Virginia Tech researchers discover potential target for diagnosing and treating Lyme disease

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You don’t have to go far to find ticks. Go outside and look for some weed. Look at the top of the shiny green blade – usually at ankle height. A tick could be there, waiting.

If something that breathes brushes against the grass, the tick takes something needle-like – called its hypostoma, which has dozens of hook barbs – and inserts it into the skin. If not detected, Lyme disease can be transferred to its host after about 24 hours of feeding.

Virginia Tech researchers have found that the bacteria that causes Lyme disease has a very unusual change in its protective molecular bag – its peptidoglycan, which is common to all bacteria.

The change in this bacteria is unprecedented – it is an unusual change in sugar that is not known to occur in any organism. One way the bacteria get this sugar change is from ticks by absorbing a carbohydrate unique to ticks. The alteration is specific to ticks and allows the bacteria to move around better and be more likely to cause disease.

“We believe this change is critical to the way the bacteria cause disease and is something we can harness for therapeutic and diagnostic purposes,” said Brandon Jutras, assistant professor of biochemistry at the College of Agriculture and Science of Life and an affiliate faculty of the Fralin Life Sciences Institute and the Center for Emerging, Zoonotic, and Arthropod-Borne Pathogens.

The findings were recently published in Nature Microbiology, which is produced by Nature Portfolio, and the research is the result of four years of work on ticks and Lyme disease, for which Jutras has been widely praised.

“Participating in this research has been the most engaging and rewarding experience of my academic career at Virginia Tech,” said lead author Tanner DeHart ’20 and ’21, who received his undergraduate and masters in biochemistry at Virginia Tech and now holds a doctorate. . student at Harvard University. “This opportunity allowed me to hone my scientific skills, become a more independent researcher, and gain first-hand experience with many techniques and experimental designs.”

Over the past two decades, the United States has seen a dramatic increase in both the number of reported cases and the geographic distribution of Lyme disease. In the state of Virginia, the disease is transmitted by the bite of blacklegged ticks, which are infected with the bacteria that cause Lyme disease. Borrelia burgdorferi.

In 2019, Jutras discovered that B. burgdorferi releases peptidoglycan once it invades the human body. Although all bacteria contain peptidoglycan, many do not release the substance.

The bacteria that causes Lyme disease is different. He has quirks in the way he makes his peptidoglycan and its components.

Years ago, researchers weren’t able to figure out these quirks. They had huge pieces of information missing. After four years of searching, they found some of the missing pieces of the puzzle. Although they don’t know how the bacteria make this change, they do know how the bacteria acquire it.

The sugar that B. burgdorferi puts in its peptidoglycan is a breakdown product of chitin, a structural carbohydrate with linked sugar molecules made from modified glucose. Chitin is an essential component of ticks.

The remarkable thing here is that the bacteria that causes Lyme disease sucks up a breakdown product from its tick vector and uses it to help make this unusual molecule. What is more fascinating is that it appears that the bacteria have developed this fine-tuned adaptation to make them move efficiently, which is a required characteristic for the disease. “

Brandon Jutras, affiliated with the Virginia Tech Postgraduate Program in Translational Biology, Medicine and Health

This adaptation makes the bacteria one of the fastest moving organisms on the planet.

From a technical standpoint, the identification of the sugar, chitobiosis – the breakdown product of chitin – was at the heart of research and discovery.

To determine that the chitobiose was the actual sugar, the researchers performed LCMS, liquid chromatography coupled with mass spectroscopy in the Mass Spectrometry Research Incubator (VT-MSI), led by Rich Helm, of Main Services. from the Fralin Life Sciences Institute. They also conducted nuclear magnetic resonance and metabolic labeling studies with C13-labeled sugars to confirm the identity of an unusual change.

In doing so, they understood why the bacteria exhibited this change.

The path B. burgdorferi spiral – or squeeze – their own body using a flagellum. The flagellum is basically a helix, but outside the sac. The propeller spins against this large molecular bag and, as a result, propels itself forward. This type of strategy allows them to move quite easily in muscle tissue, even cartilage.

Why is sugar modification so important? It allows the bag to be more flexible and to resist the torque.

The team used atomic force microscopy to probe the elasticity of the peptidoglycan.

“The material is much more flexible and elastic in the sense that it allows them to propel themselves,” Jutras said. “If they don’t have this modification, the material is much stiffer and the ability to move is impaired.”

Previously, it had been theorized that this bacteria had to be flexible, but you never knew how or why.

“We have to understand this mechanism because it would be an ideal target for therapy,” Jutras said. “We know a way – when it’s in the tick. But how does it make that change when it’s in a human? There is little or no chitin in a human. When we interfere with the ability of the bacteria. sucking up the chitobiosis, they still have that modification. There’s just a lot less. “

This means that the bacteria have another way to make this change in their peptidoglycan. Understanding how the bacteria make this change inside a human is the next step in the research – and Jutras and his team are already studying this path.

In the state of Virginia, the disease is transmitted by the bite of blacklegged ticks, which are infected with the bacteria Borrelia burgdorferi, which causes Lyme disease. Photo by Max Esterhuizen for Virginia Tech.

A long and winding road

Previous research by Jutras has shown that peptidoglycan in B. burgdorferi persists in the body of Lyme arthritis patients after the bacteria enter the body. Weeks to months after the initial infection, the peptidoglycan remains, causing inflammation and pain.

The laboratory discovered a protein associated with the peptidoglycan of Borrelia burgdorferi which plays an amplifying role in inflammation in patients with Lyme arthritis by acting as a molecular beacon that antagonizes the immune system of patients.

The new discovery by Jutras and his team may explain why peptidoglycan can hang around and cause arthritis in Lyme patients. The human body cannot process the peptidoglycan from B. burgdorferi as it can trillions of bacteria in and on the human body.

“From a bacteriologist’s perspective, this is a paradigm shift in how we understand peptidoglycan, an essential molecule produced by virtually all bacteria and the most common antibiotic target,” Jutras said. .

Since almost no other bacteria have a peptidoglycan like B. burgdorferi, it is an attractive biomarker for diagnosis. Biomarkers are unique molecular signatures, like hashtags, that indicate something has gone wrong in a system and are often used to diagnose different forms of cancer.

These previous research and findings directly led to the discovery of the self-altering properties of B. burgdorferi and its potential diagnostic methods. The new lines of research focus on this very unusual molecule and the bacteria that excrete these molecules.

“In terms of diagnostics, this is an exciting new area of ​​research for the lab with regards to this discovery, as it is a very unusual molecule,” Jutras said. “The bacteria eliminate these molecules and this discovery could lead to the development of a diagnostic tool focused on detecting this unusual molecule, much like a biomarker for Lyme disease. An approach that could make diagnosing Lyme disease as easy as a rapid COVID-19 test.

The unraveling of the mystery of the most reported vector disease in the country is progressing.

In the meantime, don’t stop doing these checks.

Source:

Journal reference:

DeHart, TG, et al. (2021) The unusual cell wall of the Lyme disease spirochete Borrelia burgdorferi is shaped by tick sugar. Natural microbiology. doi.org/10.1038/s41564-021-01003-w.


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