essential optimize design application therapeutic cocktails.

Language: Английский

Citations

2
Editorial for SARS-CoV-2 and COVID-19 Topical Collection DOI Creative Commons
Luis Martínez‐Sobrido, Fernando Almazán

Viruses, Journal Year: 2024, Volume and Issue: 16(3), P. 356 - 356

Published: Feb. 25, 2024

A previously unknown coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was isolated in Wuhan, China December 2019, from a patient with disease linked to potential contact wild animals [...]

Language: Английский

Citations

0
Human complement Factor H and Properdin act as soluble pattern recognition receptors and differentially modulate SARS-CoV-2 Infection DOI Open Access

Nazar Beirag,

Praveen M. Varghese, Chandan Kumar

et al.

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

Published: July 8, 2023

Abstract Severe cases of SARS-CoV-2 infection are characterised by an imbalanced immune response, excessive inflammation, and the development acute respiratory distress syndrome, which can lead to multiorgan failure death. Several studies have demonstrated dysregulated complement activity as indicator immunopathogenesis in infection. Notably, alternative pathway has been implicated driving inflammation during severe Reduced levels factor H (FH), a down-regulator pathway, increased properdin (Factor P/FP), only known up-regulator observed individuals with COVID-19 The present study investigated activation-independent, more direct role FH FP against Using ELISA, interactions spike (S) receptor binding domain (RBD) were assessed. S protein expressing lentiviral pseudotypes, cell luciferase-based virus entry assays employed assess potential modulatory effects FH, FP, recombinant thrombospondin repeats 4 5 (TSR4+5) on entry. We also evaluated immunomodulatory functions cytokine response triggered pseudotypes via RT-qPCR. RBD proteins found bind both FP. Treatment A549 cells human ACE2 TMPRSS2 or TSR4+5 resulted pseudotypes. In silico revealed that increases affinity between host ACE2. impact viral was reversed anti-FP antibody treatment A549-hACE2+TMPRSS2 cells. However, reduced Furthermore, challenged spike, envelope, nucleoprotein, membrane alphaviral pre-treated TSR4+5, exhibited upregulation transcripts pro-inflammatory cytokines, such IL-1β, IL-8, IL-6, TNF-α, IFN-α RANTES (as well NF-κB). Conversely, pre-treatment downregulated expression these cytokines. protein-mediated NF-κB activation, while it. These findings suggest may act inhibitor binding, thereby attenuating infection-associated inflammatory activation-independent manner. contribute entry, exacerbating response. That result potentially influencing severity

Language: Английский

Citations

0