Nucleotide-Binding Oligomerization Domain 1 (NOD1) Agonists Prevent SARS-CoV-2 Infection in Human Lung Epithelial Cells through Harnessing the Innate Immune Response
<p>NLR agonists induce innate immune activation in in vitro lung epithelial and myeloid models. (<b>A</b>) Workflow to screen for potential immunomodulators of the innate immune system in A549 lung epithelial and THP-1 myeloid cell lines. (<b>B</b>) Library classification of tested compounds according to their reported target. (<b>C</b>) Heatmap illustrates the immune activation induced by immunomodulators targeting PRR subfamilies in lung epithelial A549 and myeloid THP-1 cells, as determined by the intracellular staining of IL-8 by flow cytometry. (<b>D</b>) Representative dot-plots showing IL-8+ intracellular staining of lung epithelial A549 (<b>left panel</b>) and myeloid THP-1 (<b>right panel</b>) cells upon treatment with NLR agonists, as determined by flow cytometry compared to untreated (UN) cells.</p> "> Figure 2
<p>Cytokine response is preferentially triggered by NOD1 and dual NOD1/2 agonists in lung epithelial cells. (<b>A</b>) Cytokine response to NLR agonists triggered by NOD1-, NOD1/2- and NOD2-specific agonists in lung epithelial A549-Dual cells. Immune response was determined by the percentage of intracellular IL-8+ (<b>left</b>) and TNFα+ (<b>right</b>) cell quantification by flow cytometry after 24 h of treatment, using LPS (1 µg/mL, yellow bar) non-treated condition (UN, black bar) as controls. (<b>B</b>) Induction of the proinflammatory response upon treatment with increasing concentrations of NOD1, NOD1/2 and NOD2 ligands in lung epithelial A549-Dual cells after 24 h of treatment. The intracellular stainings of IL-8 and TNFα were determined by flow cytometry as subrogate representative markers of the proinflammatory response, using LPS and UN as controls. Mean ± SD of three independent experiments is shown. * <span class="html-italic">p</span> < 0.05; *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 3
<p>NOD1 and NOD1/2 agonists induce innate immune activation in vitro in lung epithelial through the NF-κB and ISRE pathways. (<b>A</b>) Induction of the NF-κB activity triggered by NLR agonists upon recognition by the NOD1, NOD1/2 and NOD2 receptors in lung epithelial A549-Dual cells after 24 h of treatment. LPS (yellow bar) and Poly(I:C) (grey bar) were used as controls for NF-κB activation. (<b>B</b>) Assessment of NLR agonist activity on type I IFN response signaling by the quantification of interferon-stimulated response element (ISRE)-dependent gene expression in lung epithelial A549-Dual cells after 24 h of treatment. Values were relativized to the untreated (ND, black bar) condition. (<b>C</b>) Relative mRNA expression of IL-8, CXCL10 and ISG15 in A549-Dual treated cells with 50 µM of selected NOD agonists for 8 h measured by qPCR (normalized to GAPDH expression). Mean ± SD of three independent experiments is shown. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 4
<p>Activity of NOD1 and dual NOD1/2 agonists is specific in lung epithelial cells. (<b>A</b>) Gene expression of NOD1 receptor in A549-Dual cells transiently silenced with siRNA targeting NOD1 (siNOD1). Mock and non-specific siRNA (siNT) were used as controls. (<b>B</b>) Cell viability of A549-Dual cells treated with siNOD1 and siNT, using mock condition as control. Cell viability was determined by LIVE/DEAD staining and measured by flow cytometry. (<b>C</b>) Activity of NOD1 agonists (TriDAP and C12-iE-DAP), dual NOD1/2 (M-TriDAP) and NOD2 (MDP) in A549 cells treated with siNOD1. Intracellular staining of proinflammatory IL-8+ cells was determined by flow cytometry using the mock and siNT conditions, respectively. (<b>D</b>) Induction of the NF-κB and ISRE (<b>E</b>) activation pathways in A549-Dual cells treated with NOD1, dual NOD1/2 or NOD2 agonists with 50 µM of selective NOD1 inhibitor ML130, 50 µM of NOD1/2 inhibitor NOD-IN-1 or untreated (UNT), respectively. Red dotted line indicates the basal NF-κB (<b>left</b>) or ISRE activity (<b>right</b>) in A549-Dual cells. Mean ± SD of three independent experiments is shown. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001.</p> "> Figure 5
<p>NLR agonist-induced cytokine response is preferentially triggered by NOD2 in PBMCs. (<b>A</b>) Assessment of the cytokine response to NLR agonists triggered by specific NOD1, dual NOD1/2 and NOD2 agonists in PBMCs. The percentages of intracellular IL-1β+, TNFα+ and IL-6+ cells were measured as representative markers of the proinflammatory response. Values were relativized to the non-treated condition (ND, black bar). LPS (1 µg/mL, yellow bar) and PMA (50 ng/mL) + ionomycin (1 µM) were used as positive controls. (<b>B</b>) Dose-response induction of proinflammatory cytokines IL-1β+, TNFα+ and IL-6+ in PBMCs treated with increasing concentrations of TriDAP (NOD1), M-TriDAP (dual NOD1/2) and MDP (NOD2) agonists. Mean ± SD of three independent experiments is shown. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01.</p> "> Figure 6
<p>NOD1 and dual NOD1/2 agonists impair SARS-CoV-2 replication in lung epithelial cells. Pretreatment of lung epithelial A549-Dual cells for 3 h with increasing concentrations of NOD1 and dual NOD1/2 agonists preferentially inhibits SARS-CoV-2 replication. (<b>A</b>) Representative dot-plots of infected cells treated with NOD agonists as measured by flow cytometry. (<b>B</b>) Quantification of viral replication measured as the percentage of SARS-CoV-2-GFP+ cells determined by flow cytometry after 48 h of infection. Values were relativized to the untreated condition (INF, black bar). TLR3 agonist Poly(I:C) (light gray bars) was used as control for the induction of the innate immune response. Mean ± SD of three independent experiments is shown. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; EC<sub>50</sub>: half maximal effective concentration.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Assessment of Immunomodulators Able to Activate the Innate Immune System
2.2. Identification of NLRs as Putative Innate Immune Agonists Suitable for the Activation of the Immune Response in the Respiratory Tract
2.3. NOD1 Agonists Selectively Activate the NF-κB and ISRE Signaling Pathways in Human Lung Epithelial Cells
2.4. Selective Immune Activation by NOD1 Agonist Is Specific for Lung Epithelial Cells
2.5. NOD1 Agonists Do Not Elicit Immune Innate Activation in PBMCs
2.6. NOD1 Agonists Inhibit SARS-CoV-2 Infection in Lung Epithelial Cells
3. Discussion
4. Materials and Methods
4.1. Cells
4.2. Compounds
4.3. Luminescence and Spectrophotometry Assays
4.4. Evaluation of Cytotoxicity
4.5. Flow Cytometry
4.6. Quantitative RT-Polymerase Chain Reaction (qRT-PCR)
4.7. Western Blot
4.8. Transfection and RNA Interference
4.9. Virus and Infections
4.10. Statistical Methods
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | Full Name | Target | Formula | EC50 1 | Cellular Model | Reference |
---|---|---|---|---|---|---|
TriDAP | L-alanyl-γ-D-glutamyl-meso-diaminopimelic acid | NOD1 | C15H26N4O8 | 700 ± 100 ng/mL | HEK-Blue hNOD1 | [22] |
iE-DAP | γ-D-glutamyl-meso-diaminopimelic acid | NOD1 | C12H21N3O7 | 6.3 ± 0.5 ng/mL | HEK-Blue hNOD1 | |
C12-iE-DAP | Lauroyl-γ-D-glutamyl-meso-diaminopimelic acid | NOD1 | C24H43N3O8 | 170 ± 37.6 nM | HEK-Blue hNOD1 | [23] |
M-TriDAP | N-acetyl-muramyl-L-Ala-γ-D-Glu-meso-diaminopimelic acid | NOD1/2 | C26H43N5O15 | 30 µg/mL | HCT116 | [22] |
PGN-ECndi | Insoluble peptidoglycan (Escherichia coli K12) | NOD1/2 | ||||
Murabutide | N-Acetyl-muramyl-L-Alanyl-D-Glutamin-n-butyl-ester | NOD2 | C23H40N4O11 | 100 ± 20 ng/mL | HEK-Blue hNOD2 | [24] |
MDP | N-Acetylmuramyl-L-Alanyl-D-Isoglutamine (L-D isoform) | NOD2 | C19H32N4O11 | 146 ± 26 ng/mL | HEK-Blue hNOD2 | [24] |
L18-MDP | 6-O-stearoyl-N-Acetyl-muramyl-L-alanyl-D-isoglutamine | NOD2 | C37H66N4O12 | 0.461 nM | KBM-7 | [25] |
M-TriLYS | MurNAc-Ala-D-isoGln-Lys | NOD2 | C25H44N6O12 | |||
PGN-Sandi | Insoluble peptidoglycan (Staphylococcus aureus) | NOD2 |
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Garcia-Vidal, E.; Calba, I.; Riveira-Muñoz, E.; García, E.; Clotet, B.; Serra-Mitjà, P.; Cabrera, C.; Ballana, E.; Badia, R. Nucleotide-Binding Oligomerization Domain 1 (NOD1) Agonists Prevent SARS-CoV-2 Infection in Human Lung Epithelial Cells through Harnessing the Innate Immune Response. Int. J. Mol. Sci. 2024, 25, 5318. https://doi.org/10.3390/ijms25105318
Garcia-Vidal E, Calba I, Riveira-Muñoz E, García E, Clotet B, Serra-Mitjà P, Cabrera C, Ballana E, Badia R. Nucleotide-Binding Oligomerization Domain 1 (NOD1) Agonists Prevent SARS-CoV-2 Infection in Human Lung Epithelial Cells through Harnessing the Innate Immune Response. International Journal of Molecular Sciences. 2024; 25(10):5318. https://doi.org/10.3390/ijms25105318
Chicago/Turabian StyleGarcia-Vidal, Edurne, Ignasi Calba, Eva Riveira-Muñoz, Elisabet García, Bonaventura Clotet, Pere Serra-Mitjà, Cecilia Cabrera, Ester Ballana, and Roger Badia. 2024. "Nucleotide-Binding Oligomerization Domain 1 (NOD1) Agonists Prevent SARS-CoV-2 Infection in Human Lung Epithelial Cells through Harnessing the Innate Immune Response" International Journal of Molecular Sciences 25, no. 10: 5318. https://doi.org/10.3390/ijms25105318