LL37 Inhibits Aspergillus fumigatus Infection via Directly Binding to the Fungus and Preventing Excessive Inflammation
The incidence of Aspergillus fumigatus infection and the rate of resistance to antifungal drugs have sharply increased in recent years. LL37 has been reported as a host defense peptide with broad-spectrum antibacterial activities. However, the role of LL37 during A. fumigatus infection remains uncle...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00283/full |
| _version_ | 1818538331569389568 |
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| author | Xiao-Li Luo Jian-Xiong Li Hua-Rong Huang Jie-Lin Duan Ruo-Xuan Dai Ru-Jia Tao Ling Yang Jia-yun Hou Xin-Ming Jia Jin-Fu Xu |
| author_facet | Xiao-Li Luo Jian-Xiong Li Hua-Rong Huang Jie-Lin Duan Ruo-Xuan Dai Ru-Jia Tao Ling Yang Jia-yun Hou Xin-Ming Jia Jin-Fu Xu |
| author_sort | Xiao-Li Luo |
| collection | DOAJ |
| description | The incidence of Aspergillus fumigatus infection and the rate of resistance to antifungal drugs have sharply increased in recent years. LL37 has been reported as a host defense peptide with broad-spectrum antibacterial activities. However, the role of LL37 during A. fumigatus infection remains unclear. Here, we examined the interaction between LL37 and A. fumigatus and found that synthetic LL37 could directly bind to the surface of A. fumigatus, disrupting the integrity of the cell wall in vitro. LL37 inhibited mycelial growth in a concentration-dependent manner, rather than fungicidal effect even at high concentration (e.g., 20 μM). Interestingly, low concentrations of LL37 (e.g., 4 μM) significantly attenuated mycelial adhesion and prevented the invasion and destruction of epithelial cells. Following LL37 treatment, the levels of proinflammatory cytokines released by A. fumigatus-stimulated macrophages decreased significantly, accompanied by downregulation of M1 type markers. In a mouse model of pulmonary A. fumigatus infection, LL37-treated mice showed lower amounts of fungi load, moderate pathological damage, and reduced proinflammatory cytokines. Further, LL37 transgenic mice (LL37+/+) were examined to investigate the effects of endogenous LL37 in an A. fumigatus infection model and showed lower susceptibility to A. fumigatus infection in comparison with wild-type mice. In addition, LL37 also played a protective role in an immunosuppressed mouse model of A. fumigatus infection. Thus, LL37 inhibits A. fumigatus infection via directly binding to mycelia and reducing excessive inflammation. LL37 or its analogs may therefore constitute potential drug components for A. fumigatus infection. |
| first_indexed | 2024-12-11T21:27:38Z |
| format | Article |
| id | doaj.art-5d693e24ae214c44aec47ac1bf92afc5 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T21:27:38Z |
| publishDate | 2019-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5d693e24ae214c44aec47ac1bf92afc52022-12-22T00:50:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-02-011010.3389/fimmu.2019.00283430603LL37 Inhibits Aspergillus fumigatus Infection via Directly Binding to the Fungus and Preventing Excessive InflammationXiao-Li Luo0Jian-Xiong Li1Hua-Rong Huang2Jie-Lin Duan3Ruo-Xuan Dai4Ru-Jia Tao5Ling Yang6Jia-yun Hou7Xin-Ming Jia8Jin-Fu Xu9Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, ChinaClinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, ChinaZhongshan Hospital Institute of Clinical Science, Shanghai Institute of Clinical Bioinformatics, Zhongshan Hospital, Fudan University, Shanghai, ChinaClinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, ChinaThe incidence of Aspergillus fumigatus infection and the rate of resistance to antifungal drugs have sharply increased in recent years. LL37 has been reported as a host defense peptide with broad-spectrum antibacterial activities. However, the role of LL37 during A. fumigatus infection remains unclear. Here, we examined the interaction between LL37 and A. fumigatus and found that synthetic LL37 could directly bind to the surface of A. fumigatus, disrupting the integrity of the cell wall in vitro. LL37 inhibited mycelial growth in a concentration-dependent manner, rather than fungicidal effect even at high concentration (e.g., 20 μM). Interestingly, low concentrations of LL37 (e.g., 4 μM) significantly attenuated mycelial adhesion and prevented the invasion and destruction of epithelial cells. Following LL37 treatment, the levels of proinflammatory cytokines released by A. fumigatus-stimulated macrophages decreased significantly, accompanied by downregulation of M1 type markers. In a mouse model of pulmonary A. fumigatus infection, LL37-treated mice showed lower amounts of fungi load, moderate pathological damage, and reduced proinflammatory cytokines. Further, LL37 transgenic mice (LL37+/+) were examined to investigate the effects of endogenous LL37 in an A. fumigatus infection model and showed lower susceptibility to A. fumigatus infection in comparison with wild-type mice. In addition, LL37 also played a protective role in an immunosuppressed mouse model of A. fumigatus infection. Thus, LL37 inhibits A. fumigatus infection via directly binding to mycelia and reducing excessive inflammation. LL37 or its analogs may therefore constitute potential drug components for A. fumigatus infection.https://www.frontiersin.org/article/10.3389/fimmu.2019.00283/fullLL37Aspergillus fumigatusmyceliuminflammationadhesion |
| spellingShingle | Xiao-Li Luo Jian-Xiong Li Hua-Rong Huang Jie-Lin Duan Ruo-Xuan Dai Ru-Jia Tao Ling Yang Jia-yun Hou Xin-Ming Jia Jin-Fu Xu LL37 Inhibits Aspergillus fumigatus Infection via Directly Binding to the Fungus and Preventing Excessive Inflammation Frontiers in Immunology LL37 Aspergillus fumigatus mycelium inflammation adhesion |
| title | LL37 Inhibits Aspergillus fumigatus Infection via Directly Binding to the Fungus and Preventing Excessive Inflammation |
| title_full | LL37 Inhibits Aspergillus fumigatus Infection via Directly Binding to the Fungus and Preventing Excessive Inflammation |
| title_fullStr | LL37 Inhibits Aspergillus fumigatus Infection via Directly Binding to the Fungus and Preventing Excessive Inflammation |
| title_full_unstemmed | LL37 Inhibits Aspergillus fumigatus Infection via Directly Binding to the Fungus and Preventing Excessive Inflammation |
| title_short | LL37 Inhibits Aspergillus fumigatus Infection via Directly Binding to the Fungus and Preventing Excessive Inflammation |
| title_sort | ll37 inhibits aspergillus fumigatus infection via directly binding to the fungus and preventing excessive inflammation |
| topic | LL37 Aspergillus fumigatus mycelium inflammation adhesion |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.00283/full |
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