Elucidation of platelet activation pathways during invasive mould infections

目前，每年发生的真菌感染超过10亿例，其中200多万发展为威胁生命的侵袭性真菌病。与此同时，我们目前的抗真菌疗法效果不佳，费用昂贵，而且显示出很大的副作用。因此，侵袭性真菌感染的死亡率高达95%，令人无法接受。这表明显然需要改进侵袭性真菌感染的治疗制度。最近的研究揭示了新的意想不到的免疫血小板功能，以应对感染性病原体。血小板-细菌聚集可以释放保护性的抗微生物因子，但也会导致血栓形成、夸大的炎症反应或血小板减少。侵袭性霉菌感染的特征之一是形成血栓，导致组织坏死和组织损伤。真菌病原体很容易与血小板相互作用，这表明真菌介导的血小板激活在加重疾病进展方面可能起到了作用。然而，对于真菌病原体和血小板之间相互作用的分子基础几乎一无所知。假设：因此，我们假设在侵袭性感染过程中，血小板与真菌的相互作用导致了血小板的激活。为了检验这一假设，我们将：1.)分析真菌病原体诱导血小板活化和分泌的能力。2.)描述参与真菌识别的血小板受体(S)及其下游信号通路。3.)描述易患患者的血液样本中的血小板相互作用。4.)在斑马鱼幼体模型中研究真菌孢子和血小板之间的相互作用。

Currently, over one billion fungal infections occur each year of which over two million develop into life-threatening invasive mycoses. At the same time, our current anti-fungal therapies are ineffective, expensive and show substantial side effects. As a result, invasive fungal infections present with unacceptable mortality rates of up to 95%. This shows the clear need for improved treatment regimes for invasive fungal infections. Recent research has unravelled new unexpected immunological platelet functions in response to infectious agents. Platelet-bacterial aggregation can release protective antimicrobial factors but also lead to thrombus formation, exaggerated inflammatory responses or thrombocytopenia. One of the hallmarks of invasive mould infections is the formation of thrombi leading to tissue necrosis and tissue damage. Fungal pathogens readily interact with platelets indicating the potential role of fungal mediated platelet activation in aggravating disease progression. However, next to nothing is known about the molecular basis of the interaction between fungal pathogens and platelets.Hypothesis: We therefore hypothesise that platelet-fungal interactions during invasive infection leads to platelet activation. To test this hypothesis, we will: 1.) Analyse the ability of fungal pathogens to induce platelet activation and secretion. 2.) Characterise platelet receptor(s) and downstream signalling pathways involved in fungal recognition. 3.) Characterise platelet interactions in blood samples from predisposed patients. 4.) Investigate the interaction between fungal spores and platelets in a zebrafish larval model.