Friday, October 14, 2011

1 Reader Mail Bag: What Lyme Disease Research Is Needed?

A reader, Misty, recently commented on my request for topics for discussion this week:

"I like all your ideas for topics - and hope you'll be able to continue posting. I love your "blog - it is one of the most sane Lyme sites on the web, if not the most sane and balanced.

What I wonder is - do we have enough information and diagnostic tools to be able to design useful studies on Lyme?

- we can't tell reliably who has it or doesn't
- the manifestations of Lyme in each person can be different and based on complications of co-infections and the genetic predisposition of the person to exaggerated inflammatory response
- then there is the pesky post-Lyme-Syndrome/Chronic Lyme issue of whether there is infection or post-infection inflammation

So, you may have covered it already, but I am interested in hearing about ideas for scientific studies - where is the research most needed?"

thanks,
misty

Well, Misty, addressing your questions and points:

I think we can design useful studies on Lyme disease even without being capable of accurately testing every patient who has Lyme disease. Improving serological testing and being able to accurately assess whether one has or does not have Lyme disease at present are only two pieces of the bigger picture, and there are more angles from which to approach the Lyme disease problem.

Research that can be useful in gaining a better understanding of what Borrelia burgdorferi and other Borrelia do is important to understanding how to effectively diagnose and treat infection and perhaps distinguish between patients who are affected by Lyme disease and those who are affected by a different condition.

Here's a few ideas I have on what to consider for further study:

1) Do a comparative study which looks at the proteins in the CSF of patients with chronic Lyme disease versus patients with late stage untreated and patients with acute Lyme disease.

Earlier this year, we've seen the study where hundreds of proteins were found in the CSF of patients with post-treatment Lyme disease symptoms and compared against patients with Chronic Fatigue Syndrome. The protein profile for each group was different, and each group's profile differed from healthy controls.

Let's take this study one step further, and see if there is a protein profile that distinguishes between patients who were designated as suffering from post-treatment Lyme disease symptoms and those who are  late stage and newly infected.

The outcome of this study may shed some light on what markers are present for different stages of the disease. Having different markers for different stages of the disease may help guide better test research and development.

References:
Steven E. Schutzer, Thomas E. Angel, Tao Liu, Athena A. Schepmoes, Therese R. Clauss, Joshua N. Adkins, David G. Camp II, Bart K. Holland, Jonas Bergquist, Patricia K. Coyle, Richard D. Smith, Brian A. Fallon, Benjamin H. Natelson. Distinct Cerebrospinal Fluid Proteomes Differentiate Post-Treatment Lyme Disease from Chronic Fatigue Syndrome. PLoS ONE 6(2): e17287. doi:10.1371/journal.pone.0017287 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0017287

2) Conduct longer term in vivo GFP and/or iRFP studies on mice and other mammals.

In this GFP protein study on mice, spirochetes' motion was monitored in vivo rather than in vitro (go to link to watch video of spirochetes attaching to endothelial walls). Rather than study it for as short a period of time as was done, a longer time frame for study as well as multiple studies over time in the same hosts would be educational.

With longer term imaging, one can see if spirochetes become intracellular and for how long. One can see which parts of the body they travel to and see them hide in immunological niches. One can see how likely different strains are to enter the CNS and how quickly they enter the CNS post-inoculation. (We already know specific strains are more neurotropic than others, but how serious a problem is this for the host? Does it depend on the host animal?)

Perhaps a GFP or iRFP study on mice could also be combined with an antibiotic treatment study. If we can trace the activity and polymorphic state of spirochetes in vivo, then we can see if antibiotics of specific types can affect "cyst"-like forms of spirochetes in vivo, too.

3) Repeat Klempner intracellular studies with a longer observation time and longer ceftriaxone infusion.

Also - give two weeks' ceftriaxone then provide no treatment for a few months. Try a different duration of ceftriaxone. Recheck the host animal for signs of infection at 3 months, 6 months, a year, then two years.

How can an in vivo study of this issue be completed?

References:
Kostis Georgilis, Monica Peacocke, and Mark S. Klempner. Fibroblasts Protect the Lyme Disease Spirochete, Borrelia burgdorferi, from Ceftriaxone In Vitro. Journal of Infectious Diseases. Vol. 166, pp. 440-444. 1992.
Mark S. Klempner, Richard Noring and Rick A. Rogers. Invasion of Human Skin Fibroblasts by the Lyme Disease Spirochete, Borrelia burgdorferi. The Journal of Infectious Diseases. Vol. 167, No. 5 pp. 1074-1081. May 1993. http://www.jstor.org/pss/30112679

4) Use new maltodextrin enhanced imaging study in animal subjects (and later people) to see where bacteria is.

This is a very new imaging method, but the advantages are clear: Maltodextrin is viewed by pathogenic bacteria as food, whereas regular mammalian cells (human, mouse, other) and even commensal or friendly bacteria in the gut do not view maltodextrin as food and they work to eliminate it.

With the addition of a maltodextrin contrast agent, one should be able to see where pathogenic bacteria are present in the body in vivo and do so safely.

And there's more:
"In experiments using a rat model, the researchers found that the contrast agent accumulated in bacteria-infected tissues, but was efficiently cleared from uninfected tissues. They saw a 42-fold increase in fluorescence intensity between bacterial infected and uninfected tissues. However, the contrast agent did not accumulate in the healthy bacterial microflora located in the intestines. Because systemically administered glucose molecules cannot access the interior of the intestines, the bacteria located there never came into contact with the probe. 
They also found that the probes could detect as few as one million viable bacteria cells. Current contrast agents for imaging bacteria require at least 100 million bacteria, according to the researchers. 
In another experiment, the researchers found that the maltodextrin-based probes could distinguish between bacterial infections and inflammation with high specificity. Tissues infected with E. coli bacteria exhibited a 17-fold increase in fluorescence intensity when compared with inflamed tissues that were not infected."
All of these items in bold are of particular interest to those wishing to see where Borrelia burgdorferi is present during infection. If - as a number of researchers have stated - Borrelia burgdorferi are actually low in number and produce high amounts of inflammation in tissues, maltodextrin contrast should be able to confirm this finding. We'd also have a better idea of where the bacteria is in vivo without having to do a tissue biopsy, and be able to detect biofilms if any have formed.

Initial studies should be conducted on animal models, and if proven safe and effective, I see no reason why human studies wouldn't follow.

References:
Xinghai Ning, Seungjun Lee, Zhirui Wang, Dongin Kim, Bryan Stubblefield, Eric Gilbert, Niren Murthy.Maltodextrin-based imaging probes detect bacteria in vivo with high sensitivity and specificity. Nature Materials, 2011; DOI: 10.1038/nmat3074
Scientific American: http://blogs.scientificamerican.com/lab-rat/2011/07/25/making-bacteria-visible/
Science Daily: http://www.sciencedaily.com/releases/2011/07/110718121605.htm
Nature: http://www.nature.com/nmat/journal/v10/n8/full/nmat3074.html

5) Complete more treatment studies on patients with documented late stage Lyme disease and coinfections such as Ehrlichiosis and Babesiosis.

If it's problematic to differentiate between those who suffer from a chronic, persisting infection and those who suffer from an autoimmune disorder, then circumvent the issue by finding people who are truly late stage, untreated Lyme disease patients who have coinfections and study how long it takes for them to get well on combination treatments.

Many Lyme patient activists promote more studies for those of us suffering from persistent post-treatment symptoms when perhaps it is more advantageous to first push for the study of patients who have never been treated and have evidence of late stage symptoms. There are far more studies on acutely infected patients than there are on late stage patients, and this needs to be addressed, I think, in order to bridge the gap between acute cases and post-treatment cases (chronic Lyme; PLDS) and work past any controversy.

6) Run comparative studies on all labs which conduct Lyme disease tests - C6/ELISA and Western Blot IgM and IgG.

Test all existing labs for sensitivity and specificity for various strains including Borrelia lonestari and miyamotoi - include the relapsing fever Borrelias. It would be informative to know how all the labs perform and why they receive the results they do.

These are just some of the ideas I have on studies which could be conducted that give us more answers.

Regardless of these suggestions, one has to be aware of the limitations of using animal studies to model what happens in human infection. For one thing,  even non-human primate studies may not show evidence of a Borrelia burgdorferi brain infection, even with an N40 strain of Bb which is neurotropic. For another, mice do not get brain infections and are thus a poor model for studying neuroborreliosis.

References:
Ramesh, G., Borda, J., Dufour, J., Kaushal, D., Ramamoorthy, R., Lackner, A., & Philipp, M. (2008). Interaction of the Lyme Disease Spirochete Borrelia burgdorferi with Brain Parenchyma Elicits Inflammatory Mediators from Glial Cells as Well as Glial and Neuronal Apoptosis. American Journal Of Pathology, 173 (5), 1415-1427 DOI: 10.2353/ajpath.2008.080483
Diego Cadavid, Tim O'Neill, Henry Schaefer, and Andrew R. Pachner (2000). Localization of Borrelia burgdorferi in the Nervous System and Other Organs in a Nonhuman Primate Model of Lyme Disease.Laboratory Investigation, 80 (7), 1043-1054

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