Laboratório de Bioquímica de Resposta ao Estresse, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Instituto Nacional de Ciência e Tecnologia em Entomologia Molecular (INCT-EM), Rio de Janeiro, Brazil.
Mol Microbiol. 2024 Nov;122(5):683-703. doi: 10.1111/mmi.15269. Epub 2024 May 8.
Aedes aegypti females are natural vectors of important arboviruses such as dengue, zika, and yellow fever. Mosquitoes activate innate immune response signaling pathways upon infection, as a resistance mechanism to fight pathogens and limit their propagation. Despite the beneficial effects of immune activation for insect vectors, phenotypic costs ultimately affect their fitness. However, the underlying mechanisms that mediate these fitness costs remain poorly understood. Given the high energy required to mount a proper immune response, we hypothesized that systemic activation of innate immunity would impair flight muscle mitochondrial function, compromising tissue energy demand and flight activity. Here, we investigated the dynamic effects of activation of innate immunity by intra-thoracic zymosan injection on A. aegypti flight muscle mitochondrial metabolism. Zymosan injection significantly increased defensin A expression in fat bodies in a time-dependent manner that compromised flight activity. Although oxidant levels in flight muscle were hardly altered, ATP-linked respiratory rates driven by mitochondrial pyruvate+proline oxidation were significantly reduced at 24 h upon zymosan injection. Oxidative phosphorylation coupling was preserved regardless of innate immune response activation along 24 h. Importantly, rotenone-sensitive respiration and complex I-III activity were specifically reduced 24 h upon zymosan injection. Also, loss of complex I activity compromised ATP-linked and maximal respiratory rates mediated by mitochondrial proline oxidation. Finally, the magnitude of innate immune response activation negatively correlated with respiratory rates, regardless of the metabolic states. Collectively, we demonstrate that activation of innate immunity is strongly associated with reduced flight muscle complex I activity with direct consequences to mitochondrial proline oxidation and flight activity. Remarkably, our results indicate a trade-off between dispersal and immunity exists in an insect vector, underscoring the potential consequences of disrupted flight muscle mitochondrial energy metabolism to arbovirus transmission.
埃及伊蚊雌性是登革热、寨卡和黄热病等重要虫媒病毒的天然载体。蚊子在感染后会激活先天免疫反应信号通路，作为抵抗病原体并限制其传播的机制。尽管免疫激活对昆虫载体有有益的影响，但表型成本最终会影响它们的适应性。然而，介导这些适应性成本的潜在机制仍知之甚少。鉴于产生适当免疫反应所需的高能量，我们假设先天免疫的系统性激活会损害飞行肌线粒体功能，从而影响组织的能量需求和飞行活动。在这里，我们研究了通过胸内注射几丁质聚糖对内共生免疫的动态影响对埃及伊蚊飞行肌线粒体代谢的影响。几丁质聚糖注射以时间依赖性方式显著增加了脂肪体中的防御素 A 表达，从而损害了飞行活动。尽管飞行肌中的氧化应激水平几乎没有改变，但在几丁质聚糖注射后 24 小时，由线粒体丙酮酸+脯氨酸氧化驱动的 ATP 连接呼吸速率显著降低。氧化磷酸化偶联在整个 24 小时内都得到了保留，无论先天免疫反应是否被激活。重要的是，24 小时后，旋塞霉素敏感的呼吸和复合物 I-III 活性特异性降低。此外，复合物 I 活性的丧失损害了由线粒体脯氨酸氧化介导的 ATP 连接和最大呼吸速率。最后，无论代谢状态如何，先天免疫反应激活的程度与呼吸速率呈负相关。总的来说，我们证明了先天免疫的激活与飞行肌复合物 I 活性的降低密切相关，这对线粒体脯氨酸氧化和飞行活动有直接影响。值得注意的是，我们的研究结果表明，在昆虫载体中存在着分散和免疫之间的权衡，这突显了破坏飞行肌线粒体能量代谢对虫媒病毒传播的潜在影响。
