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

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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.