Cathelicidins As Novel Therapeutic Antivirals For Dengue Infection

现代社会面临的一项重大挑战是缺乏对大量感染的治疗方法，特别是那些在发展中国家流行或广泛传播的感染。登革热是印度尼西亚的一种地方性传染病——它由蚊子传播，每年感染大约1亿人，最严重的病例可能导致死亡。目前尚无治疗登革热的方法，鉴于该疾病在全球的传播，迫切需要新的治疗方法。我们提出，人类和动物免疫系统中的小分子可以被改造和利用来对抗这种感染。我们的免疫系统含有一些最复杂、最有效的分子，可以抵抗感染。免疫系统消灭入侵病原体的方法之一是产生一种叫做抗菌肽的小肽。这些多肽存在于许多细胞、液体和组织中。我们和其他人已经证明了抗菌肽具有强大的抗病毒潜力。它们可以在消除病原体和控制炎症方面发挥关键作用。我们已经证明，在自然状态下，抗菌肽可以像普通抗病毒药物一样有效地杀死流感病毒等病毒。一项研究还表明，抗菌肽可以杀死登革热病毒，并可能在对抗这种感染的免疫反应中发挥作用。因此，我们相信基于cathelicidins结构开发新的抗菌药物有望成为对抗登革热等病原体的新方法。这项研究旨在了解cathelicidins如何促进针对登革热病毒的免疫反应，并找到利用这种强大活性开发登革热感染治疗方法的方法。此外，考虑到抗菌肽是体内自然产生的抗病毒分子，通过维生素D等物质刺激它们的产生，这对增加抗菌肽的释放非常有效，也可能是战胜感染的有效方法。我们将使用实验室培养的细胞和小鼠模型来研究如何使用抗菌肽和抗菌肽产生的刺激剂，如维生素D，来治疗登革热感染。我们还将研究登革热是否刺激或阻止抗菌肽释放，还将使用感染轻度或重度登革热的人类患者的样本，并测量其血液中的抗菌肽浓度。我们相信我们可以检查cathelicidin状态和疾病严重程度之间的关系。此外，我们将使用细胞模型来了解如何使用cathelicidins治疗登革热感染，不仅通过它们对病毒的抗病毒活性，而且通过抑制病毒在其感染的细胞中的复制。我们知道登革热可以劫持正常的细胞过程进行复制。一种叫做自噬的过程是健康细胞回收旧的或受损的细胞蛋白质所必需的，这样细胞就可以分解它们以生存。当登革热病毒感染细胞时，它劫持自噬系统，并利用它复制和释放更多的病毒，传播到其他细胞。我们将研究抗菌肽是否能阻止病毒劫持自噬机制。我们知道，抗菌肽可以诱导一种受控的细胞死亡形式——细胞凋亡，在感染的情况下，这有助于阻止被感染的细胞被用来产生更多的传染性病毒颗粒。因此，我们认为，通过使用抗菌肽来改变登革热感染中自噬与细胞凋亡的平衡，将是一种有效且有针对性的治疗登革热病毒的方法。这个项目提供了一个前所未有的机会，可以更好地了解如何利用免疫系统中的关键分子来治疗目前没有有效治疗方法的病毒，如登革热。

A significant challenge faced by modern society is the lack of therapeutics for a large number of infections, particularly those that are endemic or widely spread in developing countries. Dengue is one such infection which is endemic in Indonesia - it is transmitted by mosquitoes and infects approximately 100 million people per year, potentially causing death in the most severe cases. There is no treatment for dengue fever and given the spread of the disease around the globe, new treatment approaches are urgently required. We propose that small molecules present in the immune systems of humans and animals could be modified and exploited to fight this infection. Our immune system contains substances that are some of the most complex and effective molecules to defeat infections. One of the ways in which the immune system can destroy invading pathogens is by the production of small peptides called cathelicidins. These peptides are present in many cells, fluids and tissues. We, and others, have shown cathelicidins to have powerful antiviral potential. They can play a key role in eliminating pathogens and controlling inflammation. We have shown that, in their natural state, cathelicidins can kill viruses such as influenza virus just as effectively as common antiviral drugs. One study has also shown that cathelicidins can kill Dengue virus, and may play in role in the immune response against this infection. Thus, we believe that developing new antimicrobial medicines based on the structure of cathelicidins offers promise as a novel way to fight pathogens such as dengue. This study aims to understand how cathelicidins contribute to the immune response against dengue virus, and to find ways of harnessing this powerful activity to develop a treatment for dengue infection. In addition, given that cathelicidins are naturally occurring antiviral molecules in the body, stimulating their production through substances such as Vitamin D, which is incredibly effective at increasing cathelicidin release, may also be an effective way of defeating the infection. We will use both cells grown in the lab, and mouse models, to examine how cathelicidins, and stimulators of cathelicidin production, like Vitamin D, can be used to treat dengue infection. We will also study whether dengue stimulates or prevents cathelicidin release, and will also use samples from human patients who have contracted mild or severe dengue, and measure cathelicidin concentrations in their blood. We believe we can then examine the association between cathelicidin status, and severity of disease. Furthermore, we will use cell models to understand how cathelicidins could be used to treat dengue infection, not just through their antiviral activity towards the virus, but by suppressing virus replication in the cells it infects. We know that dengue can hijack normal cell processes to replicate. One process, called autophagy, is required by healthy cells to recycle old or damaged cell proteins, so that the cell can break them down in order to survive. When dengue virus infects a cell, it hijacks the autophagy system, and uses it to replicate and release more virus, spreading to other cells. We will examine whether cathelicidins can prevent the virus from hijacking the autophagy machinery. We know that cathelicidins can induce a controlled form of cell death called apoptosis, and that in instances of infection, this can be beneficial in stopping infected cells from being used to generate more infectious virus particles. Thus we believe that by using cathelicidins to shift the balance from autophagy to apoptosis in dengue infection, this will be an effective and targeted way of treating this virus.This project represents an unprecedented opportunity to gain a better understanding of how key molecules in the immune system can be harnessed to treat viruses, like dengue, that currently do not have an effective treatment.