Understanding Infection-associated Chronic Illness: How the Immune System Responds to Persistent Infection

Distinguished Speaker Series with Michal Tal, PhD

Distinguished Speaker Series Transcript

 

Mihal Tal, PhD“I want to leave you with hope. I think we’re going to be unstoppable because I think that these are solvable problems. These are answerable questions. I think that there are already a lot of existing tools in immunology that just need to be brought into the fight, and we can change this.”

– Michal Caspi Tal, PhD

Michal Caspi Tal: In the chronic illness world, I think that there is something about hope with a capital ‘H’ that is precious. I think it always has to be. I want to talk a little bit about what my lab is doing, where I think we could go in the future and the hope that I have for how we move forward, how we solve this, and how we change this for those who come after us. So, I’ll tell you a little bit about some of the recent things that have come out of the lab, what the lab is working on now, and where we want to go. 

New Study Shows How Borrelia burgdorferi Evades the Immune System

Recently, we published a study in collaboration with Hanna Ollila’s lab where we compared people who’ve had Lyme and have had a diagnosis of Lyme versus people who’ve never had a diagnosis of Lyme. We found a genetic difference in a sweat protein that nobody—including me—had ever thought about before. We tested it against the bacteria in our lab, and we saw that it had a huge effect; we tested it in mice, and it had a huge effect. So that’s really exciting. We had another paper that came online yesterday that is one of these last papers from my postdoctoral work over at Stanford, where we actually managed to figure out some of how Borrelia burgdorferi, the bacteria that causes Lyme, manages to evade immune clearance. 

Michal Tal, PhDAny respectable pathogen that can establish a persistent infection needs to figure out your immune system to the point that it can evade it. The fact that it has persisted means that it was able to evade your immune clearance. And so, I got to that from a very interesting direction working on immune regulation, trying to understand these brakes on the immune response and how they impact the response to infection. The immune system has the power to kill you and obviously, nobody has any incentive for that to happen. So, there are a lot of mechanisms in place to put brakes on the immune system and reign it in. One of the huge developments in cancer over the last two decades has been reevaluating the question: can we take those brakes off? So in my postdoc, I was studying a particular checkpoint where this was turning into an exciting immuno-oncology target, and I said, ‘I want to look at how this checkpoint is used in infection.’ I realized that this checkpoint was being used to help you survive an acute infection, but created a vulnerability for pathogens to evade immune clearance and establish chronic infection much like it allows cancer cells to evade immune clearance. In an amazing collaboration with Irv Weissman, Balyn Zaro, and Jenifer Coburn we realized that the bacteria that cause Lyme disease manipulate this brake and that’s how I became fascinated with Lyme.  But I also became concerned about turning off this brake in cancer patients because I was concerned about what would happen if you used this on cancer patients during an active infection. Indeed, the clinical trials on this drug were ended due to increased death from infection, and I wish it hadn’t been tested during a worldwide pandemic.

Unlocking the Mysteries of Tick-borne Infections: Lyme Disease Biobank’s Tissue Collection Program Drives Research Momentum

Kirsten Stein and the Lyme Disease Biobank

BAL Leading the Way Series

 

“My family knows that after I die, my tissues will be donated to Lyme Disease Biobank to provide researchers with the vital material they need to solve this horrible disease. I urge anyone with chronic/persistent Lyme to register with NDRI today. Let’s end this suffering together.” 

-Kirsten Stein, Lyme Advocate

Lyme Disease Biobank®, led by Liz Horn, PhD, MBI, is central to Bay Area Lyme Foundation’s 10-year search for answers to Lyme’s most intractable questions and is the most important program in the Foundation’s mission to make Lyme disease easy to diagnose and simple to cure. 

The original Lyme Disease Biobank sample collection launched in 2014 focused on obtaining blood, urine, and serum samples from patients with early/acute Lyme disease. Once this program had been fully established, the Lyme Disease Biobank team explored adding tissue samples to the Biobank. Tissue samples could help researchers expand their investigations beyond the early stage of infection into how chronic/persistent Lyme and other tick-borne diseases impact the central nervous system, joints, and organs of Lyme patients. 

With the tissue bank objectives defined, the Biobank connected with specialist organizations to provide the critical support needed to support sample collection and make the development of a tissue bank a reality.

Post-Mortem Tissue Collection Planning

NDRILyme Disease Biobank established a key partnership with the nonprofit National Disease Research Interchange (NDRI) to provide logistics for post-mortem tissue collection for the new tissue program. The Biobank also partnered with MyLymeData.org, allowing Lyme patients registered with the Biobank to link their MyLymeData profile to their tissue donation if desired. Bringing these two resources together provides for the organizing and recovery of post-mortem (after death) tissue. It ensures samples include redacted (removes identifying information) detailed patient medical histories—an important nuance for Lyme disease researchers. 

“Although it is an emotional and difficult idea for anyone to plan to donate parts of their body to science after they have died, we believe that this decision is an important way for Lyme patients to change the course of Lyme disease research. Having access to tissues from the brain, heart, joints, and central nervous system of Lyme patients allows researchers to prove unequivocally that Lyme is present in tissue and contributes to patient suffering,” explains Linda Giampa, Executive Director, Bay Area Lyme Foundation and board member of Lyme Disease Biobank.

Young Hearts, Hidden Battles: A pediatric infectious disease physician’s perspective on Lyme disease and neuropsychiatric manifestations

Charlotte Mao, MD MPH

Distinguished Speaker Series Transcript

 

“Everything about this disease is infinitely more complex and nuanced than is taught to physicians.”

– Charlotte Mao, MD MPH

Charlotte Mao, MD MPHCharlotte Mao: Thank you Dana for that amazing introduction and Brandi too. I want to thank Brandi for so generously opening up your beautiful home for this event and Bay Area Lyme Foundation for inviting me to speak tonight about my personal perspectives as a pediatric infectious disease physician about Lyme disease in children, particularly neuropsychiatric manifestations. 

When Brandi asked if I might give a talk for this Speaker Series, I suggested this topic because, first, I hope there might be something instructive in some of my personal musings on key lessons I’ve learned about Lyme disease in the course of caring for children with this contested disease. Second, I want to highlight neuropsychiatric manifestations because I feel they generally are the least recognized by physicians as being potential manifestations of Lyme disease. Yet, taking into account all levels of severity, they are, in my view, actually quite common—certainly not uncommon—and when severe, they are among the most devastating of Lyme manifestations to the lives of children and their families.

New Study Reveals Potential Treatment for Neurologic Lyme Disease

Geetha Parthasarathy, PhD

FOR IMMEDIATE RELEASE

 

 New Study Reveals Potential Treatment for Neurologic Lyme Disease

Blocking certain fibroblast growth factor receptors is shown to be effective in reducing inflammation and cell death caused by neurologic Lyme infection in laboratory studies

PORTOLA VALLEY, Calif. April 18, 2024—Bay Area Lyme Foundation, a leading sponsor of Lyme disease research in the US, recently announced the publication of a laboratory study showing that fibroblast growth factor receptor (FGFR) inhibitors may be appropriate as an anti-inflammatory supplementary treatment for neurologic Lyme disease, for which there are no universally effective treatments. Published in the peer-reviewed journal Frontiers in Immunology, this study shows FGFRs are activated in response to both live and non-viable Lyme bacteria in preclinical brain tissue models. Further, inhibition of FGFR1, FGFR2, and FGFR3 may help mitigate the neuroinflammatory and neuropathogenic effects of infection by the bacteria that causes Lyme disease, Borrelia burgdorferi.  

“Our research shows a potential connection between neurological Lyme disease and several other neurological conditions, and this common pathway may explain why Lyme can be confused with many other conditions. Increasing our knowledge of FGFRs and their effect on the brain will help us understand the common mechanisms that may underlie Lyme disease and other neurological diseases,” said Geetha Parthasarathy, PhD, assistant professor at Tulane National Primate Research Center, Tulane School of Medicine, and a Bay Area Lyme Foundation 2019 Emerging Leader Award winner. “This data shows that FGFRs can be novel targets of anti-inflammatory therapeutics in Lyme patients with persistent neuroinflammation.”

“Our findings from this and our previous studies also offer important insight that may help to explain why some patients still experience chronic neurological symptoms even after a short course of antibiotics,” added Dr. Parthasarathy.

 New Study Demonstrates Protein May Provide Protection Against Lyme Disease

Mikki Thal, PhD

FOR IMMEDIATE RELEASE

 

 New Study Demonstrates Protein May Provide Protection Against Lyme Disease

Sweat protein protects against Lyme disease in vivo and is a potential therapeutic avenue for drug development

PORTOLA VALLEY, Calif. April 3, 2024—Bay Area Lyme Foundation, a leading sponsor of Lyme disease research in the US, recently announced the identification of an unknown common missense variant at the gene encoding for Secretoglobin family 1D member 2 (SCGB1D2) protein that increases the susceptibility for Lyme disease as well as two previously known variants. Published in the peer-reviewed journal Nature Communications, this study shows normal versions of the SCGB1D2 protein prevent infection by Borrelia in vivo and appear to be a host defense factor present in the skin, sweat, and other secretions, opening an exciting potential therapeutic avenue for Lyme disease. This research was also featured on NBC10 News in Boston.

“We are excited that our international collaboration with Hanna Ollia’s group and our co-authors has turned up such an exciting and unexplored avenue in the body’s defenses against Lyme disease,” said Michal Tal, PhD, Principal Scientist in the Department of Biological Engineering at MIT, and a Bay Area Lyme Foundation 2018 Emerging Leader Award winner. “This discovery reveals a human protein with protective activity against the bacteria that cause Lyme disease, which we hope could lead to a future path for exploring new methods to prevent and treat Lyme disease.”

This research has shown that the genetic variant of the SCGB1D2 which creates a misshapen protein appears to be specific for Lyme disease and has not been previously reported as associated with any other disease, phenotype, or infection. The researchers also found that about one-third of the population carries a genetic variant of this protein that is associated with Lyme disease in genome-wide association studies (GWAS).

Research Funded by Bay Area Lyme Foundation Identifies New Investigational Therapy Regimen Capable of Irreversibly Damaging Lyme Bacteria in Laboratory Tests 

Tim Haystead, PhD

FOR IMMEDIATE RELEASE

 

Research Funded by Bay Area Lyme Foundation Identifies New Investigational Therapy Regimen Capable of Irreversibly Damaging Lyme Bacteria in Laboratory Tests  

Inspired by research that targets cancer tumors, these new findings in Lyme could also lead to novel R&D strategies for other diseases 

PORTOLA VALLEY, Calif. November 1, 2023—Bay Area Lyme Foundation, a leading sponsor of Lyme disease research in the US, today announced the development of a potential new drug, HS-291, that targets and destroys Borrelia burgdorferi, the bacterium that causes Lyme disease. Published in the peer-reviewed journal Cell Chemical Biology, this laboratory study represents a novel paradigm shift for anti-microbial treatment research as it is the first to target and inhibit Borrelia burgdorferi HtpG (high temperature protein G), a specific type of enzyme within the bacteria that causes Lyme disease— a condition affecting nearly 500,000 new patients annually. The research was conducted at Duke University School of Medicine, with collaboration from University of North Carolina, Tulane University, and Stanford University, and HS-291 is currently in preclinical stage testing at UC Davis. 

“As Lyme disease is currently treated with broad spectrum antibiotics and there are no targeted treatments, we are particularly excited about this discovery, and hopeful that our novel Lyme disease therapeutic HS-291 will specifically destroy the Lyme bacterium without off-target effects or antibiotic resistance,” said Timothy Haystead, PhD, professor of Pharmacology and Cancer Biology, Duke University School of Medicine, Bay Area Lyme Foundation grantee, and co-lead author. “This research has been an incredible opportunity to leverage knowledge from oncology to Lyme disease in order to design an investigational therapeutic that could one day benefit hundreds of thousands of patients with Lyme.” 

This new discovery has implications beyond Lyme disease as it demonstrates that using the drug HS-291 to deliver cellular toxins to HtpG, a type of non-essential enzyme that assists the folding or unfolding of large and complex proteins, greatly expands what can be considered druggable within any pathogen and opens a whole new area of infectious disease research.  

Bay Area Lyme Foundation Now Accepting Applications for 2024 Emerging Leader Award and Grant 

Emerging Leader Award Call for Entries 2023

FOR IMMEDIATE RELEASE

 

Bay Area Lyme Foundation Now Accepting Applications for 2024 Emerging Leader Award and Grant 

Annual grant seeks to attract innovative researchers with a new approach for diagnosing and treating tick-borne diseases

PORTOLA VALLEY, Calif., October 26, 2023—Bay Area Lyme Foundation, a leading sponsor of Lyme disease research in the US, is announcing a call for entries for their 2024 Emerging Leader Awards (ELA), which aim to recognize U.S. researchers from academia or the private sector who bring new approaches to the field of Lyme disease and embody the future of Lyme disease research leadership. This year, the Foundation ELA will present a $150,000 award for a researcher who is at the post-doctoral level through associate professor level. 

While applicants must have a defined scientific approach to advancing diagnostics and/or therapeutics for Lyme disease, the grants are open to researchers from other therapeutic areas as well as those who have previously worked in Lyme disease research. Applications will be accepted through March 1, 2024 at 11:59pm, Pacific Time. The full criteria and application for this award can be found here. 

“The world is seeing firsthand the damage that infections can cause – both in acute and chronic forms –and Lyme is no exception. Even today, it presents a significant hurdle for the scientific research community,” said Wendy Adams, research grant director Bay Area Lyme Foundation. “We intend for our Emerging Leader Award to encourage creative, driven scientists to embrace the challenge of developing accurate diagnostic tests and effective therapeutics for various stages of tick-borne diseases.”

Bay Area Lyme Foundation ELA Winner Uses Metabolic Modeling to Predict 77 Unique Drug Targets in Lyme Disease Bacterium

Peter Gwynne, PhD

FOR IMMEDIATE RELEASE

 

Bay Area Lyme Foundation ELA Winner Uses Metabolic Modeling to Predict 77 Unique Drug Targets in Lyme Disease Bacterium

Results will help inform future research and development of new Lyme disease therapeutics

PORTOLA VALLEY, Calif., October 19, 2023—Bay Area Lyme Foundation, a leading sponsor of Lyme disease research in the US, today announced the findings of a study identifying new essential gene and enzyme drug targets in Lyme disease bacterium, which resulted, in-part, from a grant provided to Peter Gwynne, one of Bay Area Lyme Foundation’s 2022 Emerging Leader Award (ELA) winners. Published in the peer-reviewed journal mSystems, the study uses the most comprehensive metabolic modeling to date to predict 77 unique drug targets in Borrelia burgdorferi, the bacterium that causes Lyme disease—a condition affecting nearly 500,000 new patients annually.

“Lyme disease is often treated using long courses of antibiotics, which can cause side effects for patients and risks the evolution of antimicrobial resistance. Our research supplies the blueprint and scaffolding to build better Lyme disease therapeutics that do not have off-target effects for patients,” said Peter Gwynne, PhD, lead author on the study, research assistant professor at Tufts University School of Medicine, and Emerging Leader Award winner of the Bay Area Lyme Foundation. “Many of the 77 genes and enzymes predicted as essential represent candidate targets for the development of novel antiborrelial drug development.”

Current clinical guidelines recommend treatment of Lyme borreliosis with broad-spectrum antibiotics, which can pose risks to the patient’s microbiome. The bacterium that causes Lyme disease is extremely host-dependent, with a small genome and limited metabolism—making it an excellent candidate for the development of targeted, narrow-spectrum antimicrobials.

In the study, the researchers used in silico genome-scale metabolic computer modeling to construct a map of B. burgdorferi metabolism. This map was used to predict essential genes and enzymes that can be used as drug targets. Gwynne and the Tufts University School of Medicine research team validated these targets by repurposing existing drugs that kill B. burgdorferi in culture. While these drugs are not viable treatment options themselves, they provide a blueprint for future novel drug development.

Foundational Work Scores Results

John Aucott, MD

BAL 10-year Anniversary Series

 

10 Years of Collaboration Bringing Hope: How Dr. John Aucott’s Relationship with Bay Area Lyme Helped Get Groundbreaking Biobanks Launched to Fuel the Research Engine of Lyme Disease Investigations

 

John Aucott, MDIn this blog, part of our 10-year anniversary blog series, we talk with John Aucott, MD, Associate Professor of Medicine at Johns Hopkins University, Director of the Lyme Disease Research Center, about his work and how his investigations are helping us understand persistent/chronic Lyme infections. A long-term collaborator and grant recipient of Bay Area Lyme Foundation, Dr. Aucott reflects on his history with our organization, the ongoing plight of Lyme disease patients, and the slow growth in government funding for investigations into the disease. He talks about the early days of identifying the need for well-characterized samples from Lyme patients and his role in helping launch biobank programs, including his own SLICE Study Biorepository and BAL’s Lyme Disease Biobank. 

Bay Area Lyme: I want to take you right back to the very beginning of your relationship with Bay Area Lyme (BAL), the founding of your SLICE study and our Lyme Disease Biobank (LDB) and talk about everything that was happening 10 years ago. People talk about the “norming, storming and forming” stages of organizations, and there was an awful lot of activity going on 10 years ago in the world of Lyme disease. And so, please share your thoughts on what was happening around that time, your part in it, and how you came into the picture with BAL and our biobank.

SLICE Studies
The Study of Lyme disease Immunology and Clinical Events (SLICE), Johns Hopkins University Lyme Disease Research Center

John Aucott: My first memory is that I flew out to California and my agenda at that time was getting people interested in research. There was very little funding for Lyme disease research, and to some extent there still isn’t a great amount of funding for Lyme disease, especially the kind of research I do, which is clinical translational research. I’m an MD, so my research involves bridging basic science to human beings to patients. So, to be very candid about it, I was interested in getting BAL interested in my work. I pitched what we were doing. We had already set up the Johns Hopkins SLICE study, the Study of Lyme disease Immunology and Clinical Events. And at that point it was one of only two large scale biobanks collecting for Lyme disease. The other one is Dr. Gary Wormser’s, who still has a biobank in Valhalla, New York.

So, I was pitching the idea of a Lyme disease biobank to BAL, and this was a whole new concept. A biobank is a hard concept to sell initially because people don’t understand that setting up a biobank is like being Levi Strauss: It’s selling the Levis and the picks, and the shovels—not selling them the actual gold in your pocket. And it’s a hard pitch because people don’t understand that somebody has to supply the foundational work so that other people can mine for the gold. But BAL caught on to the idea that the biobank that we had at Hopkins was a crucial resource that would enable collaboration with other researchers to advance the scientific understanding of disease mechanisms and potentially identify and validate biomarkers for improving diagnostics and treatments.

LymeAid 2013
LymeAid 2014 Scientific Panel (from left): Wendy Adams, John Aucott, MD, Carin Rollins, and Bill Robinson, MD, PhD

Bay Area Lyme bought into the importance of this idea. The first thing that happened was you asked me to be on the BAL Scientific Advisory Board soon thereafter. BAL expressed support for the SLICE study’s biobank at Hopkins and you actually gave us one of our first grants to help support our biobank work. So, that was the first thing that happened. We applied for a grant, and we got a grant from BAL to help us because we had not yet gotten federal funding for it. So, that was one of the first grants to support it, and now in 2023 we are finally receiving our first NIH funding.

Bay Area Lyme Ambassador Shares Her Story

Guest Blog by Jessica Devine

 

Bay Area Lyme Foundation is one of the first sources of information I found when I was finally diagnosed.  I realized through the years that only a few resources could always be relied upon for accurate information based on scientific research. I also feel connected to BAL because I was bit in California by a tick that carried Lyme, Babesia, Bartonella, Erhlichia, Rocky Mountain Spotted Fever and more. I have always trusted their information for over a decade now. What they do and continue to do to help this community is something I will always be grateful for.

Jessica Devine and her family
Jessica Devine and her family

Creating an uplifting space for Lyme patients has been my dream since my first TV interview when a local station asked me to come on and share my story. Once on camera, I was filled with passion when given the chance to speak about my story, the injustices of Lyme disease treatment and getting a late diagnosis.

From there, people started reaching out to me needing help. I had kind of lost myself in my illness and slowly, through advocacy work, I gained a feeling that I can only describe as finding your true purpose. When I help someone, I have peace.

I found groups to be depressing and I knew the only way to have the group that best served a patient in the ways I needed was to create it myself. I wanted a solution based group that required all of its members to act with kindness. Alongside my own Lyme doctor’s methods, member polls and an accumulation of top resources, I finally was able to create the first Lyme Disease and Co-Infections Directory to cover almost any topic related to these diseases. An easy way for a patient to find the information quickly and learn. I feel the more we understand about these diseases, why we have the symptoms we have and how to help ourselves heal, we become more hopeful and empowered.