Upregulation of PD-1/PD-L1 and downregulation of immune signaling pathways lead to more severe visceral leishmaniasis in undernutrition mice
Abstract Background Leishmaniasis is mainly prevalent in tropical and subtropical developing countries, where chronic undernutrition often co-exists. Undernutrition is reported to promote the progression of leishmaniasis, but its immune mechanisms have not been fully elucidated. Methods To simulate...
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Parasites & Vectors |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13071-023-06018-2 |
| _version_ | 1797355900981215232 |
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| author | Jinlei He Jianhui Zhang Xuechun Liao Yuying Xiao Jiao Li Zhiwan Zheng Dali Chen Jianping Chen |
| author_facet | Jinlei He Jianhui Zhang Xuechun Liao Yuying Xiao Jiao Li Zhiwan Zheng Dali Chen Jianping Chen |
| author_sort | Jinlei He |
| collection | DOAJ |
| description | Abstract Background Leishmaniasis is mainly prevalent in tropical and subtropical developing countries, where chronic undernutrition often co-exists. Undernutrition is reported to promote the progression of leishmaniasis, but its immune mechanisms have not been fully elucidated. Methods To simulate chronic undernutrition of patients in epidemic areas and explore the immune mechanism of undernutrition promoting leishmaniasis, BALB/c mouse models with different nutritional imbalances were established, including undernutrition 75%, undernutrition 65% and obesity mouse models. After infection with Leishmania donovani in these model mice, we focused on evaluating the progress of leishmaniasis in the spleen and liver, the expression of important immunosuppressive and immunoactivation molecules, and changes of spleen transcriptome. The immune signaling pathways enriched by differentially expressed genes and hub genes were analyzed. Results The results showed that among the mouse infection models, undernutrition 75% + infection group had the highest parasite load in the spleen and liver at the 8th week post-infection, possibly due to the continuous increase of PD-1, PD-L1 and TCR. Spleen RNA-seq results suggested that some immune signaling pathways were downregulated in undernutrition 75% + infection group, including neutrophil extracellular trap formation, IL-17 signaling pathway, natural killer cell-mediated cytotoxicity, etc. Among them, neutrophil extracellular trap formation pathway had the largest number of downregulated genes. This also explained why undernutrition 75% + infection group had the highest parasite load. Through PPI network analysis, hub genes such as Lcn2, Ltf, Mpo, Dnaja1, Hspa1a, Hspa1b and Hsph1 were screened out and might play important roles in the process of undernutrition promoting leishmaniasis. Conclusions Undernutrition upregulated PD-1 and PD-L1 expression and downregulated immune signaling pathways in mice with visceral leishmaniasis. The signaling pathways and hub genes may serve as drug targets or intervention targets for the treatment of leishmaniasis patients with undernutrition. Graphical Abstract |
| first_indexed | 2024-03-08T14:18:47Z |
| format | Article |
| id | doaj.art-0fb8e6e36bcc485291a48d14e74d2b10 |
| institution | Directory Open Access Journal |
| issn | 1756-3305 |
| language | English |
| last_indexed | 2024-03-08T14:18:47Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Parasites & Vectors |
| spelling | doaj.art-0fb8e6e36bcc485291a48d14e74d2b102024-01-14T12:13:37ZengBMCParasites & Vectors1756-33052024-01-0117111710.1186/s13071-023-06018-2Upregulation of PD-1/PD-L1 and downregulation of immune signaling pathways lead to more severe visceral leishmaniasis in undernutrition miceJinlei He0Jianhui Zhang1Xuechun Liao2Yuying Xiao3Jiao Li4Zhiwan Zheng5Dali Chen6Jianping Chen7Department of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityDepartment of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityDepartment of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityDepartment of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityDepartment of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityDepartment of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityDepartment of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityDepartment of Pathogenic Biology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan UniversityAbstract Background Leishmaniasis is mainly prevalent in tropical and subtropical developing countries, where chronic undernutrition often co-exists. Undernutrition is reported to promote the progression of leishmaniasis, but its immune mechanisms have not been fully elucidated. Methods To simulate chronic undernutrition of patients in epidemic areas and explore the immune mechanism of undernutrition promoting leishmaniasis, BALB/c mouse models with different nutritional imbalances were established, including undernutrition 75%, undernutrition 65% and obesity mouse models. After infection with Leishmania donovani in these model mice, we focused on evaluating the progress of leishmaniasis in the spleen and liver, the expression of important immunosuppressive and immunoactivation molecules, and changes of spleen transcriptome. The immune signaling pathways enriched by differentially expressed genes and hub genes were analyzed. Results The results showed that among the mouse infection models, undernutrition 75% + infection group had the highest parasite load in the spleen and liver at the 8th week post-infection, possibly due to the continuous increase of PD-1, PD-L1 and TCR. Spleen RNA-seq results suggested that some immune signaling pathways were downregulated in undernutrition 75% + infection group, including neutrophil extracellular trap formation, IL-17 signaling pathway, natural killer cell-mediated cytotoxicity, etc. Among them, neutrophil extracellular trap formation pathway had the largest number of downregulated genes. This also explained why undernutrition 75% + infection group had the highest parasite load. Through PPI network analysis, hub genes such as Lcn2, Ltf, Mpo, Dnaja1, Hspa1a, Hspa1b and Hsph1 were screened out and might play important roles in the process of undernutrition promoting leishmaniasis. Conclusions Undernutrition upregulated PD-1 and PD-L1 expression and downregulated immune signaling pathways in mice with visceral leishmaniasis. The signaling pathways and hub genes may serve as drug targets or intervention targets for the treatment of leishmaniasis patients with undernutrition. Graphical Abstracthttps://doi.org/10.1186/s13071-023-06018-2LeishmaniasisPD-1PD-L1UndernutritionRNA-seq |
| spellingShingle | Jinlei He Jianhui Zhang Xuechun Liao Yuying Xiao Jiao Li Zhiwan Zheng Dali Chen Jianping Chen Upregulation of PD-1/PD-L1 and downregulation of immune signaling pathways lead to more severe visceral leishmaniasis in undernutrition mice Parasites & Vectors Leishmaniasis PD-1 PD-L1 Undernutrition RNA-seq |
| title | Upregulation of PD-1/PD-L1 and downregulation of immune signaling pathways lead to more severe visceral leishmaniasis in undernutrition mice |
| title_full | Upregulation of PD-1/PD-L1 and downregulation of immune signaling pathways lead to more severe visceral leishmaniasis in undernutrition mice |
| title_fullStr | Upregulation of PD-1/PD-L1 and downregulation of immune signaling pathways lead to more severe visceral leishmaniasis in undernutrition mice |
| title_full_unstemmed | Upregulation of PD-1/PD-L1 and downregulation of immune signaling pathways lead to more severe visceral leishmaniasis in undernutrition mice |
| title_short | Upregulation of PD-1/PD-L1 and downregulation of immune signaling pathways lead to more severe visceral leishmaniasis in undernutrition mice |
| title_sort | upregulation of pd 1 pd l1 and downregulation of immune signaling pathways lead to more severe visceral leishmaniasis in undernutrition mice |
| topic | Leishmaniasis PD-1 PD-L1 Undernutrition RNA-seq |
| url | https://doi.org/10.1186/s13071-023-06018-2 |
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