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从减毒的 LdCen 寄生虫中删除 MIF 基因可增强保护性 CD4 T 细胞免疫。

Deletion of MIF gene from live attenuated LdCen parasites enhances protective CD4 T cell immunity.

机构信息

Cellular and Molecular Immunology Research Group, René Rachou Institute (FIOCRUZ), Belo Horizonte, Brazil.

Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.

出版信息

Sci Rep. 2023 May 5;13(1):7362. doi: 10.1038/s41598-023-34333-2.

DOI:10.1038/s41598-023-34333-2
PMID:37147351
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10163264/
Abstract

Vaccination with live attenuated Leishmania parasites such as centrin deleted Leishmania donovani (LdCen) against visceral leishmaniasis has been reported extensively. The protection induced by LdCen parasites was mediated by both CD4 and CD8 T cells. While the host immune mediators of protection are known, parasite determinants that affect the CD4 and CD8 T cell populations remain unknown. Parasite encoded inflammatory cytokine MIF has been shown to modulate the T cell differentiation characteristics by altering the inflammation induced apoptosis during contraction phase in experimental infections with Leishmania or Plasmodium. Neutralization of parasite encoded MIF either by antibodies or gene deletion conferred protection in Plasmodium and Leishmania studies. We investigated if the immunogenicity and protection induced by LdCen parasites is affected by deleting MIF genes from this vaccine strain. Our results showed that LdCenMIF immunized group presented higher percentage of CD4 and CD8 central memory T cells, increased CD8 T cell proliferation after challenge compared to LdCen immunization. LdCenMIF immunized group presented elevated production of IFN-γ and TNF-α CD4 T cells concomitant with a reduced parasite load in spleen and liver compared to LdCengroup following challenge with L. infantum. Our results demonstrate the role of parasite induced factors involved in protection and long-term immunity of vaccines against VL.

摘要

已广泛报道，用活减毒利什曼原虫寄生虫（如 centrin 缺失的利什曼原虫（LdCen））进行疫苗接种可预防内脏利什曼病。LdCen 寄生虫诱导的保护作用是由 CD4 和 CD8 T 细胞介导的。虽然宿主免疫保护介质是已知的，但影响 CD4 和 CD8 T 细胞群体的寄生虫决定因素仍不清楚。寄生虫编码的炎症细胞因子 MIF 已被证明通过改变利什曼原虫或疟原虫实验感染过程中收缩阶段诱导的炎症相关细胞凋亡来调节 T 细胞分化特征。用抗体或基因缺失中和寄生虫编码的 MIF 可在疟原虫和利什曼原虫研究中提供保护。我们研究了从这种疫苗株中删除 MIF 基因是否会影响 LdCen 寄生虫诱导的免疫原性和保护作用。我们的结果表明，与 LdCen 免疫组相比，LdCenMIF 免疫组的 CD4 和 CD8 中央记忆 T 细胞百分比更高，在受到挑战后 CD8 T 细胞增殖增加。与 LdCengroup 相比，LdCenMIF 免疫组在受到 L. infantum 挑战后，脾脏和肝脏中的寄生虫载量减少，同时 IFN-γ和 TNF-αCD4 T 细胞的产生增加。我们的结果表明，寄生虫诱导的因素在保护和针对 VL 的疫苗的长期免疫中起作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/100e/10163264/3764cd48a8f0/41598_2023_34333_Fig10_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/100e/10163264/a8a0963d5415/41598_2023_34333_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/100e/10163264/6f82b9c72fe7/41598_2023_34333_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/100e/10163264/1f816230c2b6/41598_2023_34333_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/100e/10163264/2239e27b8ec9/41598_2023_34333_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/100e/10163264/77c541cb59b1/41598_2023_34333_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/100e/10163264/38aa89600b08/41598_2023_34333_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/100e/10163264/3764cd48a8f0/41598_2023_34333_Fig10_HTML.jpg

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Front Immunol. 2022 Mar 28;13:864031. doi: 10.3389/fimmu.2022.864031. eCollection 2022.
2
Targeted Deletion of Centrin in Using CRISPR-Cas9-Based Editing.利用 CRISPR-Cas9 编辑技术靶向敲除 中的 Centrin。
Front Cell Infect Microbiol. 2022 Feb 17;11:790418. doi: 10.3389/fcimb.2021.790418. eCollection 2021.
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Centrin-deficient Leishmania mexicana confers protection against New World cutaneous leishmaniasis.
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NPJ Vaccines. 2022 Mar 2;7(1):32. doi: 10.1038/s41541-022-00449-1.
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Protective CD4+ Th1 cell-mediated immunity is reliant upon execution of effector function prior to the establishment of the pathogen niche.保护性 CD4+ Th1 细胞介导的免疫依赖于在病原体定殖之前执行效应功能。
PLoS Pathog. 2021 Sep 20;17(9):e1009944. doi: 10.1371/journal.ppat.1009944. eCollection 2021 Sep.
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