scholarly journals Peptide Mimicrying Between SARS Coronavirus Spike Protein and Human Proteins Reacts with SARS Patient Serum

2008 ◽  
Vol 2008 ◽  
pp. 1-8 ◽  
Author(s):  
K.-Y. Hwa ◽  
W. M. Lin ◽  
Y.-I. Hou ◽  
T.-M. Yeh
Keyword(s):  
Sequence Homology ◽  
Molecular Mimicry ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
General Strategy ◽  
Sars Coronavirus ◽  
S Protein ◽  
Lung Epithelial ◽  
Human Proteins ◽  
A Cell

Molecular mimicry, defined as similar structures shared by molecules from dissimilar genes or proteins, is a general strategy used by pathogens to infect host cells. Severe acute respiratory syndrome (SARS) is a new human respiratory infectious disease caused by SARS coronavirus (SARS-CoV). The spike (S) protein of SARS-CoV plays an important role in the virus entry into a cell. In this study, eleven synthetic peptides from the S protein were selected based on its sequence homology with human proteins. Two of the peptides D07 (residues 927–937) and D08 (residues 942–951) were recognized by the sera of SARS patients. Murine hyperimmune sera against these peptides bound to proteins of human lung epithelial cells A549. Another peptide D10 (residues 490–502) stimulated A549 to proliferate and secrete IL-8. The present results suggest that the selected S protein regions, which share sequence homology with human proteins, may play important roles in SARS-CoV infection.

scholarly journals Host DNA Repair Proteins in Response toPseudomonas aeruginosain Lung Epithelial Cells and in Mice

2010 ◽  
Vol 79 (1) ◽  
pp. 75-87 ◽  
Author(s):  
Min Wu ◽  
Huang Huang ◽  
Weidong Zhang ◽  
Shibichakravarthy Kannan ◽  
Andrew Weaver ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Epithelial Cells ◽  
Critical Role ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Myeloperoxidase Activity ◽  
Gram Negative ◽  
Lung Epithelial ◽  
Dna Repair Proteins

ABSTRACTAlthough DNA repair proteins in bacteria are critical for pathogens' genome stability and for subverting the host defense, the role of host DNA repair proteins in response to bacterial infection is poorly defined. Here, we demonstrate, for the first time, that infection with the Gram-negative bacteriumPseudomonas aeruginosasignificantly altered the expression and enzymatic activity of 8-oxoguanine DNA glycosylase (OGG1) in lung epithelial cells. Downregulation of OGG1 by a small interfering RNA strategy resulted in severe DNA damage and cell death. In addition, acetylation of OGG1 is required for host responses to bacterial genotoxicity, as mutations of OGG1 acetylation sites increased Cockayne syndrome group B (CSB) protein expression. These results also indicate that CSB may be involved in DNA repair activity during infection. Furthermore, OGG1 knockout mice exhibited increased lung injury after infection withP. aeruginosa, as demonstrated by higher myeloperoxidase activity and lipid peroxidation. Together, our studies indicate thatP. aeruginosainfection induces significant DNA damage in host cells and that DNA repair proteins play a critical role in the host response toP. aeruginosainfection, serving as promising targets for the treatment of this condition and perhaps more broadly Gram-negative bacterial infections.

scholarly journals SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway

2021 ◽  
Author(s):  
Shahanshah Khan ◽  
Mahnoush S. Shafiei ◽  
Christopher Longoria ◽  
John Schoggins ◽  
Rashmin C. Savani ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Lung Epithelial Cells ◽  
Dependent Manner ◽  
S Protein ◽  
Cytokines And Chemokines ◽  
Lung Epithelial ◽  
Mouse Macrophages ◽  
Human And Mouse

Pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induces inflammatory cytokines and chemokines including IL-6, IL-1b, TNFa, CXCL1, CXCL2, and CCL2, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and neucleocapsid (N) proteins. When stimulated with extracellular S protein, human lung epithelial cells A549 also produce inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly are non-inflammatory, but elicit an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein triggers inflammation via activation of the NF-kB pathway in a MyD88-dependent manner. Further, such an activation of the NF-kB pathway is abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein induces IL-6, TNF-a, and IL-1b in wild-type, but not Tlr2-deficient mice. Together these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection and suggest that TLR2 could be a potential therapeutic target for COVID-19.

scholarly journals Targeting the coronavirus nucleocapsid protein through GSK-3 inhibition

2021 ◽  
Vol 118 (42) ◽  
pp. e2113401118
Author(s):  
Xiaolei Liu ◽  
Anurag Verma ◽  
Gustavo Garcia ◽  
Holly Ramage ◽  
Anastasia Lucas ◽  
...  
Keyword(s):  
Nucleocapsid Protein ◽  
Glycogen Synthase ◽  
Lung Epithelial Cells ◽  
Dependent Manner ◽  
Virion Assembly ◽  
N Protein ◽  
Consensus Sequences ◽  
Lung Epithelial ◽  
A Cell ◽  
Transcription And Replication

The coronaviruses responsible for severe acute respiratory syndrome (SARS-CoV), COVID-19 (SARS-CoV-2), Middle East respiratory syndrome-CoV, and other coronavirus infections express a nucleocapsid protein (N) that is essential for viral replication, transcription, and virion assembly. Phosphorylation of N from SARS-CoV by glycogen synthase kinase 3 (GSK-3) is required for its function and inhibition of GSK-3 with lithium impairs N phosphorylation, viral transcription, and replication. Here we report that the SARS-CoV-2 N protein contains GSK-3 consensus sequences and that this motif is conserved in diverse coronaviruses, raising the possibility that SARS-CoV-2 may be sensitive to GSK-3 inhibitors, including lithium. We conducted a retrospective analysis of lithium use in patients from three major health systems who were PCR-tested for SARS-CoV-2. We found that patients taking lithium have a significantly reduced risk of COVID-19 (odds ratio = 0.51 [0.35–0.74], P = 0.005). We also show that the SARS-CoV-2 N protein is phosphorylated by GSK-3. Knockout of GSK3A and GSK3B demonstrates that GSK-3 is essential for N phosphorylation. Alternative GSK-3 inhibitors block N phosphorylation and impair replication in SARS-CoV-2 infected lung epithelial cells in a cell-type–dependent manner. Targeting GSK-3 may therefore provide an approach to treat COVID-19 and future coronavirus outbreaks.

scholarly journals Peroxisome Proliferator-Activated Receptors Mediate Host Cell Proinflammatory Responses to Pseudomonas aeruginosa Autoinducer

2008 ◽  
Vol 190 (13) ◽  
pp. 4408-4415 ◽  
Author(s):  
Aruna Jahoor ◽  
Rashila Patel ◽  
Amanda Bryan ◽  
Catherine Do ◽  
Jay Krier ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Epithelial Cells ◽  
Transcriptional Activity ◽  
Expression Patterns ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Pparγ Agonist ◽  
Lung Epithelial

ABSTRACT The pathogenic bacterium Pseudomonas aeruginosa utilizes the 3-oxododecanoyl homoserine lactone (3OC12-HSL) autoinducer as a signaling molecule to coordinate the expression of virulence genes through quorum sensing. 3OC12-HSL also affects responses in host cells, including the upregulation of genes encoding inflammatory cytokines. This proinflammatory response may exacerbate underlying disease during P. aeruginosa infections. The specific mechanism(s) through which 3OC12-HSL influences host responses is unclear, and no mammalian receptors for 3OC12-HSL have been identified to date. Here, we report that 3OC12-HSL increases mRNA levels for a common panel of proinflammatory genes in murine fibroblasts and human lung epithelial cells. To identify putative 3OC12-HSL receptors, we examined the expression patterns of a panel of nuclear hormone receptors in these two cell lines and determined that both peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) and PPARγ were expressed. 3OC12-HSL functioned as an agonist of PPARβ/δ transcriptional activity and an antagonist of PPARγ transcriptional activity and inhibited the DNA binding ability of PPARγ. The proinflammatory effect of 3OC12-HSL in lung epithelial cells was blocked by the PPARγ agonist rosiglitazone, suggesting that 3OC12-HSL and rosiglitazone are mutually antagonistic negative and positive regulators of PPARγ activity, respectively. These data identify PPARβ/δ and PPARγ as putative mammalian 3OC12-HSL receptors and suggest that PPARγ agonists may be employed as anti-inflammatory therapeutics for P. aeruginosa infections.

scholarly journals The Novel Fibrinogen-Binding Protein FbsB Promotes Streptococcus agalactiae Invasion into Epithelial Cells

2004 ◽  
Vol 72 (6) ◽  
pp. 3495-3504 ◽  
Author(s):  
Heike Gutekunst ◽  
Bernhard J. Eikmanns ◽  
Dieter J. Reinscheid
Keyword(s):  
Epithelial Cells ◽  
Streptococcus Agalactiae ◽  
Deletion Mutant ◽  
Binding Protein ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Bacterial Invasion ◽  
Fibrinogen Binding ◽  
Lung Epithelial

ABSTRACT Streptococcus agalactiae is a major cause of bacterial sepsis and meningitis in human newborns. The interaction of S. agalactiae with host proteins and the entry into host cells thereby represent important virulence traits of these bacteria. The present report describes the identification of the fbsB gene, encoding a novel fibrinogen-binding protein that plays a crucial role in the invasion of S. agalactiae into human cells. In Western blots and enzyme-linked immunosorbent assay (ELISA) experiments, the FbsB protein was demonstrated to interact with soluble and immobilized fibrinogen. Binding studies showed the N-terminal 388 residues of FbsB and the Aα-subunit of human fibrinogen to recognize each other. By reverse transcription (RT)-PCR, the fbsB gene was shown to be cotranscribed with the gbs0851 gene in S. agalactiae. Deletion of the fbsB gene in the genome of S. agalactiae did not influence the binding of the bacteria to fibrinogen, suggesting that FbsB does not participate in the attachment of S. agalactiae to fibrinogen. In tissue culture experiments, however, the fbsB deletion mutant was severely impaired in its invasion into lung epithelial cells. Bacterial invasion could be reestablished by introducing the fbsB gene on a shuttle plasmid into the fbsB deletion mutant. Furthermore, treatment of lung epithelial cells with FbsB fusion protein blocked S. agalactiae invasion of epithelial cells in a dose-dependent fashion. These results suggest an important role of the FbsB protein in the overall process of host cell entry by S. agalactiae.

scholarly journals Targeting the Coronavirus Nucleocapsid Protein through GSK-3 Inhibition

2021 ◽  
Author(s):  
Xiaolei Liu ◽  
Anurag Verma ◽  
Holly Ramage ◽  
Gustavo Garcia ◽  
Rebecca L. Myers ◽  
...  
Keyword(s):  
Nucleocapsid Protein ◽  
Glycogen Synthase ◽  
Lung Epithelial Cells ◽  
Dependent Manner ◽  
Virion Assembly ◽  
N Protein ◽  
Consensus Sequences ◽  
Lung Epithelial ◽  
A Cell ◽  
Transcription And Replication

AbstractThe coronaviruses responsible for severe acute respiratory syndrome (SARS-CoV), COVID-19 (SARS-CoV-2), Middle East respiratory syndrome (MERS-CoV), and other coronavirus infections express a nucleocapsid protein (N) that is essential for viral replication, transcription, and virion assembly. Phosphorylation of N from SARS-CoV by glycogen synthase kinase 3 (GSK-3) is required for its function and inhibition of GSK-3 with lithium impairs N phosphorylation, viral transcription, and replication. Here we report that the SARS-CoV-2 N protein contains GSK-3 consensus sequences and that this motif is conserved in diverse coronaviruses, despite limited overall sequence conservation, raising the possibility that SARS- CoV-2 may be sensitive to GSK-3 inhibitors including lithium. We conducted a retrospective analysis of lithium use in patients from three major health systems who were PCR tested for SARS-CoV-2. We found that patients taking lithium have a significantly reduced risk of COVID- 19 (odds ratio = 0.51 [0.34 - 0.76], p = 0.001). We also show that the SARS-CoV-2 N protein is phosphorylated by GSK-3. Knockout of GSK3A and GSK3B demonstrates that GSK-3 is essential for N phosphorylation. Alternative GSK-3 inhibitors block N phosphorylation and impair replication in SARS-CoV-2 infected lung epithelial cells in a cell-type dependent manner.Targeting GSK-3 may therefore provide a new approach to treat COVID-19 and future coronavirus outbreaks.

scholarly journals 969. GRP78 and Integrin β1/α3 Play Disparate Roles in Epithelium Invasion During Mucormycosis

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S37-S37
Author(s):  
Abdullah Alqarihi ◽  
Teclegiorgis Gebremariam ◽  
Sondus Alkhazraji ◽  
Priya Uppuluri ◽  
John E Edwards ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Host Cell ◽  
Cell Injury ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Β1 Integrin ◽  
Dependent Manner ◽  
Cell Receptors ◽  
Lung Epithelial

Abstract Background Mucormycosis is a lethal fungal infection caused by Mucorales. Inhalation is the major route of entry resulting in rhino-orbital or pulmonary infections. Nasal and lung epithelial cells are among the first cells that encounter inhaled spores. We sought to identify the nasal and lung epithelial cell receptors interacting with Rhizopus during tissue invasion. Methods R. delemar-induced nasal (CCL30) or lung epithelial (A549) cell invasion was studied using Uvetix dye, while host cell injury was determined by 51Cr-release assay. Epithelial cell receptors were isolated by affinity purification of biotinylated host cell membrane proteins and then identified by LC-MS. Blocking antibodies were used to confirm the role of the receptor in the invasion/injury assays. For survival studies, ICR mice were immunosuppressed with cyclophosphamide and cortisone acetate on day-2, +3, and +8. Mice were infected with 2.5 × 105R. delemar spores intratracheally, and then treated with a single dose of 100 μg (i.p.) anti-β1 integrin antibody. Placebo mice received 100 µg of isotype-matching IgG. Results R. delemar invades and damages both cells in a time-dependent manner. Nasal Grp78 and alveolar β1α3 integrin were isolated as putative receptors. Polyclonal antibodies targeting Grp78 or β1 integrin blocked R. delemar-mediated endocytosis of nasal and lung cells by ~70%. Also, anti-Grp78 and anti-β1 integrin antibodies blocked R. delemar-induced nasal and lung cell injury by ~60% (P < 0.001). Elevated glucose, iron, or BHB increased the expression of nasal Grp78 by 2- to 6-fold which resulted in enhanced R. delemar-mediated invasion and injury of host cells, while having no effect on β1α3 integrin expression. Finally, β1 antibodies protected mice from mucormycosis with median survival time of 16 days for treated mice versus 11 days for placebo and an overall survival of 30% versus 0% for placebo mice (P = 0.0006). Conclusion The upregulation of Grp78 on nasal epithelial cells in response to physiological elevated concentrations of glucose, iron, and BHB and subsequent enhanced invasion likely to provide insights into why diabetics in ketoacidosis are infected with the rhino-orbital mucormycosis rather than pulmonary disease. Our studies also provide a foundation for therapeutic interventions against mucormycosis. Disclosures All authors: No reported disclosures.

scholarly journals Role for Nonstructural Protein 1 of Severe Acute Respiratory Syndrome Coronavirus in Chemokine Dysregulation

2006 ◽  
Vol 81 (1) ◽  
pp. 416-422 ◽  
Author(s):  
Anna H. Y. Law ◽  
Davy C. W. Lee ◽  
Benny K. W. Cheung ◽  
Howard C. H. Yim ◽  
Allan S. Y. Lau
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Nonstructural Protein ◽  
Lung Epithelial Cells ◽  
Sars Coronavirus ◽  
Cytokine Induction ◽  
Nonstructural Protein 1 ◽  
Lung Epithelial ◽  
Novel Coronavirus ◽  
Factor Interactions

ABSTRACT Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a novel coronavirus. Since its associated morbidity and mortality have been postulated to be due to immune dysregulation, we investigated which of the viral proteins is responsible for chemokine overexpression. To delineate the viral and cellular factor interactions, the role of four SARS coronavirus proteins, including nonstructural protein 1 (nsp-1), nsp-5, envelope, and membrane, were examined in terms of cytokine induction. Our results showed that the SARS coronavirus nsp-1 plays an important role in CCL5, CXCL10, and CCL3 expression in human lung epithelial cells via the activation of NF-κB.

scholarly journals The analysis on the human protein domain targets and host-like interacting motifs for the MERS-CoV and SARS-CoV/CoV-2 infers the molecular mimicry of coronavirus

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246901
Author(s):  
Yamelie A. Martínez ◽  
Xianwu Guo ◽  
Diana P. Portales-Pérez ◽  
Gildardo Rivera ◽  
Julio E. Castañeda-Delgado ◽  
...  
Keyword(s):  
Molecular Mimicry ◽  
Protein Domain ◽  
Host Cells ◽  
T Cell Epitopes ◽  
Highly Pathogenic ◽  
Channel Regulation ◽  
Common Strategy ◽  
Human Proteins ◽  
Pathogenic Viruses ◽  
Coronavirus Infection

The MERS-CoV, SARS-CoV, and SARS-CoV-2 are highly pathogenic viruses that can cause severe pneumonic diseases in humans. Unfortunately, there is a non-available effective treatment to combat these viruses. Domain-motif interactions (DMIs) are an essential means by which viruses mimic and hijack the biological processes of host cells. To disentangle how viruses achieve this process can help to develop new rational therapies. Data mining was performed to obtain DMIs stored as regular expressions (regexp) in 3DID and ELM databases. The mined regexp information was mapped on the coronaviruses’ proteomes. Most motifs on viral protein that could interact with human proteins are shared across the coronavirus species, indicating that molecular mimicry is a common strategy for coronavirus infection. Enrichment ontology analysis for protein domains showed a shared biological process and molecular function terms related to carbon source utilization and potassium channel regulation. Some of the mapped motifs were nested on B, and T cell epitopes, suggesting that it could be as an alternative way for reverse vaccinology. The information obtained in this study could be used for further theoretic and experimental explorations on coronavirus infection mechanism and development of medicines for treatment.

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