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MELBOURNE, March 11 (Talk) Crocodiles and their relatives have roamed our planet for millions of years, evolving robust immune systems to help fight potentially harmful microbes in the marshes and waterways they call home .
Our recent study, published in Nature Communications, took a closer look at antimicrobial proteins called defensins found in saltwater crocodiles. These proteins play a key role in reptiles’ first line of defense against infectious diseases.
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As the threat of antibiotic-resistant microorganisms increases, so does our need for new and effective treatments. Could the defensins of these beasts hold the answer and help create a new wave of life-saving treatments?
What are defensins?
Defensins are small proteins produced by all plants and animals. In plants, defensins are usually produced by flowers and leaves, while in animals defensins are produced by white blood cells and mucous membranes such as the lungs and intestines. Their role is to protect the host by killing infectious organisms.
Studies of defensins in different plant and animal species have found that they can target a wide range of disease-causing pathogens. These include bacteria, fungi, viruses and even cancer cells.
The most common way defensins kill these pathogens is by attaching themselves to the outer membrane — the layer that holds cells together. Once there, the defensins create holes in the membrane that allow the cell contents to leak out, killing the cell in the process.
What’s so special about crocodile defensins?
Despite living in dirty water, crocodiles rarely get infections, although they are often injured while hunting and fighting for territory. This shows that crocodiles have a strong immune system. We want to better understand how their defensins adjust over time to protect them in these harsh environments.
By searching the genome of saltwater crocodiles, we discovered that a specific defensin called CpoBD13 is effective in killing Candida albicans, the leading cause of fungal infections in humans worldwide. Although several plant and animal defensins have previously been shown to target C. albicans, the mechanism behind CpoBD13’s antifungal activity makes it unique.
This is because CpoBD13 can self-regulate its activity according to the pH value of the surrounding environment. At neutral pH (eg, in blood), defensins are inactive. However, when it reaches the site of infection, which has a lower acidic pH, the defensin is activated and helps clear the infection. This is the first time such a mechanism has been observed in defensins.
Our team discovered this mechanism by revealing the structure of CpoBD13 using a process called X-ray crystallography. This involves ‘shooting’ lab-grown protein crystals with high-energy X-rays, which we did at the Australian Synchrotron.
Are fungi really a threat to human health?
Fungal infections are usually less serious than bacterial and viral infections. After all, epidemics throughout human history have been caused only by the former. In fact, the most common cause of the fungus in the general public is athlete’s foot and toenail infections — conditions that are rarely life-threatening.
But the fungus can cause serious problems for human health, especially for people with compromised immune systems. Worldwide, approximately 1.5 million people die each year from fungal infections.
Our current antifungal arsenal is limited to a few drugs. Also, we haven’t had a new class of antifungal drugs since the early 2000s. To make matters worse, the overuse of our existing antifungal drugs has resulted in some resistant fungal strains.
Rising global temperatures are also making once-cold regions more susceptible to pathogenic fungi. Climate change has even been linked to the emergence of new drug-resistant species such as Candida auris.
The long road from crocodile to clinic
In the search for new medicines, our study and studies like it are important in finding potential antibiotics for the future. By characterizing crocodile defensins, we provide the basis needed to develop CpoBD13 as a potent antifungal agent. However, conducting clinical trials is a lengthy and expensive process. From initial discovery, it can take anywhere from five to 20 years for a new drug to be approved.
Currently, protein-based treatments can sometimes inadvertently harm the body’s healthy cells. By taking advantage of what we know about alligator defensins, it may be possible to design other proteins that take on CpoBD13’s pH-sensing mechanism. Therefore, they only “turn on” after infection.
Although much work remains to be done before crocodile defensins are seen in the clinic, we hope to one day harness the uniquely raw power of the crocodile immune system to help the global fight against infectious disease. (dialogue)
(This is an unedited and auto-generated story from a Syndicated News feed, the content body may not have been modified or edited by LatestLY staff)
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