Have you ever heard of Lyme disease? Well yeah, that's all thanks to me! Hi, I’m your neighborhood Borrelia burgdorferi bacterium, responsible for Lyme disease. I know, I know. So cool, right? Now you might be wondering how exactly I (a small little bacterium) can cause a whole autoimmune disease. Well I’m going to tell you!
Lyme disease occurs most commonly in the Northeast, mid-Atlantic and upper-Midwest regions of the United States where ticks are common. I chose ticks as my vector because they are small and very good at getting themselves attached to the skin of humans or other animals. I am partial to the blacklegged species of ticks (they are so cute), so when a blacklegged tick bites a human, I am able to enter the host’s blood stream. If I have successfully entered the blood stream, the host tends to have symptoms such as fever, headache, fatigue, and a characteristic skin rash that looks like a bulls-eye. So cool, right? If left untreated, I will cause the host to experience joint pain, as well as heart and nervous system problems.
To go more in depth, the bacterium of my suit can cause three different stages of Lyme disease known as early localization, early disseminated, and late disseminated. Symptoms of localized Lyme disease will begin within hours or days after my friend (the tick) has successfully bit the host and I have begun entering the bloodstream. At this point of infection, my bacterium has not yet spread throughout the body. The red bulls-eye rash is typically one of the first indications to the host that I have begun seeping into their bloodstream. The rash does not occur in all cases, but the flu symptoms such as chills, fever, and headache are rather common. Unfortunately for me, Lyme disease is the easiest to kill at this stage with antibiotic treatment, such as two to six weeks of doxycycline (noooooo).
If I have been able to survive for several weeks or months within my host, the second stage of the disease will start to develop. Early disseminated Lyme is caused when I start spreading throughout the host's body. In addition to the flu-like symptoms from stage one, I will also grace my host with symptoms such as pain or numbness of limbs, vision changes, heart problems, body rashes, and facial paralysis. Hosts will experience some or all of these symptoms depending on how far I have been able to spread and develop. Once again, I would be killed with a heavy antibiotic treatment, but come on, who would want to do that? I’m having so much fun!
If I have survived this long and the Lyme disease has not been treated within the first two stages, late disseminated Lyme will occur. This stage of Lyme disease, often referred to as “chronic or neurological,” can occur weeks, months, or even years after the initial bite. At this point, I have managed to spread throughout the body and nervous system. Many untreated hosts will develop chronic Lyme arthritis, or neurological or cardiac problems. Other detrimental symptoms include vertigo, chronic fatigue syndrome, insomnia, and mental fogginess. At this advanced stage, they have to bring out the big guns (more antibiotics) to try to take me down. Commonly used antibiotics at this chronic stage include four to six weeks of doxycycline, amoxicillin, or cefuroxime.
But I’m not invincible! This paper has found one of my biggest weaknesses, and it all comes down to how I produce energy.
I actually have a pretty limited metabolism compared to most bacteria and don’t have a full metabolic pathway. For example, I lack the tricarboxylic acid cycle (TCA cycle), which is a major metabolic pathway that most organisms use for energy production. Instead, I have to rely on glycolysis to survive. Because of this, there’s one specific enzyme that I really have to rely on, and that’s lactate dehydrogenase, or BbLDH. This enzyme helps me convert pyruvate into lactate (which is a key part of glycolysis) while also balancing the ratio of NAD+ and NADH, and if that balance gets interrupted, then I can no longer produce any energy. Since glycolysis is my only way of making energy, then BbLDH is what’s able to keep me going, which is exactly what this paper focuses on!
In this study, the researchers first needed to confirm whether BbLDH does in fact do what it’s supposed to do, so they expressed and purified it using affinity and size exclusion chromatography in order to target and purify proteins and found that it was converting lactate into pyruvate and balancing NAD+ and NADH, just as it should.
They then moved on to their main question: what happens when BbLDH is removed? To determine this, the researchers attempted to completely delete the gene that encodes for BbLDH but were unable to do so, as I couldn’t survive without it (some pretty good evidence that the gene is essential). To work around this, they created what’s called a conditional knockout strain of the enzyme, which allows them to turn off BbLDH under controlled conditions. When they were able to successfully reduce BbLDH’s function, I basically stopped growing. Like, completely. Without this one enzyme, my entire energy system falls apart. Since I rely so heavily on glycolysis, the disruption of BbLDH makes it so I can’t keep up with the energy demands needed for my survival.
What’s even more convincing is when the researchers tested this in mice (Figure 4), strains of mine with disrupted BbLDH function showed much lower levels in ear tissues and a weaker immune response, meaning I was significantly less effective at infecting the host with Lyme disease. So BbLDH is not only needed for my survival, but also for making hosts sick.
Now that the researchers knew exactly what I needed for my survival (RATS!!) they started to try and figure out more ways to inhibit BbLDH. They screened the Natural Products Set IV library, which contains 419 different compounds, and using a fluorescence-based high-throughput screening (HTS) assay, 23 of those compounds showed that they could inhibit the LDH activity of BbLDH and a second screening gave rise to four lead compounds. All four of these compounds were structurally different gossypol, the only inhibitor that I really had to worry about before. To determine which compound was going to be the most effective against me, the researchers tested how each compound affected my growth at different concentrations.
As shown in Figure 5, one compound in particular, compound 45923 (methoxsalen), was especially effective. It inhibited my growth at levels comparable to gossypol, making it a very promising candidate for targeting BbLDH.
So now that all of the science is out of the way, you may be wondering where that leaves me. Currently I am safe from all of this because it is still relatively new science and the researchers haven’t started using lactate dehydrogenase as a treatment target yet. This study does show that lactate dehydrogenase can be a potential target for developing genus specific metabolic inhibitors against me as well as my friends, the other tick-born pathogens. This means that there are now more options for stopping my takeover than just antibiotics. The researchers are really happy about this because this will help reduce antibiotic resistance. This can also help with late disseminated Lyme when antibiotics are no longer effective. My grip over the host's body is slowly weaning (nooooo).
Sources:
https://www.cdc.gov/lyme/about/index.html
https://www.globallymealliance.org/about-lyme/treatment/
https://dnrec.delaware.gov/fish-wildlife/ticks/diseases/
https://www.globallymealliance.org/about-lyme/treatment/
https://dnrec.delaware.gov/fish-wildlife/ticks/diseases/
About the Authors:
Coming soon!
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