Mannose receptor‐derived peptides neutralize pore‐forming toxins and reduce inflammation and development of pneumococcal disease
Abstract Cholesterol‐dependent cytolysins (CDCs) are essential virulence factors for many human pathogens like Streptococcus pneumoniae (pneumolysin, PLY), Streptococcus pyogenes (streptolysin O, SLO), and Listeria monocytogenes (Listeriolysin, LLO) and induce cytolysis and inflammation. Recently, w...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-11-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202012695 |
| _version_ | 1797284730433961984 |
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| author | Karthik Subramanian Federico Iovino Vasiliki Tsikourkitoudi Padryk Merkl Sultan Ahmed Samuel B Berry Marie‐Stephanie Aschtgen Mattias Svensson Peter Bergman Georgios A Sotiriou Birgitta Henriques‐Normark |
| author_facet | Karthik Subramanian Federico Iovino Vasiliki Tsikourkitoudi Padryk Merkl Sultan Ahmed Samuel B Berry Marie‐Stephanie Aschtgen Mattias Svensson Peter Bergman Georgios A Sotiriou Birgitta Henriques‐Normark |
| author_sort | Karthik Subramanian |
| collection | DOAJ |
| description | Abstract Cholesterol‐dependent cytolysins (CDCs) are essential virulence factors for many human pathogens like Streptococcus pneumoniae (pneumolysin, PLY), Streptococcus pyogenes (streptolysin O, SLO), and Listeria monocytogenes (Listeriolysin, LLO) and induce cytolysis and inflammation. Recently, we identified that pneumococcal PLY interacts with the mannose receptor (MRC‐1) on specific immune cells thereby evoking an anti‐inflammatory response at sublytic doses. Here, we identified the interaction sites between MRC‐1 and CDCs using computational docking. We designed peptides from the CTLD4 domain of MRC‐1 that binds to PLY, SLO, and LLO, respectively. In vitro, the peptides blocked CDC‐induced cytolysis and inflammatory cytokine production by human macrophages. Also, they reduced PLY‐induced damage of the epithelial barrier integrity as well as blocked bacterial invasion into the epithelium in a 3D lung tissue model. Pre‐treatment of human DCs with peptides blocked bacterial uptake via MRC‐1 and reduced intracellular bacterial survival by targeting bacteria to autophagosomes. In order to use the peptides for treatment in vivo, we developed calcium phosphate nanoparticles (CaP NPs) as peptide nanocarriers for intranasal delivery of peptides and enhanced bioactivity. Co‐administration of peptide‐loaded CaP NPs during infection improved survival and bacterial clearance in both zebrafish and mice models of pneumococcal infection. We suggest that MRC‐1 peptides can be employed as adjunctive therapeutics with antibiotics to treat bacterial infections by countering the action of CDCs. |
| first_indexed | 2024-03-07T17:53:00Z |
| format | Article |
| id | doaj.art-9ff4d456d5594dcc94df8d7eff0cd162 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:53:00Z |
| publishDate | 2020-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-9ff4d456d5594dcc94df8d7eff0cd1622024-03-02T13:39:19ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-11-011211n/an/a10.15252/emmm.202012695Mannose receptor‐derived peptides neutralize pore‐forming toxins and reduce inflammation and development of pneumococcal diseaseKarthik Subramanian0Federico Iovino1Vasiliki Tsikourkitoudi2Padryk Merkl3Sultan Ahmed4Samuel B Berry5Marie‐Stephanie Aschtgen6Mattias Svensson7Peter Bergman8Georgios A Sotiriou9Birgitta Henriques‐Normark10Department of Microbiology, Tumor and Cell Biology Karolinska Institutet Stockholm SwedenDepartment of Microbiology, Tumor and Cell Biology Karolinska Institutet Stockholm SwedenDepartment of Microbiology, Tumor and Cell Biology Karolinska Institutet Stockholm SwedenDepartment of Microbiology, Tumor and Cell Biology Karolinska Institutet Stockholm SwedenDepartment of Laboratory Medicine Karolinska Institutet Huddinge SwedenDepartment of Medicine Center for Infectious Medicine Karolinska Institutet Karolinska University Hospital Huddinge SwedenDepartment of Microbiology, Tumor and Cell Biology Karolinska Institutet Stockholm SwedenDepartment of Medicine Center for Infectious Medicine Karolinska Institutet Karolinska University Hospital Huddinge SwedenDepartment of Laboratory Medicine Karolinska Institutet Huddinge SwedenDepartment of Microbiology, Tumor and Cell Biology Karolinska Institutet Stockholm SwedenDepartment of Microbiology, Tumor and Cell Biology Karolinska Institutet Stockholm SwedenAbstract Cholesterol‐dependent cytolysins (CDCs) are essential virulence factors for many human pathogens like Streptococcus pneumoniae (pneumolysin, PLY), Streptococcus pyogenes (streptolysin O, SLO), and Listeria monocytogenes (Listeriolysin, LLO) and induce cytolysis and inflammation. Recently, we identified that pneumococcal PLY interacts with the mannose receptor (MRC‐1) on specific immune cells thereby evoking an anti‐inflammatory response at sublytic doses. Here, we identified the interaction sites between MRC‐1 and CDCs using computational docking. We designed peptides from the CTLD4 domain of MRC‐1 that binds to PLY, SLO, and LLO, respectively. In vitro, the peptides blocked CDC‐induced cytolysis and inflammatory cytokine production by human macrophages. Also, they reduced PLY‐induced damage of the epithelial barrier integrity as well as blocked bacterial invasion into the epithelium in a 3D lung tissue model. Pre‐treatment of human DCs with peptides blocked bacterial uptake via MRC‐1 and reduced intracellular bacterial survival by targeting bacteria to autophagosomes. In order to use the peptides for treatment in vivo, we developed calcium phosphate nanoparticles (CaP NPs) as peptide nanocarriers for intranasal delivery of peptides and enhanced bioactivity. Co‐administration of peptide‐loaded CaP NPs during infection improved survival and bacterial clearance in both zebrafish and mice models of pneumococcal infection. We suggest that MRC‐1 peptides can be employed as adjunctive therapeutics with antibiotics to treat bacterial infections by countering the action of CDCs.https://doi.org/10.15252/emmm.202012695calcium phosphate nanoparticlesmannose receptor C type 1pore‐forming toxinsStreptococcus pneumoniaetoxin inhibitory peptides |
| spellingShingle | Karthik Subramanian Federico Iovino Vasiliki Tsikourkitoudi Padryk Merkl Sultan Ahmed Samuel B Berry Marie‐Stephanie Aschtgen Mattias Svensson Peter Bergman Georgios A Sotiriou Birgitta Henriques‐Normark Mannose receptor‐derived peptides neutralize pore‐forming toxins and reduce inflammation and development of pneumococcal disease EMBO Molecular Medicine calcium phosphate nanoparticles mannose receptor C type 1 pore‐forming toxins Streptococcus pneumoniae toxin inhibitory peptides |
| title | Mannose receptor‐derived peptides neutralize pore‐forming toxins and reduce inflammation and development of pneumococcal disease |
| title_full | Mannose receptor‐derived peptides neutralize pore‐forming toxins and reduce inflammation and development of pneumococcal disease |
| title_fullStr | Mannose receptor‐derived peptides neutralize pore‐forming toxins and reduce inflammation and development of pneumococcal disease |
| title_full_unstemmed | Mannose receptor‐derived peptides neutralize pore‐forming toxins and reduce inflammation and development of pneumococcal disease |
| title_short | Mannose receptor‐derived peptides neutralize pore‐forming toxins and reduce inflammation and development of pneumococcal disease |
| title_sort | mannose receptor derived peptides neutralize pore forming toxins and reduce inflammation and development of pneumococcal disease |
| topic | calcium phosphate nanoparticles mannose receptor C type 1 pore‐forming toxins Streptococcus pneumoniae toxin inhibitory peptides |
| url | https://doi.org/10.15252/emmm.202012695 |
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