Gene Signature Could Lead To A New Way Of Diagnosing Lyme

[shannah]

Some research on Lyme released today from UCSF.

They noted how similar the gene signatures are at six months between Lyme, CFS, RA and Lupus.


https://www.ucsf.edu/news/2016/02/401581/gene-signature-could-lead-new-way-diagnosing-lyme

From the article:

"Researchers at UC San Francisco and Johns Hopkins may have found a new way to diagnose Lyme disease, based on a distinctive gene “signature” they discovered in white blood cells of patients infected with the tick-borne bacteria."

"In an effort to find better ways of diagnosing the disease, and discovering molecular pathways that might explain how Lyme disease could cause long-term symptoms, researchers used a next-generation sequencing technique, called RNA-seq, to investigate the transcriptome – the genes that are being turned on – in peripheral blood mononuclear cells.

Researchers examined 29 patients before and after they received a three-week course of antibiotic treatment and also six months later. Compared to patients with other active bacterial or viral infections, the Lyme disease patients had distinctive gene signatures that persisted for at least three weeks, even after they had taken the antibiotics. Some differences in the transcriptome lingered for six months."

"Six months after treatment, 15 of the 29 patients in the study had fully recovered, while 13 had persistent symptoms, and one had dropped out. Despite the stark differences in how the patients reported feeling, the researchers could not detect transcriptional differences between the two groups. They said larger studies are needed to confirm this finding.

Researchers found similarities between the transcriptional changes after Lyme disease infection and other diseases. The acute phase of Lyme disease infection had similarities with influenza. At six months, the gene signatures of Lyme disease patients showed some similarities to those from patients with immune diseases like systematic lupus erythematosus, rheumatoid arthritis and chronic fatigue syndrome.

The researchers said measureable and persistent changes to the transcriptome may also be characteristic of a number of other infections, such as chronic hepatitis C."

 

[anciendaze]

This is important, and the title is somewhat misleading, as most people will be thinking that genes are something innate that cannot be changed. This looks at RNA transcribed from DNA. It tells you what the body is actually doing in response to infection.

I've just had a discussion about an elderly relative who had an ordinary bacterial infection and was treated with antibiotics. She failed to improve and even had a number of slow falls, fortunately without serious injury. She was again treated with antibiotics, and given diuretics to remove some toxins she had accumulated due to another problem. Trouble persisted, and there appeared to be an allergic reaction. The third time she was hospitalized they did a definitive test for the known type of bacteria, and found the infection was still active. The "allergic response" was response to bacteria, not medication. If the bacteria had been difficult to culture this would not have been possible. Now that the infection has been treated and resolved she is able to recover strength, before she was in hospice care, and not expected to survive for more than some number of months. If you can't tell the effects of treatment from the disease you are in deep trouble.

Months of treatment for a known problem, and three hospitalizations, does not sound like an effective response by the medical system to a known and treatable bacterial infection.

Finding bacteria under a microscope can be extremely difficult if they cannot be cultured and are not present in huge numbers. Your best shot may come from pathological specimens after the patient has died. Testing for antibodies will not easily distinguish active infections from treated ones which have resolved. The immune system "knows" something is wrong, but we have not previously been able to interrogate it in any very specific way. RNA sequencing from monocytes is a much more informative way of doing this than simply counting blood cells. It tells you what they are actually doing.

This general kind of approach has been touted as "precision medicine". I'd describe it as simply having some real idea about what is going on inside the patient. Far too many important medical decisions are based on guesses.

 

[duncan]

It's hard to get past the Johns Hopkins thing. At least Aucott gives credence to the severity of patient symptoms. But he seems dogmatic in his drive to demonstrate immune abnormalities. A possible give away: referencing symptoms "...even after a bacterial infection has been treated with appropriate antibiotics..." It appears he believes that current IDSA-recommended therapy is adequate.

 

[Bob]

I've found the research paper...

Longitudinal Transcriptome Analysis Reveals a Sustained Differential Gene Expression Signature in Patients Treated for Acute Lyme Disease
Jerome Bouquet, Mark J. Soloski, Andrea Swei, Chris Cheadle, Scot Federman, Jean-Noel Billaud, Alison W. Rebman, Beniwende Kabre, Richard Halpert, Meher Boorgula, John N. Aucott, Charles Y. Chiu.
February 2016
mBio vol. 7 no. 1 e00100-16
doi: 10.1128/mBio.00100-1612
http://mbio.asm.org/content/7/1/e00100-16.full

ABSTRACT
Lyme disease is a tick-borne illness caused by the bacterium Borrelia burgdorferi, and approximately 10 to 20% of patients report persistent symptoms lasting months to years despite appropriate treatment with antibiotics. To gain insights into the molecular basis of acute Lyme disease and the ensuing development of post-treatment symptoms, we conducted a longitudinal transcriptome study of 29 Lyme disease patients (and 13 matched controls) enrolled at the time of diagnosis and followed for up to 6 months. The differential gene expression signature of Lyme disease following the acute phase of infection persisted for at least 3 weeks and had fewer than 44% differentially expressed genes (DEGs) in common with other infectious or noninfectious syndromes. Early Lyme disease prior to antibiotic therapy was characterized by marked upregulation of Toll-like receptor signaling but lack of activation of the inflammatory T-cell apoptotic and B-cell developmental pathways seen in other acute infectious syndromes. Six months after completion of therapy, Lyme disease patients were found to have 31 to 60% of their pathways in common with three different immune-mediated chronic diseases. No differential gene expression signature was observed between Lyme disease patients with resolved illness to those with persistent symptoms at 6 months post-treatment. The identification of a sustained differential gene expression signature in Lyme disease suggests that a panel of selected human host-based biomarkers may address the need for sensitive clinical diagnostics during the “window period” of infection prior to the appearance of a detectable antibody response and may also inform the development of new therapeutic targets.

 

[anciendaze]

I think the emphasis on Lyme disease is too narrow. There is a list of pathogens other than b. burghdorferi that can cause similar effects, just for starters. This is a crack in a difficult problem which may lead somewhere. It is nowhere near the end of the battle.

Using RNA sequencing to find out what specific classes of immune cells are actually doing in response to infection is a powerful technique which offers the potential for breakthroughs bypassing a large number of unsatisfactory clinical investigations of ambiguous diseases.

In the case of several illnesses I have been wondering "if depletion of CD20+ B-cells with Rituximab results in apparent remissions, even in a few cases, why aren't we applying such methods as RNA sequencing to find out what those cells being removed were actually doing?"

 

[duncan]

@anciendaze, have they refined this process enough to pinpoint specific strains of specific pathogens, or is this a progress in progress?

 

[anciendaze]

@duncan
This is still a learning process for everyone. It would be nice to simply have the kind of information that would tell doctors whether they should be looking for bacteria or a virus. Currently we regularly see people treated with antibiotics when they have a viral infection, and people with persistent viral infections that lack convenient clinical signs.

You could identify specific pathogens if you were looking for expression of bacterial or viral genes. Unfortunately this will not help you if you don't even know which pathogen you should be looking for.

At present these tests seem too expensive for regular clinical use, but I'm hopeful they can be used in a research context to develop a better understanding of what clinicians should be looking for, and to produce better clinical tests they can use, once we know what markers are associated with a disease.

 

[voner]

I found this to be an intriguing post on Dr. Francis Collin's NIH directors blog:

http://directorsblog.nih.gov/2016/0...-signatures-may-catch-the-infection-sooner-2/

it discusses how unique gene expression signatures have been found in acute Lyme disease. it also says that in post treatment Lyme disease (chronic Lyme disease?) there appears to be "some disruption of the immune system that persists after the pathogen has been eliminated".

here is another intriguing tidbit in the blog (my bolding) :

..Their analyses uncovered changes in the expression of more than 1,000 genes at the time of diagnosis. Many of the changes reflect inflammatory and immune responses, as expected in a person battling an infection. Further analyses showed that just under half of the observed differences in gene expression were shared with other common illnesses, making Lyme disease a relatively unique infection. Interestingly, the gene expression signature in early Lyme disease had more in common with viral influenza infections than infections caused by other bacteria.

For the vast majority of infectious diseases, effective treatment allows the immune system to stop fighting and return gene expression levels to normal. Remarkably, that was not the case with Lyme disease. The immune cells had post-treatment transcriptomes that varied from those of healthy controls by about 1,000 genes. This signature also included many of the underlying inflammatory and immune features seen in the pre-treatment response, and even as patients began to feel better...

and finally,

...the (gene) signature 6 months after treatment showed intriguing similarities with autoimmune diseases, including lupus, rheumatoid arthritis, and chronic fatigue syndrome...

there are two references at the end of the blog that appeared to be well worth reading.

References:

[1] Longitudinal Transcriptome Analysis Reveals a Sustained Differential Gene Expression Signature in Patients Treated for Acute Lyme. Bouquet J, Soloski MJ, Swei A, Cheadle C, Federman S, Billaud JN, Rebman AW, Kabre B, Halpert R, Boorgula M, Aucott JN, Chiu CY. mBio. 2016 Feb 12;7(1): e00100-16.
...........
[3] Development of a metabolic biosignature for detection of early Lyme disease. Mollins CR, Ashton LV, Wormser GP, Hess AM, Delorey MJ, Mahapatra S, Schriefer ME, Belisle JT. Clin Infect Dis. 2015 Jun 15;60(12):1767-1775.

 

[Antares in NYC]

Wouldn't it be awesome if they actually did study what we have, instead of squandering taxpayer money away with zero results or studies to show?

 

[duncan]

Still fundamentally an acute Lyme study.

What ever happened to exploring tertiary Lyme?

It doesn't seem to exist in the corridors of the CDC/NIH.

I can assure everybody it exists in the real world.

"...some disruption of the immune system that persists after the pathogen has been eliminated"...Geesh. Talk about your assumptive close. Shouldn't they prove the pathogen has been eliminated first?

 

[Antares in NYC]

Still fundamentally an acute Lyme study.

What ever happened to exploring tertiary Lyme?
It doesn't seem to exist in the corridors of the CDC/NIH.

I can assure everybody it exists in the real world.

It's like they using "magical doxy." After two weeks of magical CDC doxy you can't possibly have bacterial persistence anymore. You are cured even if you remain hopelessly ill, period, and whatever you have must be something else... Or it's subjective and in your head.

Most bacterial infections have mechanisms and circumstances by which they can persist and become chronic. All but Lyme disease! The moment you take a couple of weeks of that magical doxy, it's gone, end of the story, good luck to you. Move along, malingerer!

Snake oil traveling doctors from Western movies seem to have more integrity than this bunch.

 

[duncan]

Not to mention there is some good evidence (Sapi?) that doxy can cause Bb to morph into cyst form and become actually more difficult to treat.

Gotta love the folks behind the wheel at the IDSA/NIH/CDC jalopy.

 

[*GG*]

Wouldn't it be awesome if they actually did study what we have, instead of squandering taxpayer money away with zero results or studies to show?

Damn, is that the guys last name? How appropriate! I am so glad I do not have Lyme! Enough with this illness, even though I have had many ticks on me over the years!

GG

 

[barbc56]

Damn, is that the guys last name? How appropriate! I am so glad I do not have Lyme! Enough with this illness, even though I have had many ticks on me over the years!

GG

There's a thread for weird doctor names. I'll come back and post the url later.

 

[Bob]

Interesting blog about this study, by Francis Collins the NIH director.

Lyme Disease: Gene Signatures May Catch the Infection Sooner
Posted on February 23, 2016
by Dr. Francis Collins
http://directorsblog.nih.gov/2016/0...-signatures-may-catch-the-infection-sooner-2/

Thanks @Simon for flagging it on your blog.

 

[duncan]

Thanks for posting, @Bob

Now I trust Collins even less.

 

[Bob]

Now I trust Collins even less.

Why?

 

[duncan]

@Bob, he appears to be spouting party lines, at least in part, and that alone is unfortunate.

He seems primarily focused on acute cases, more or less leaving late stagers out in the cold. Even PTLDS is discussed almost as an after thought, and when it is, he actually takes the controversial stand that post-treatment symptoms are probably not due to persistent infection. Perhaps he is unfamiliar with the works of Zhang and Lewis and Embers which demonstrate Bb persistence in the face of traditional IDSA treatment protocol. Regardless, he seems to have forgotten or dismissed as irrelevant the entire school of ILADS thought, and that is simply not a good thing to do.

I suspect that to many familiar with Lyme politics, this blog will come off as business as usual. That for me does not inspire confidence or trust.

 

[anciendaze]

It isn't just Lyme and borrelia, or even "minor" diseases, which raise questions about post-treatment disease. I've just learned, via a private contact, about an apparently healthy young adult who simply did not wake up one morning. None of the ordinary suspects, like drug abuse, seem to be factors. What we do hear is that he was treated for Rocky Mountain Spotted Fever some months ago, and declared free of the disease.

This is a tick-borne disease with an incredible 75% lethality, if left untreated. His was said to have been caught in time. We now wonder if the infection had been cleared, or if damage to his heart or CNS was missed in post-treatment follow up to the infection.

A test which could reveal a post-treatment pathological state would be welcome here.

 

[duncan]

In theory.