Cathelicidins As Novel Therapeutic Antivirals For Dengue Infection

点击翻译按钮获取中文摘要

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.