Molecular drivers of the physiological interaction between the mosquito immune and circulatory systems

当一种微生物侵入蚊子体内时，它会被蚊子血液的流动（称为血淋巴）推进到全身。当这种情况发生时，血淋巴的流动也会传播被称为血细胞的免疫细胞，这些细胞会不断地检查身体，寻找感染微生物。然而，并不是所有的血细胞都能循环。相反，一些血细胞附着在组织上，它们优先附着在心脏瓣膜周围的区域。在感染的几秒钟内，这些与心脏相关的血细胞，称为骨膜血细胞，开始有效地摧毁入侵身体的微生物。这种免疫反应会降低心率，并向心脏招募更多的血细胞，从而增强免疫反应的强度。该项目的目标是发现驱动蚊子心脏上发生的免疫反应的基因和蛋白质，并确定血细胞在调节心脏节律中所起的作用。这个项目的完成将极大地扩展我们对昆虫如何对抗感染的认识。这一重要信息将使我们能够操纵免疫系统来保护有益昆虫（传粉者），并控制有害昆虫（农业害虫和疾病传播者）。该项目支持培训本科生和研究生，以及纳什维尔公立学校的小学生和中学生，从而培养下一代STEM领导者。参与该项目的学员还将通过编辑和改进可公开访问的数字百科全书中的条目来教育全球受众。蚊子的免疫系统和循环系统在功能上是一体化的，因此感染会在心脏表面引发强烈的免疫过程。这些与心脏相关的免疫反应是有利的，因为它们发生在身体经历最多血淋巴流动的区域，并由称为骨膜血细胞的特定细胞驱动。虽然这种功能整合的结构机制已经被揭示，但血细胞迁移到心脏的分子基础及其对心脏节律的影响仍然未知。基因表达数据提出了IMD/JNK途径驱动血细胞向心脏迁移以及心脏细胞外基质引导血细胞到达最终位置的可能性。因此，以冈比亚按蚊（Anopheles gambiae）作为研究系统，本项目将(i)确定IMD/JNK途径和其他免疫基因在驱动外周血细胞聚集中的具体作用，以及破坏这一途径或基因是否会调节循环生理；（ii）揭示破坏细胞外基质和其他靶基因是否会损害血细胞向心脏和循环生理的迁移；（iii）区分了骨膜血细胞和心包细胞在心脏相关免疫反应中的相对贡献，同时揭示了血细胞在调节循环生理学中的作用。由于在不同的昆虫类群中都会发生皮肤免疫反应，因此这项研究将增强我们对昆虫如何在其环境中生存的理解，并将为保护有益昆虫同时针对有害昆虫提供潜在的方法。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

When a microbe invades of a mosquito, it is propelled throughout the body by the flow of the insect’s blood, called hemolymph. As this happens, the flow of hemolymph also disseminates immune cells, called hemocytes, that continually survey the body for infecting microbes. However, not all hemocytes circulate. Instead, some hemocytes attach to tissues, and they preferentially attach to the regions surrounding the valves of the heart. Within seconds of infection, these heart-associated hemocytes, called periostial hemocytes, begin to efficiently destroy the microbes that invade the body. This immune response lowers the heart rate and recruits additional hemocytes to the heart, which amplifies the strength of the immune response. The goals of this project are to discover the genes and proteins that drive the immune responses that occur on the mosquito heart, and to determine the role that hemocytes play in regulating heart rhythmicity. Completion of this project will greatly expand our knowledge of how insects fight infection. This important information will allow us to manipulate the immune system to protect beneficial insects (pollinators), and control detrimental insects (agricultural pests and disease transmitters). This project supports training of undergraduate and graduate students, and of primary and secondary school students from Metro Nashville Public Schools, thus training the next generation of STEM leaders. Trainees participating in this project will also educate a global audience by editing and improving entries in publicly accessible digital encyclopedias.The immune and circulatory systems of mosquitoes are functionally integrated, whereby an infection induces intense immune processes that occur on the surface of the heart. These heart-associated immune responses are advantageous because they occur in regions of the body that experience the most hemolymph flow and are driven by specific cells called periostial hemocytes. Although the structural mechanics of this functional integration have been uncovered, the molecular basis of hemocyte migration to the heart and its impact on heart rhythmicity remains unknown. Gene expression data raise the possibility that the IMD/JNK pathway drives hemocyte migration to the heart and that the cardiac extracellular matrix guides hemocytes to their final location. Therefore, using the societally important mosquito, Anopheles gambiae, as the study system, this project will (i) define the specific roles that the IMD/JNK pathway and other immune genes play in driving periostial hemocyte aggregation, and whether disrupting this pathway or genes modulates circulatory physiology; (ii) uncover whether disrupting the extracellular matrix and other target genes impairs hemocyte migration to the heart and circulatory physiology; and (iii) distinguish the relative contribution of periostial hemocytes and pericardial cells in heart-associated immune responses, while unveiling the role that hemocytes play in modulating circulatory physiology. Because periostial immune responses occur in diverse insect taxa, this research will enhance our understanding of how insects survive in their environments and will inform on potential ways to protect beneficial insects while targeting detrimental ones.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.