TFPI-2 protects against gram-negative bacterial infection
Tissue factor pathway inhibitor-2 (TFPI-2) has previously been characterized as an endogenous anticoagulant. TFPI-2 is expressed in the vast majority of cells, mainly secreted into the extracellular matrix. Recently we reported that EDC34, a C-terminal peptide derived from TFPI-2, exerts a broad ant...
| Main Authors: | , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2018
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| Online Access: | https://hdl.handle.net/10356/89583 http://hdl.handle.net/10220/46296 |
| _version_ | 1811694867061932032 |
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| author | Ali, Mohamad N. Kasetty, Gopinath Elvén, Malin Alyafei, Saud Jovic, Sandra Egesten, Arne Herwald, Heiko Schmidtchen, Artur Papareddy, Praveen |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Ali, Mohamad N. Kasetty, Gopinath Elvén, Malin Alyafei, Saud Jovic, Sandra Egesten, Arne Herwald, Heiko Schmidtchen, Artur Papareddy, Praveen |
| author_sort | Ali, Mohamad N. |
| collection | NTU |
| description | Tissue factor pathway inhibitor-2 (TFPI-2) has previously been characterized as an endogenous anticoagulant. TFPI-2 is expressed in the vast majority of cells, mainly secreted into the extracellular matrix. Recently we reported that EDC34, a C-terminal peptide derived from TFPI-2, exerts a broad antimicrobial activity. In the present study, we describe a previously unknown antimicrobial mode of action for the human TFPI-2 C-terminal peptide EDC34, mediated via binding to immunoglobulins of the classes IgG, IgA, IgE, and IgM. In particular the interaction of EDC34 with the Fc part of IgG is of importance since this boosts interaction between the immunoglobulin and complement factor C1q. Moreover, we find that the binding increases the C1q engagement of the antigen-antibody interaction, leading to enhanced activation of the classical complement pathway during bacterial infection. In experimental murine models of infection and endotoxin challenge, we show that TFPI-2 is up-regulated in several organs, including the lung. Correspondingly, TFPI-2−/− mice are more susceptible to pulmonary Pseudomonas aeruginosa bacterial infection. No anti-coagulant role of TFPI-2 was observed in these models in vivo. Furthermore, in vivo, the mouse TFPI-2-derived C-terminal peptide VKG24, a homolog to human EDC34 is protective against systemic Escherichia coli bacterial infection. Moreover, in sputum from cystic fibrosis patients TFPI-2 C-terminal fragments are generated and found associated with immunoglobulins. Together our data describe a previously unknown host defense mechanism and therapeutic importance of TFPI-2 against invading Gram-negative bacterial pathogens. |
| first_indexed | 2024-10-01T07:14:23Z |
| format | Journal Article |
| id | ntu-10356/89583 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:14:23Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | ntu-10356/895832020-11-01T05:27:25Z TFPI-2 protects against gram-negative bacterial infection Ali, Mohamad N. Kasetty, Gopinath Elvén, Malin Alyafei, Saud Jovic, Sandra Egesten, Arne Herwald, Heiko Schmidtchen, Artur Papareddy, Praveen Lee Kong Chian School of Medicine (LKCMedicine) DRNTU::Science::Medicine TFPI-2 Antimicrobial Peptide Tissue factor pathway inhibitor-2 (TFPI-2) has previously been characterized as an endogenous anticoagulant. TFPI-2 is expressed in the vast majority of cells, mainly secreted into the extracellular matrix. Recently we reported that EDC34, a C-terminal peptide derived from TFPI-2, exerts a broad antimicrobial activity. In the present study, we describe a previously unknown antimicrobial mode of action for the human TFPI-2 C-terminal peptide EDC34, mediated via binding to immunoglobulins of the classes IgG, IgA, IgE, and IgM. In particular the interaction of EDC34 with the Fc part of IgG is of importance since this boosts interaction between the immunoglobulin and complement factor C1q. Moreover, we find that the binding increases the C1q engagement of the antigen-antibody interaction, leading to enhanced activation of the classical complement pathway during bacterial infection. In experimental murine models of infection and endotoxin challenge, we show that TFPI-2 is up-regulated in several organs, including the lung. Correspondingly, TFPI-2−/− mice are more susceptible to pulmonary Pseudomonas aeruginosa bacterial infection. No anti-coagulant role of TFPI-2 was observed in these models in vivo. Furthermore, in vivo, the mouse TFPI-2-derived C-terminal peptide VKG24, a homolog to human EDC34 is protective against systemic Escherichia coli bacterial infection. Moreover, in sputum from cystic fibrosis patients TFPI-2 C-terminal fragments are generated and found associated with immunoglobulins. Together our data describe a previously unknown host defense mechanism and therapeutic importance of TFPI-2 against invading Gram-negative bacterial pathogens. Published version 2018-10-12T04:01:02Z 2019-12-06T17:28:54Z 2018-10-12T04:01:02Z 2019-12-06T17:28:54Z 2018 Journal Article Ali, M. N., Kasetty, G., Elvén, M., Alyafei, S., Jovic, S., Egesten, A. . . . Papareddy, P. (2018). TFPI-2 Protects Against Gram-Negative Bacterial Infection. Frontiers in Immunology, 9, 2072-. doi:10.3389/fimmu.2018.02072 https://hdl.handle.net/10356/89583 http://hdl.handle.net/10220/46296 10.3389/fimmu.2018.02072 en Frontiers in Immunology © 2018 Ali, Kasetty, Elvén, Alyafei, Jovic, Egesten, Herwald, Schmidtchen and Papareddy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. 13 p. application/pdf |
| spellingShingle | DRNTU::Science::Medicine TFPI-2 Antimicrobial Peptide Ali, Mohamad N. Kasetty, Gopinath Elvén, Malin Alyafei, Saud Jovic, Sandra Egesten, Arne Herwald, Heiko Schmidtchen, Artur Papareddy, Praveen TFPI-2 protects against gram-negative bacterial infection |
| title | TFPI-2 protects against gram-negative bacterial infection |
| title_full | TFPI-2 protects against gram-negative bacterial infection |
| title_fullStr | TFPI-2 protects against gram-negative bacterial infection |
| title_full_unstemmed | TFPI-2 protects against gram-negative bacterial infection |
| title_short | TFPI-2 protects against gram-negative bacterial infection |
| title_sort | tfpi 2 protects against gram negative bacterial infection |
| topic | DRNTU::Science::Medicine TFPI-2 Antimicrobial Peptide |
| url | https://hdl.handle.net/10356/89583 http://hdl.handle.net/10220/46296 |
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