Tag Archives: Borrelia burgdorferi

borrelia burgdorferi_mice

GLA POV: Ability of Stationary Phase Persister/Biofilm Microcolonies of Borrelia burgdorferi to Cause More Severe Disease

by Timothy Sellati, Ph.D., Chief Scientific Officer, GLA

Ying Zhang, Ph.D., a Global Lyme Alliance (GLA)-funded investigator, and his team at Johns Hopkins University just published a seminal study in the journal Discovery Medicine titled “Stationary phase persister/biofilm microcolony of Borrelia burgdorferi causes more severe disease in a mouse model of Lyme arthritis: Implications for understanding persistence, post-treatment Lyme disease syndrome (PTLDS), and treatment failure”.

Lyme disease patients, infected via tick bite with the bacterial spirochete B. burgdorferi, are routinely treated with two to four weeks of Doxycycline, Amoxicillin, or Cefuroxime, which is curative in many cases if treated at the onset of the infection. However, research shows that despite treatment, up to 20% of patients continue to suffer lingering symptoms of fatigue, pain, or joint and muscle aches, and neurocognitive manifestations that last 6 months or more.  This clinically-defined condition is known as post-treatment Lyme disease syndrome (PTLDS).  A long-standing mystery is whether development of PTLDS reflects 1) persistence of B. burgdorferi in a patient’s tissues, consistent with chronic infection, or 2) self-perpetuating inflammation caused by tissue damage triggered by the original infectious insult.

Zhang and colleagues published several influential papers over the past five years revealing a potential answer to this mystery. His lab showed that in vitro stationary phase (non-growing) cultures of B. burgdorferi contain different morphological variants. These bacterial variants include planktonic (free-swimming) spirochetal forms, round body forms, and aggregated microcolony (biofilm-like) forms, which have varying levels of persistence (e.g., the capacity to tolerate antibiotic exposure) in comparison to the log phase culture, which mainly consists of rapidly growing spirochetal forms with no or few persisters. B. burgdorferi develops into these morphological variants under stress conditions but their relevance to severe and persistent Lyme disease was unclear until the publication of this new study.

Zhang et al. report that biofilm-like microcolony (MC) and planktonic (free-swimming spirochete and round body; SP) variants found in stationary phase cultures were not only more tolerant of exposure to antibiotics but also caused more severe arthritis in mice than the log phase spirochetes (LOG). Importantly, the authors show that the murine infection caused by LOG could be eradicated by Ceftriaxone (CefT) whereas the persistent infection established with MC could not be eradicated by Doxycycline (Doxy), CefT, or Vancomycin (Van), or Doxy+CefT or Van+CefT, but could only be eradicated by the persister drug combination Daptomycin (Dapto)+Doxy+CefT. This GLA-funded work establishes for the first time that varying levels of persistence and the severity of disease pathology caused by infection with B. burgdorferi is linked to different morphological forms of the spirochete.

The following facts highlight the importance of this novel discovery. The number of patients developing PTLDS, or chronic Lyme, which is less clinically well-defined, is on the rise; a trend that is consistent with the rise in annual incidence of Lyme disease, which is ~427,000 cases. The absence of a full understanding of the cause(s) of PTLDS hampers efforts to effectively treat patients suffering with this syndrome. The authors demonstrated that the degree of persistence or persistent infection varied with different inoculae, where biofilm-like microcolony inoculae produced a more severe and persistent disease that could not be eradicated by the current Lyme antibiotics or even some two-drug combinations but could be eradicated by the persister drug combination Dapto+Doxy+CefT. In contrast, the disease induced by the log phase spirochetal forms is more readily eradicated by CefT. That the inclusion of persister drug Dapto, in combination with Doxy and CefT, is critical for eradicating the persistent infection established by persister inoculae validates the relevance of Dr. Zhang’s GLA-funded efforts to screen for drugs or drug combinations against stationary phase bacteria enriched in persisters in vitro, which were published by Feng et al. in 2014 and 2015 (see influential papers here).

Finally, the reported findings may not only provide a new understanding of PTLDS and perhaps chronic Lyme disease, but also will inform and accelerate development and testing of novel persister drug combination regimens that can more effectively cure persistent Lyme disease in the future. GLA’s goal in the near future will be to support human clinical trials to evaluate if the persister drug combination could more effectively treat or cure patients with PTLDS/chronic Lyme disease.

Pictured: Image of joint histopathology taken from a mouse infected with micro-colony/biofilm-like B. burgdorferi. Read Dr. Zhang’s full paper here.


timothy sellatiTimothy J. Sellati, PH.D. is Chief Scientific Officer at Global Lyme Alliance

As GLA’s Chief Scientific Officer, Dr. Sellati leads GLA’s research initiatives to accelerate the development of more effective methods of diagnosis and treatment of Lyme and other tick-borne diseases.

catherine brissette_meet the researcher

Meet the Researcher: Catherine Brissette, Ph.D.

MEET THE RESEARCHER IS A BLOG SERIES TO INTRODUCE GLA-FUNDED LYME DISEASE RESEARCHERS MAKING A DIFFERENCE IN THE FIGHT AGAINST LYME DISEASE.


#MEETTHERESEARCHER
NAME: Catherine Brissette, Ph.D.
TITLE: Associate Professor, Biomedical Sciences
INSTITUTION: University of North Dakota

Catherine (Cat) Brissette received her B.S. degree in Zoology from Louisiana State University, her M.S. with Dr. Paula Fives-Taylor at the University of Vermont, and her Ph.D. from the University of Washington for her work with Dr. Sheila Lukehart on interactions of oral spirochetes with the gingival epithelium. She continued work with spirochetes as a postdoc with Dr. Brian Stevenson at the University of Kentucky, where she switched to the Lyme disease spirochete Borrelia burgdorferi. Her work with Dr. Stevenson involved studies of outer surface adhesions and regulation of virulence factors. Cat accepted a faculty position at the University of North Dakota in the Department of Microbiology and Immunology (now part of Biomedical Sciences), where she continues her work with pathogenic Borrelia species. Her lab is particularly interested in understanding why B. burgdorferi has a tropism for the central nervous system; that is, why the B.burgdorferi’s surface proteins interact with the hosts’ extracellular matrix, cells, and components of the immune system, and the regulatory mechanisms controlling the expression of these infection-associated proteins.

Dr. Brissette is also a member of GLA’s esteemed Scientific Advisory Board.

Drs. Eva Sapi, Ali Divan, Catherine Brissette, Janakiram Seshu, and Mayla Hsu, GLA’s Director of Research and Science, at GLA’s Lyme Disease Research Symposium 2017

GLA: WHAT MOTIVATED YOU TO FOCUS ON LYME AND TICK-BORNE DISEASE RESEARCH?

CB: My Ph.D. work involved a different kind of spirochete (one involved in periodontal disease); the challenge of working with a different pathogen (the agent of Lyme disease) was exciting.

GLA: WHAT ARE YOU WORKING ON NOW?

CB: We are working on several different aspects of neurological Lyme disease. More specifically, how the bacteria gets into the central nervous system in the first place, how the immune system responds, and how the bacteria adapt to that pressure. We have recently demonstrated that aspects of Bburgdorferi meningeal infections can be modeled in laboratory mice, which opens up a lot of research avenues. In particular, we are interested in the behavioral changes that occur as a result of meningeal infection. For instance, anxiety and memory problems are often reported by Lyme patients, particularly in people with long-term disease or Post-Treatment Lyme Disease Syndrome, and we want to understand how the Lyme disease bacterium and the host immune system contribute to these devastating symptoms. Having a small animal model allows us to more easily test potential treatments and interventions in the lab, prior to testing in people.

GLA: ARE YOU CONFIDENT WE WILL FIND A CURE?

CB: Absolutely. Lyme researchers, like Lyme patients, are tenacious and persistent. We won’t stop.

GLA-FUNDED RESEARCH GRANTS WITH DR. BRISSETTE INCLUDE:

  • “Adverse outcomes in gestation as a consequence of immune responses to B.  burgdorferi infection during pregnancy” (2017-18)
  • “Control of Bb DNA expression” (2016-17)

PUBLICATIONS RE: NEUROBORRELIOSIS

  1. Divan, A., Casselli, T.,Narayanan, S.A., Mukherjee, S., Zawieja, D.C., Watt, J.A., Brissette, C.A., Newell-Rogers, M.K. (2018) Borrelia burgdorferi adhere to blood vessels in the dura mater and are associated with increased meningeal T cells during murine disseminated borreliosis. PLoS One 13(5):e0196893. doi: 10.1371/journal.pone.0196893. PMID: 29723263
  2. Greenmyer, J., Gaultney, R.A., Brissette,A., Watt, J.A. (2018) Primary human microglia are phagocytically active and respond to Borrelia burgdorferi with upregulation of chemokines and cytokines. Front Microbiol. 9:811. doi: 10.3389/fmicb.2018.00811. PMID: 29922241
  3. Casselli, T., Qureshi, H., Peterson, E., Perley, D., Blake, E., Jokinen, B., Abbas, A., Nechaev, S., Watt, J.A., Dhasarathy, A@., Brissette@, C.A. (2017) MicroRNA and mRNA transcriptome profiling in primary human astrocytes infected with Borrelia burgdorferi. PLoS One 12(1):e0170961. doi: 10.1371/journal.pone.0170961. PMID: 28135303 @Co-corresponding authors
  4.  Brissette,A., E.D. Kees, M. Burke, R.A. Gaultney, A.M. Floden, and J.A. Watt (2013) The multifaceted responses of primary human astrocytes and brain microvascular endothelial cells to the Lyme disease spirochete, Borrelia burgdorferi.ASN Neuro 5(3). doi:pii: e00119. PMID: 23883071 Paper highlighted with a podcast: http://www.asnneuro.org/an/005/3/default.htm
  5. Brissette, C.A., H.M. Houdek, A.M. Floden, and T.A. Rosenberger (2012) Acetate supplementation reduces microglia activation and brain interleukin-1beta levels in a rat model of Lyme neuroborreliosis. J Neuroinflammation 9:249. PMID: 23134838

Click here to see GLA’s Research Report, detailing GLA’s research accomplishments

pre-exposure prophylaxis, borrelia burgdorferi

Promising New Research: PrEPping for Ticks

by Mayla Hsu, Ph.D.
Director, Research and Science
Global Lyme Alliance

Stopping Lyme disease before it starts. Promising new research based on pre-exposure prophylaxis, or PrEP.

 

It’s frustrating that there are so few ways to protect ourselves from Lyme disease. We use tick repellents, rodent and deer control, and search for ticks on our bodies. But none of these are completely foolproof. What we need is creative approaches that go beyond fundamental tick-bite prevention. Now, there is intriguing news of a potentially novel method of pre-treating humans with a protective antibody. If the approach is eventually successful, it may become possible to prevent infection even after being bitten.

Promising new research published recently in the Journal of Infectious Disease, although still very preliminary, paves the way for new ways to protect ourselves from Lyme disease. This study used a technique called pre-exposure prophylaxis, or PrEP.

The studies were led by Dr. Mark Klempner at Mass Biologics and the University of Massachusetts Medical School. Lyme disease results when people are bitten by ticks infected with the bacterium called Borrelia burgdorferi. This research team found that pre-treating mice with antibodies that bind to Borrelia burgdorferi protected the mice from becoming infected after being bitten by infected ticks.

Two of the antibodies had dose-dependent effect, which means that when less antibody was pre-treated, fewer mice were protected. When more antibody was pre-treated, more mice were protected. This is strongly suggestive that the protective effect was due to the presence of the antibody. In contrast, a control antibody that does not recognize Borrelia failed to protect mice, who became infected.

Antibodies are proteins made by our immune systems to stave off infections. Some antibodies stick to bacteria and prompt immune cells to find and digest them. Other antibodies, once bound to bacteria, recruit defense proteins called complement proteins, which poke holes in microbes and kill them. Like a lock and key, antibodies recognize specific bacterial shapes, sticking only to precise locations on them. In other words, they direct immune defenses to highly specific places, leaving healthy bystander cells safely alone.

But not all antibodies work well. Initially, the research group immunized mice with OspA protein, which is on the outer surface of Borrelia burgdorferi. In response, hundreds of antibodies recognizing OspA were produced by the mice. But only four were able to promote the killing of Borrelia. In addition, these four antibodies targeted not only Borrelia burgdorferi, but also Borrelia garinii and Borrelia afzelii, two species of Borrelia bacteria that cause Lyme disease in Europe and Asia.

When the four antibodies were analyzed in depth, the team found that they all bound the purified OspA protein and recognized defined domains, or portions of OspA. Identifying these particular parts of OspA that are bound by the effective antibodies showed important potential targets for design of future vaccines or new Borrelia-targeted drugs. It was these four that were tested, and found effective at protecting mice from infection by Borrelia-harboring ticks.

The research results also suggest that certain parts of the OspA protein are common to all three species of Borrelia, even though there are other genetic differences between them. It shows that there might be a way to potentially block all three from infecting people. Naturally, this which would be enormously useful for people at risk for Lyme disease in other parts of the world as well as in the U.S.

Although a limited number of mice were studied, this data shows what is called  “proof-of-concept” that an antibody pre-treatment strategy might work to prevent infection by Lyme bacteria. The authors were careful to interpret their results cautiously, noting that we do not yet know whether the protection might last the duration of tick season, or even whether protection against all strains of Borrelia burgdorferi is possible.

These findings are only the beginning of a process for developing new preventive medicine and vaccines. Nonetheless, they are encouraging. They provide a rationale for continuing to develop this strategy, and raise the hope that another protective tool might eventually be available in our defense against Lyme disease.


Mayla Hsu, Ph.D.
Director, Research and Science
Global Lyme Alliance

Mayla manages GLA’s research grant program, working with the Scientific Advisory Board and creating viable partnerships to help advance the development of a reliable diagnostic test, effective treatments and ultimately a cure for Lyme.

GLA: Lyme Disease Research Symposium Highlights

by Mayla Hsu, Ph.D
Director of Research and Science, GLA

GLA hosts top researchers to discuss Lyme disease research.

 

How can we understand Lyme disease better? Are there drugs that can kill persistent bacteria? Why do some Lyme patients get well, while others remain sick? Questions like these were discussed at the 2017 Global Lyme Alliance Research Symposium, which was held March 31-April 1 in Greenwich, CT.

About 30 scientists from all over the United States met to share the latest data about Lyme disease. These were researchers who have received GLA grants, as well as Scientific Advisory Board members whose expertise spans both the clinical and basic sciences.

Norma Russo, board member, GLA; Dr. Ying Zhang, Johns Hopkins University
Norma Russo, board member, GLA; Dr. Ying Zhang, Johns Hopkins University

One highlight was the discussion of a new way of using the mouse model of Lyme disease, in which evidence of brain penetration by spirochetes has been found. In the past, this has not always been easy to demonstrate, and the new data will fuel further discovery of its direct effect on neurological infection and brain function.

Another area of discussion was focused on the 10-20% of Lyme disease patients who despite antibiotic therapy are not cured. Such patients often suffer debilitating pain, fatigue, and neurocognitive difficulties, which are termed post-treatment Lyme disease syndrome (PTLDS). Understanding the immune response in PTLDS patients and what causes a chronic inflammatory state is the subject of GLA-funded work, both in the mouse model as well as in the study of human subjects.

The search for more effective treatments for Lyme disease patients was also presented in talks and posters. The bacterium that causes Lyme disease is called Borrelia burgdorferi. When grown in the test tube and treated with antibiotics, some bacteria survive as persisters, which are very slow-growing bacteria. In patients, persisters may be the cause of long-lasting symptoms. Therefore, new drugs and drug combinations that directly target persister bacteria are a focus of research interest.

Lew Leone_Armin Alaedini
Lew Leone, board member, GLA: Dr. Armin Alaedini, Columbia University

The symposium wrapped up with a lively group conversation about the diagnostic blood test for Lyme disease, with widespread agreement that the existing two-tiered test recommended by the Centers for Disease Control is unacceptably insensitive. What it should be replaced with, however, is still being debated.

Overall, GLA was pleased to host this gathering of premier-level scientists. The newer research underway will in due course be published in high-quality, peer-reviewed scientific journals consulted by authorities in the tick-borne research field. We look forward to seeing the final results and to supporting ongoing studies.

The Mighty White-Footed Mouse

by Mayla Hsu, Ph.D., GLA Director of Research and Science

What makes the white-footed mouse more mighty than a lab mouse when it comes to tolerating Borrelia burgdorferi, the bacterium that causes Lyme disease?

 

When we think of mice, we envision cute furry rodents with big eyes and little feet, and we don’t usually associate them with disease. But when we discuss Lyme disease, we need to consider the wild, white-footed mouse because it is one of the most important reasons for the spread and continued existence of this illness.

Dr. Alan Barbour at the University of California at Irvine is a pioneer in tick-borne disease research and a Global Lyme Alliance grantee. He published a recent article that explained why it is important that we study Lyme disease in wild mice and not only in lab mice.

Peromyscus leucopus—the scientific name of the white-footed wild mouse—is abundant in North America, along with its close relative, Peromyscus maniculatus. Together, they act as natural hosts, or reservoirs, for numerous disease-causing microbes. This means that they provide a long-term home for pathogens to survive in nature. They are also blood meal sources for vectors, like ticks, which transmit the pathogens from one animal to another.

One reason why we should study Lyme disease in wild mice, Dr. Barbour writes, is because they are genetically quite distant from lab mice. Peromyscus mice are actually more closely related to hamsters and voles than to lab mice, which are genetically grouped with the black rat. The genetic distance between the species might explain why there are important differences in how wild mice and lab mice respond to pathogens like Borrelia burgdorferi, the bacterium that causes Lyme disease.

Capture of wild field mice indicates that compared to other small mammals, they are more heavily burdened by ticks. Although there is variation between different studies, up to 100% of these ticks have been found infected with B. burgdorferi. Dr. Barbour summarized studies showing that in the northeast and north-central United States, P. leucopus mice typically get infected during the spring and summer months. As part of their immune response, they produce antibodies in their blood that recognize OspC, a protein on the outside of the bacteria. This also occurs in lab mice and in humans infected with Lyme disease, suggesting that this part of the immune response is common to all three.

blog_mayla_white footed mouse_quoteBut what’s different about wild Peromyscus mice is that they exhibit no obvious pathology. In multiple studies, even though the bacteria could be recovered from the urinary bladder, kidney, heart, spleen, ears, tails and joints, there was no evident organ damage. There was no variation in the types of immune cells found in infected animals as compared to uninfected animals. Infected animals did not appear to differ in their body weight from uninfected ones, suggesting that there was no obvious impact on overall health. And the amount of time that Borrelia-infected P. leucopus mice spent running on their exercise wheels did not differ from the uninfected mice.

In contrast, lab mice, when challenged by Borrelia burgdorferi infection, typically develop arthritis, carditis, and joint inflammation. Studying infection in these animals is useful to understand how the bacteria cause disease and the dysfunction of the immune response, but that only tells part of the story.

It’s not well-understood why Peromyscus mice don’t get sick from Lyme bacteria, but we do have some clues. It has been speculated that B. burgdorferi infections have occurred for hundreds of years in North America. With time, it is likely that the host-pathogen relationship evolved into a balance allowing both of them to survive. While in the mouse, the pathogen has to reproduce to sufficient levels so that it can enter ticks and be transmitted from one animal to another.  But the pathogen can’t kill its host, or weaken it so that it can’t efficiently reproduce. The mouse host must live long enough to have progeny, in order to produce a new generation of hosts in which the pathogen can be maintained.

Somehow, Peromyscus mice are able to tolerate Borrelia infection without any obvious illness. If we study these animals, especially by comparing the immune response in both uninfected and infected mice, we may be able to learn much that might explain how Peromyscus mice avoid the damage caused by B. burgdorferi infection.

Tick-borne Infections on the Rise in Gray Wolves

by Mayla Hsu, Ph.D., GLA Science Officer

As the majority of emerging infectious diseases stem from wildlife, the rise of tick-borne Infections in gray wolves is a good indicator of the future of Lyme and other tick-borne diseases.

 

Wild gray wolves evoke images of unfettered nature and animals loping freely through forests and meadows. But a new study of wolf populations in northwest Wisconsin shows that a high percentage of them are actually infected with tick-borne infections, which suggests that they are potentially suffering ill health.

Many of us know that rodents like squirrels and mice, as well as larger animals like white-tailed deer, are hosts for Ixodes scapularis, the tick that transmits Lyme disease. The bacteria that cause Lyme disease (Borrelia burgdorferi), anaplasmosis (Anaplasma) and ehrlichiosis (Ehrlichia), grow in these host animals and colonize the ticks who bite them to take blood meals. When infected ticks then bite humans, we too become infected by the bacteria, and get sick.

Scientists analyzed 373 blood samples drawn from wild gray wolves between 1985 and 2011. Using the Snap 4Dx test, which is used by veterinarians to test for tick-borne illnesses in dogs, they looked for antibodies that recognize these microbes. Their presence indicates past exposure to the pathogens. Overall, they found antibodies to B. burgdorferi in 65.6% of animals, Anaplasma antibodies in 47.7% and Ehrlichia antibodies in 5.7%. These findings show that tick-borne pathogens are common in gray wolves in Wisconsin, and as expected, the American dog tick Dermacentor, and I. scapularis tick vectors that transmit them were routinely found on the animals.

While the sex of the wolves was unrelated to the percentage infected, their age was important. A higher proportion of adult wolves had B. burgdorferi, Anaplasma, and Ehrlichia antibodies than pups. This is unsurprising, since greater age means increased probability of being bitten by ticks. Also, adult wolves move greater distances, with greater exposure to questing ticks, compared to pups, who generally stay near their den.blog_tick-borne-gray-wolves-2

The research also showed a 50% increase in the prevalence of B. burgdorferi between 1985 and 2011 among gray wolves.  The counties in which wolf exposure has increased the most are among the Wisconsin counties in which human Lyme disease has also expanded the most.  By contrast, the prevalence of heartworm, a parasitic disease spread by mosquito bites, did not change during this time frame, suggesting that conditions favorable to ticks, but not mosquitoes, may be driving disease spread.

Why should we care about tick-borne diseases in wild wolves? They are free-ranging animals whose exposure to ticks is greater than that of pets or humans. They go places that we don’t go, and humans do not remove ticks from them as they do from domestic dogs. Thus, they can be regarded as sentinels of infectious diseases in wilderness spaces. Nationally, the Lyme disease epidemic in humans is expanding, particularly in the Northeast, Wisconsin and Minnesota. Several studies suggest that climate change may favor the growth of ticks and mosquitoes. So, information about vectors and microbes in wild animals everywhere will help us to plan and implement measures for safeguarding public health. In the last 75 years, 71.8% of emerging infectious diseases came from wildlife.

But aside from illnesses that we as humans may acquire, the health of gray wolves is important for another reason. They are predators and preserve ecosystem health, by preventing the overpopulation of prey species. Whether gray wolves become severely sick from tick-borne illness isn’t well known, with a few documented cases of captive wolves losing weight after Borrelia infection. So far, it appears that the wild wolf population, rebounding from near-extinction, has not been harmed by tick-borne microbes. However, we have a responsibility to remain vigilant to health threats to all species and in all habitats, not just our own.

 

Symptoms of Lyme Disease

What are the effects of Borrelia burgdorferi on the body?

 

When early-stage Lyme is not properly diagnosed and treated, symptoms can worsen. Dr. Harriet Kotsoris, chief scientific officer with Global Lyme Alliance, discusses some of Lyme’s more debilitating symptoms in a recent podcast, “The Facts on Lyme Disease”. Below is an excerpt.


 

Host: How does Borrelia burgdorferi cause symptoms in the body?

Dr. Kotsoris:   Borrelia burgdorferi causes the symptoms in the body based on what organ systems it has particular affected. For example in the joints it will cause inflammation of the joint capsule, production of what’s known as a joint effusion, or a collection of fluid in the joint space, in doing so with inflammation cause pain, swelling, and limited mobility. If it affects the heart in Lyme carditis, classically it has affected the heart by creating what’s known as conduction delays. In other words, that the electrical signal from the top to the bottom of the heart may be impeded, and many patients with Lyme carditis develop a conduction system delay that can actually even progress to a complete heart block requiring either a temporary or permanent pacemaker.

Patients also can develop cognitive dysfunction, behavioral changes, if it affects the brain. Actually even although still controversial and not 100% proven, may actually lead to changes pathologically that resemble Alzheimer’s disease in the creation of what’s known as Amyloid plaques. This can lead to a dementing type of illness late in the disease. All things considered, Borrelia burgdorferi is a systemic illness, and by that I mean it can affect anything, eyes, skin, intestines, heart … Everything.

A detailed list of Lyme’s 300-plus symptoms may be found here.

Listen to the entire podcast here.

 

Podcast: The Facts on Lyme Disease

Understanding Lyme disease can be as complicated as the bacteria that causes it. Global Lyme Alliance is launching a podcast series to help make sense of it all. The podcasts will cover everything from basic Lyme disease facts to research initiatives.

The first podcast features GLA’s Dr. Harriet Kotsoris, Chief Scientific Officer, and Dr. Mayla Hsu, Science Officer. Dr. Kotsoris and Dr. Hsu help clarify some of the basic facts about Lyme disease, including symptoms and diagnosis. Below is an excerpt.


 

Host:  In this series of podcasts we’ll answer a few common questions and unveil some surprising truths about Lyme disease. In this first podcast we’re hoping to cover some basic facts about Lyme disease. To get us started, Harriet, what exactly is Lyme disease?

Dr. Harriet Kotsoris:  Lyme disease is an infectious disease that’s transmitted by a vector known as the blacklegged tick or Ixodes scapularis on the East Coast. Ixodes pacificus is on the West Coast. The disease is caused by a corkscrew shaped bacterium or spirochete known as Borrelia burgdorferi. It’s a multi-organ, multi-system disease. It’s acute onset may be heralded by an Erythema migrans or expanding bull’s-eye rash leading to flu-like illness consisting of headache, chills, fever, malaise, muscle aches and pains. Later stages of the disease can involve other organ systems of the body including the heart, brain, and joints. In it’s delayed or late disseminated phase it is particularly difficult and entrenched in the body, and more difficult to treat.

Host: What is the incidence of Lyme disease in America and around the world?

Dr. Kotsoris: The incidence of Lyme disease has been recently recognized to have grown exponentially. In the United States alone there are over 330,000 new cases reported each year. It is estimated that over 1 million in Europe have been affected by the disease and 1 in 25 people all around the world. These statistics come from European studies and actually one of our Scientific Advisory Board members, doctor Luc Montagnier, co-discoverer of the HIV.

Host: What are some of the tests used to diagnose Lyme disease? Are these tests dependable?

Dr. Mayla Hsu: The diagnostic test that is approved for Lyme disease testing here in the United States consists of 2 separate tests. The first is an ELISA or EIA Assay, and what that detects is antibodies that are specific for the Lyme bacterium, the Borrelia burgdorferi. Typically what happens is the person’s blood is drawn, and it goes through this first level of test and if it is positive or equivocal it goes through a second round of testing which is called the Western Blot. The Western Blot is a more specific test. It actually separates out the Borrelia burgdorferi proteins and then it looks for antibodies against 10 specific Borrelia proteins. There has to be 5 out of 10 possible antibodies against the bacteria that are present in the person’s blood for that test to be scored as a positive.

You asked whether or not these tests are dependable? Actually, they’re not, and that’s a big problem in Lyme disease because up to 60% of the two-tiered test negatives are considered to be possibly false negatives. We really don’t know in cases like that. If you get a Lyme disease test that’s positive, okay great. If tested positive now we can determine what your treatment is going to be, but if you test negative and you still have symptoms that are very much in line with Lyme disease it’s very hard to know if you were actually negative or not.

Below is the the full podcast with Dr. Kotsoris and Dr. Hsu. They continue their overview of Lyme disease, discussing diagnosis, treatment and prevention.


 

Follow Global Lyme Alliance on SoundCloud to hear future podcasts.

Blood and Water: How Infection Changes Tick Behavior

By Hannah Staab

In order to survive, ticks constantly struggle to balance their two vital resources: blood and water. However, a tick’s maintenance of blood and water are in direct competition with one another, forcing the ticks’ behaviors to shift back and forth in an inefficient manner. Ticks need three blood meals to provide nutrients and energy, promoting development from larva to nymph to egg laying adults. To obtain a blood meal, ticks quest from the top peaks grasses and leaves, latching onto any potential host that passes. Ticks also need to sustain a healthy water level to stay alive. To ingest water, ticks don’t drink like we do; their bodies absorb water by extracting water vapor from the atmosphere while they are closer to the ground.

Consequentially, the priorities of blood and water are in direct conflict, one requiring the tick to be on the ground, and the other prompting the tick to climb to the highest perch possible. In addition to luring the tick in the opposite direction of water, waiting for hosts on top of long strands of grass also exposes the tick to the sun and drier air, causing dehydration. Uninfected ticks spend most of their time trying to balance these two needs, absorbing water while they are on the ground, climbing up to the tips of vegetation while looking for hosts, then returning to ground level when they start dehydrating. However, for ticks infected with the Borrelia burgdorferi bacterium, which causes Lyme disease, their priorities shift in favor of finding a blood meal.

It is not unexpected then that a vector-borne disease such as Lyme interferes with the behavior of the vector. When other disease vectors such as mosquitoes, sand flies, and tsetse flies are infected with a pathogen, the presence of that microbe in their bodies alters their behavior to make them bite more frequently, and aim to bite more people. The behavioral changes in mosquitoes, ticks, and other disease vectors can all be explained by the pathogen’s drive to find a host and reproduce as much as possible. In the case of the tick, the Borrelia burgdorferi bacterium manipulates the metabolism, and maybe even the expression of certain genes, to amplify the tick’s impulse to search for blood meals, and silences its drive to return to the ground for water.

More research is needed to understand how the bacterium causes these behavioral changes, but it is possible that the bacterium’s presence modifies the function of certain tick genes involved in metabolism, which has been shown for another pathogen called Anaplasma. Current studies on this topic have revealed that uninfected ticks pursue humid areas for host-seeking and to help satisfy their water needs, choosing areas with about 80% relative humidity. However ticks infected with the Lyme bacterium preferred areas with 70-75% relative humidity, and also chose higher questing positions, showing that they are more tolerant of water loss, and are not as heavily impacted by dry conditions. The Lyme bacteria can even change physical features of the tick, with infected ticks having a bodily fat content 12.1% higher than uninfected ticks. By causing this physical change, the bacterium confers on the tick more energy reserves so it can spend a longer time climbing vegetation and searching for a host.

The Borrelia burgdorferi bacterium causes a series of metabolic adaptations that allow the infected tick to prioritize finding a blood meal over maintaining a certain water balance. These adaptations have also made infected ticks more suited to survive the challenging weather conditions that will come with climate change. Along with increasing temperatures, some areas of the globe are projected to become significantly drier. Therefore when tick populations encounter these warmer weather conditions, the Lyme bacterium will make them hardier and more likely to survive. It is possible that areas experiencing hot and dry conditions will have a higher density of infected ticks, and therefore increased the risk for humans to contract Lyme disease. The intersection of infection, tick behavior, and climate are all factors we need to be conscious of when we consider Lyme disease awareness.

For more on Lyme disease and climate change, click here

Lyme Disease Needs Better Test, Better Answers

Dr. Harriet Kotsoris, Chief Scientific Officer, Global Lyme Alliance and Dr. Mayla Hsu, Science Officer, Global Lyme Alliance

It’s now 35 years since a corkscrew-shaped bacterium was identified as the cause of Lyme disease. But we still have no safe and effective vaccine, no reliable diagnostic test and no adequate therapy.

What we do have is tens of thousands of lives annually devastated by significant health, personal and financial costs.

The National Institutes of Health, the leading funding body for biomedical research in this country, should scale up research funding for Lyme disease. In its absence, nonprofit organizations like ours have taken up the challenge, while hundreds of thousands suffer in misery from a spring fever that for some may not end.

Lyme disease, first described more than 40 years ago, now infects more than 320,000 Americans each year, and has been identified in every state. Transmitted by black-legged tick bites that peak in the warm months, Lyme disease is now the country’s most common illness spread by a bug bite. Symptoms range from skin rashes to fatigue and joint pain, and for most people, a few weeks of antibiotics are enough to clear the infection. However, researchers at the Lyme Disease Clinical Research Center at Johns Hopkins University have shown that about 10 percent to 20 percent of those infected progress to chronic multi-organ illness, such as severe musculoskeletal pain, cardiac failure and neural impairment, including memory and cognitive loss.

Although the causes of post-treatment Lyme disease syndrome, or PTLDS, are unknown, its devastating toll is well-documented. It’s a condition that can mean months and even years of disability, with a tremendous impact on school attendance and employment. Researchers at the Centre for Infectious Disease Control in the Netherlands calculated more than nine years of healthy life lost in people with persistent Lyme disease. Recently, it was estimated that health care costs for Lyme disease patients exceed $1 billion per year, according to Dr. John Aucott of Johns Hopkins University School of Medicine.

Early diagnosis, then, should be key to reducing this health and economic burden. What complicates the treatment of all Lyme disease patients, however, is the lack of a definitive diagnostic test. The standard blood test detects antibodies that recognize the Lyme bacteria, which is called Borrelia burgdorferi. This test is laborious and lacks sensitivity, correctly identifying only 29 percent to 40 percent of patients who have a skin rash commonly associated with tick bites. Furthermore, at least 20 percent of patients do not even develop a skin rash.

Read the complete article here.

The article first appeared as an op-ed in The Hartford Courant on March 6, 2016.