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Abstract：
The multifaceted functions ranging from cellular and developmental mechanisms to inflammation and immunity have rendered TGF-ß signaling pathways as critical regulators of conserved biological processes. Recent studies have indicated that this evolutionary conserved signaling pathway among metazoans contributes to the Drosophila melanogaster anti-nematode immune response. However, functional characterization of the interaction between TGF-ß signaling activity and the mechanisms activated by the D. melanogaster immune response against parasitic nematode infection remains unexplored. Also, it is essential to evaluate the precise effect of entomopathogenic nematode parasites on the host immune system by separating them from their mutualistic bacteria. Here, we investigated the participation of the TGF-ß signaling branches, activin and bone morphogenetic protein (BMP), to host immune function against axenic or symbiotic Heterorhabditis bacteriophora nematodes (parasites lacking or containing their mutualistic bacteria, respectively). Using D. melanogaster larvae carrying mutations in the genes coding for the TGF-ß extracellular ligands Daw and Dpp, we analyzed the changes in survival ability, cellular immune response, and phenoloxidase (PO) activity during nematode infection. We show that infection with axenic H. bacteriophora decreases the mortality rate of dpp mutants, but not daw mutants. Following axenic or symbiotic H. bacteriophora infection, both daw and dpp mutants contain only plasmatocytes. We further detect higher levels of Dual oxidase gene expression in dpp mutants upon infection with axenic nematodes and Diptericin and Cecropin gene expression in daw mutants upon infection with symbiotic nematodes compared to controls. Finally, following symbiotic H. bacteriophora infection, daw mutants have higher PO activity relative to controls. Together, our findings reveal that while D. melanogaster Dpp/BMP signaling activity modulates the DUOX/ROS response to axenic H. bacteriophora infection, Daw/activin signaling activity modulates the antimicrobial peptide and melanization responses to axenic H. bacteriophora infection. Results from this study expand our current understanding of the molecular and mechanistic interplay between nematode parasites and the host immune system, and the involvement of TGF-ß signaling branches in this process. Such findings will provide valuable insight on the evolution of the immune role of TGF-ß signaling, which could lead to the development of novel strategies for the effective management of human parasitic nematodes.
摘要：
从细胞和发育机制到炎症和免疫的多方面功能使TGF-β信号通路成为保守生物过程的关键调节剂。最近的研究表明，后生动物之间的这种进化保守的信号通路有助于果蝇抗线虫免疫反应。然而,TGF-β信号活性与黑腹D.针对寄生线虫感染的免疫反应激活的机制之间相互作用的功能表征仍未被研究。此外，通过将昆虫病原线虫寄生虫与它们的相互细菌分离来评估它们对宿主免疫系统的精确影响是至关重要的。这里,我们调查了TGF-β信号分支的参与，活化素和骨形态发生蛋白（BMP），宿主针对无菌或共生的异型横纹肌细菌线虫（缺乏或含有其共生细菌的寄生虫，分别)。使用在编码TGF-β胞外配体Daw和Dpp的基因中携带突变的D.melanogaster幼虫，我们分析了生存能力的变化，细胞免疫反应，和线虫感染期间的酚氧化酶（PO）活性。我们表明，感染无菌H.bacteriophora降低了dpp突变体的死亡率，但不是daw变种人.无菌或共生H.bacteriophora感染后，daw和dpp突变体都只含有浆细胞。与对照相比，我们进一步检测到dpp突变体在共生性线虫感染后的双氧化酶基因表达水平较高，而daw突变体在共生性线虫感染后的双蝶星和Cecropin基因表达水平较高。最后,共生H.bacteriophora感染后，相对于对照,daw突变体具有更高的PO活性。一起,我们的发现表明，虽然D.melanogasterDpp/BMP信号活性调节DUOX/ROS对无菌H.bacteriophora感染的反应，Daw/激活素信号传导活性调节抗微生物肽和黑化对无菌H.bacteriophora感染的反应。这项研究的结果扩展了我们目前对线虫寄生虫与宿主免疫系统之间的分子和机制相互作用的理解，以及TGF-β信号分支参与这一过程。这些发现将为TGF-β信号的免疫作用的演变提供有价值的见解，这可能导致开发有效管理人类寄生线虫的新策略。
