Tag Archives: timothy sellati

Ixodes scapularis ticks

GLA POV: Microbiome analysis of Ixodes scapularis ticks from New York and Connecticut

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

GLOBAL LYME ALLIANCE’S CHIEF SCIENTIFIC OFFICER OFFERS PERSPECTIVE ON NEW RESEARCH OUT OF COLUMBIA UNIVERSITY WITH ANALYSIS OF BLACKLEGGED TICKS

 

Ixodes scapularis, the blacklegged tick, is among the most clinically important tick species in the U.S. Not only does this tick transmit the most common vector-borne infectious agents in the U.S., Borrelia burgdorferi sensu stricto (s.s.) and B. mayonii, which cause Lyme disease, but it also transmits the greatest diversity of pathogens of any tick within the US. In addition to Lyme disease, other tick-borne illnesses include babesiosis (Babesia microti), anaplasmosis (Anaplasma phagocytophilum), Borrelia miyamotoi disease (B. miyamotoi), ehrlichiosis (Ehrlichia muris eauclairensis) and tick-borne encephalitis (Powassan virus).

It is this diversity of pathogens and the public health concern they provoke that spurred Rafal Tokarz (a Global Lyme Alliance-funded investigator) and colleagues to use high-throughput sequencing of the tick microbiome to catalogue the full range of microbes (i.e., bacteria, archaea, protists, fungi and viruses) found in ticks collected throughout New York and Connecticut.

Dr. Tokarz’s lab examined 197 individual I. scapularis adults and pools from 132 adults and 197 nymphs. Focusing on Borrelia, they found two species in the ticks tested, B. burgdorferi s.s. and B. miyamotoi, which were found in 56.3% and 5.07% of individual ticks, respectively. Importantly, these results were consistent with previously published surveillance studies of I. scapularis by the Tokarz group and others. Across the five sites where ticks were collected, the prevalence of B. burgdorferi s.s. ranged from 40% to 62.5%. Two other human pathogens transmitted by black-legged ticks, B. mayonii and Ehrlichia muris eauclairensis, have been detected in up to 3% of I. scapularis in the Upper Midwest, but were not detected in the ticks collected for this study, suggesting these pathogens have yet to establish themselves, at least at detectable levels, in the northeast.

Another human infectious agent, a protozoan parasite, B. microti was found in 7.6% of ticks, but two other species of Babesia, B. duncani and B. divergens, which also have been implicated in babesiosis in the U.S., were not found.  The absence of B. duncani and B. divergens sequences in their data suggests that I. scapularis is not a vector for these species, at least not in the northeast.

Reports of Bartonella DNA in tick species (i.e., I. scapularis, I. affinis, and I. pacificus), coupled with detection of this bacterium in patients with Lyme disease, have led to the perception that Bartonella is a tick-transmitted pathogen. Recently, there has been an upsurge in Bartonella testing of patients with a suspected tick-borne illness. However, Bartonella sequences were not found in the hundreds of ticks tested as part of this study. The authors speculated that differences between their findings and published reports might have several explanations, which they sought to investigate. One possibility was that the presence of microbial DNA within a tick does not conclusively establish the tick’s competence as a vector, or the viability of the microbe within the tick. The DNA may instead be a remnant of a previous blood meal, and there’s enough of it to be detectable by sensitive genetic techniques such as PCR. Another possibility is that in previous studies, the Bartonella detection techniques were not specific enough. In a 2004 study by Adelson et al., 33% of I. scapularis nymphs in New Jersey had Bartonella DNA. However, the ‘molecular tools’ used for PCR screening could not discriminate between Bartonella DNA and that of a wide range of soil bacteria. So, trace amounts of soil bacterial contaminants in ticks could explain the wrong conclusion that I. scapularis harbors Bartonella. To test this hypothesis, Tokarz’s group designed molecular tools that could distinguish between Bartonella and soil bacterial DNA. Again, they confirmed a lack of Bartonella in the 45 ticks from their study but using the Adelson group’s reagents, an apparent 13% of ticks from NY and CT were now positive for Bartonella.  These findings point to the possibility of false positive results if reagents used for PCR-based tests are not optimized for specificity.

These results do not, however, exclude the possibility that a subset of Lyme disease patients may indeed have a Bartonella infection. In fact, well-accepted means of exposure to Bartonella include contact with infected domestic cats or flea bites. Thus, a conclusion one can draw from this current study is that Lyme patients diagnosed with Bartonella are more likely infected by cats or fleas and not by I. scapularis ticks.  Although not mentioned in this study, the results presented offer a cautionary tale regarding PCR-based diagnosis of Bartonella or any other pathogen. One must be certain that the molecular tools used to detect Bartonella DNA are highly specific to that organism. Care must be taken to avoid detecting a person’s likely exposure to a wide variety of soil bacteria, something that can easily occur in daily life.  The use of non-specific molecular tools in this diagnostic scenario might generate false positives – a possibility that will hopefully be explored by other researchers and diagnostic testing companies.

The survey also revealed a high co-infection rate with 19% of all ticks being co-infected with known pathogens (A. phagocytophilum, B. burgdorferi s.s., B. miyamotoi, B. microti, and Powassan virus). In addition to bacteria, the tick microbiome was found to include a wide variety of common viruses [e.g., phleboviruses 1 and 2 (73%), South Bay virus (22%), Suffolk (10%), and the pathogenic Powassan virus (3.6%) ticks] as well as three rare viruses and even a filarial worm.

In conclusion, this new study provides insight into the impressive microbial diversity within I. scapularis in NY and CT. In conjunction with recently published microbiome studies from other geographical sites, scientists now possess a better understanding of the spectrum of agents harbored by I. scapularis, which can serve to focus research and clinical treatment.  Recognition of the multitude of pathogens found within black-legged ticks also should drive efforts to develop blood and urine based multi-pathogen diagnostic tests instead of just asking whether a patient has Lyme disease or not.  GLA is pioneering the advancement of novel “NextGen” multi-pathogen diagnostic tools through funding of companies and researchers at the top academic institutions in the country.


Read study here.

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.

outbreak news_podcast_lyme disease

Podcast: Outbreak News Interview on Lyme Disease, TBDWG, and IDSA

Robert Herriman with Outbreak News interviews GLA’s Chief Scientific Officer Timothy Sellati, Ph.D. to discuss Lyme disease, the Tick-borne Disease Working Group, and the IDSA

 

Read the complete transcript below or listen to the podcast:

 

Robert Herriman: Well hey everybody, this is Robert, and welcome to Outbreak News Interviews. Now the Federal Tick-Borne Disease Working Group recently released their first report to Congress about one year after the panel first convened. The Infectious Disease Society of America, or the IDSA, responded to the report in a letter that contained some criticisms of the report. So what is the Federal Tick-Borne Disease Working Group, what’s in the report, and what did the IDSA have to say? Well joining me to discuss these issues is Chief Scientific Officer for the Global Lyme Alliance, Timothy Sellati, Ph.D. Dr. Sellati, welcome to the show, sir.

Timothy Sellati: Thank you for having me.

Robert Herriman: You bet. So Dr. Sellati, let’s go ahead and start out with some basics ’cause some people may not be aware of this. What is the Federal Tick-Borne Disease Working Group, what’s their mission, and what’s the personnel composition of this group?

Timothy Sellati: So the Working Group was established as part of the Congress’s passage of the 21st Centuries Act, back in December 2016. The intent of that Act was to promote new healthcare initiatives for addressing array of public health issues, and one in particular was the advancement of research on tick-borne diseases. So with that as a backdrop, the US Department of Health and Human Services established the Federal Advisory Committee, the Tick-Borne Disease Working Group. So the Working Group is comprised of 14 voting members, there were seven public members and seven Federal members, and the composition of the Working Group was really drawn from a diverse group of professions. We had individuals that are world renounced research scientists, and physicians from top tier academic institutions and hospitals, subject matter experts from government agencies, as well as key stakeholders from the public sector including patients, and their advocates from several Lyme and other tick-borne disease nonprofit organizations.

Robert Herriman: Okay. So they recently released their first report, it’s a pretty hefty 108-page document. Dr. Sellati, what did you find good and important in the report?

Timothy Sellati: So I think some of the most important or key recommendations out of the report really related to epidemiology, and ecology, that was one of the subcommittees of the Working Group. And there, it was really driven home, the idea that Lyme disease surveillance criteria, which is a criteria that the CDC the Centers for Disease Control and Prevention, use for calculating the number of Lyme disease cases that occur annually. Those really should be used for surveillance purposes alone, and not for diagnostic purposes. The other important take home message from the prevention subcommittee was a focus on development of anti tick feeding vaccines, and really trying to work with key stakeholders to build trust via transparent mechanism to help examine and discuss the past Lyme disease vaccine activities, what some of the issues were with it, and the potential for adverse events so that that information coming from a number of different sources could help inform future vaccine development in Lyme disease. In terms of diagnosis, the real take home message was the importance of evaluating new technologies or approaches for the diagnosis of Lyme disease and other tick-borne diseases because of the inherent limitations with the current two-tier testing method. And the importance of including children in the process of diagnostic test validation as well, because children are particularly prone to the devastating consequences of dealing with Lyme disease, or other tick-borne diseases.

Timothy Sellati: In terms of treatment, I think conduct of additional clinical trials using appropriate target populations where gaps may exist. And there really, the glaring gap is with respect to patients, that experience, persistent symptoms and disability and diminished quality of life following the current standard of care, which is 10 to 28 days of antibiotics. So it’s really important to understand, this really came through as the overall gestalt of the report, that Lyme disease can be treated with antibiotics, but as many as 10% to 20% of infected individuals do not respond favorably to those antibiotics, so they go on to develop what we call Post Treatment Lyme Disease Syndrome, or in some circles, chronic Lyme disease. And so it’s really important to really address that gap in our understanding of how best to treat that patient population.

Timothy Sellati: And then the one last thing, and this was really a common theme that came out of all of the subcommittees’ reports, was the need to allocate increased funding for tick-borne diseases in the areas of research, treatment, and prevention, and have it really pegged to the burden of illness. So proportionally, there is much less federal funding to tackle tick-borne diseases than there are funding for other infectious diseases where the number of cases per year are considerably smaller.

Robert Herriman: Yeah. Now, were you 100% on board with everything in the report, or were there any issues that you had a problem with?

Timothy Sellati: I didn’t have any issues per se, with the report, as much as a concern about one of the recommendations. And this related to the protection of the rights of license and qualified clinicians to use individual clinical judgment to diagnose and treat patients in accordance with the needs and goals of each individual patient. I’m sort of reading that, verbatim almost, and while I don’t have any concerns about allowing licensed and qualified clinicians to care for their patients as they see fit, I also recognize that as a result of desperation on the part of some patients that have dealt with Lyme and other tick-borne diseases for years, if not decades, they are driven to seek out medical care from clinicians using treatment options that have not been carefully vetted by the scientific research establishment, or the medical research establishment. And so there’s a concern that there are some treatment options out there that really have not been proven to effectively treat the symptoms or the diseases that these desperate patients are dealing with.

Robert Herriman: Not too long after the release of the Working Group’s report, the IDSA sent a letter to DHHS Secretary Alex Azar, and it contained some criticisms of the report. You responded to the letter in a post on the Global Lyme Alliance website. Can you spend some time talking about that?

Timothy Sellati: Sure.

Some of the criticisms leveled by the IDSA that really caught my attention was that they had significant concerns with the Working Group’s lack of transparency, and minimal opportunities for meaningful public input. And I just didn’t understand the basis for that criticism, given that the Working Group was really comprised of so many different subject matter experts, and physicians that are treating patients, and the patients themselves, that I think the greater concern on the part of IDSA is that perhaps they didn’t have as much input into the report, or the content of the report, that came out of the Working Group’s extensive efforts.

Timothy Sellati: The IDSA also suggested that some of the recommendations of the working group would “cause significant harm to patients in public health,” and they really urged Alex Azar to ensure that the Federal government response to tick-borne disease’s fallacy rooted in the best available scientific evidence. And you know, part of the problem is in the controversy surrounding Lyme disease, is that the IDSA takes a strict parochial approach to considering Lyme disease, and the consequences of infection with bacteria that causes Lyme disease. From their perspective, they think Lyme disease, or promulgates this idea that Lyme disease is easily treated, and it’s easily diagnosed, and only very rarely does it result in lasting consequences of infection. But there is more and more well established scientific evidence in the main stream literature that argues against that very narrow understanding or narrative that IDSA wants to push forward.

Robert Herriman: Now, going to your first point, on the Working Group, is there any former or current IDSA members on that Working Group? I mean, do you know that?

Timothy Sellati:  Yes, I believe there are.

Robert Herriman:  Okay.

Timothy Sellati: I believe there are. But on the flip side, there are also, from what I understand, members of the ILADS organization as well. The composition of the subcommittees also was careful to include research scientists and physicians that really span the spectrum from IDSA on one of the end of the spectrum, to ILADS on the other. So I really do think that within the limited, within the capabilities of the Working Group, they were as intent as possible, in terms of hearing the voices of a wide variety of individuals. And again, to some extent, maybe IDSA would like to have had a larger bullhorn in terms of influencing the Working Group’s final report to the Congress.

Robert Herriman: So I just take it from your previous answer, that you don’t think most of the IDSA criticisms really hold a lot of water?

Timothy Sellati: No. No, I really don’t. And that’s what really spurred me to write this rebuttal in the first place. Again, I believe many of IDSA’s criticisms stem from the fact that the overall content of the report doesn’t necessarily fit into their mantra that Lyme disease is easy to diagnose, it’s easy to treat, and only very rarely results in lasting consequences of infection. So when you come into trying to solve a problem with that mindset, it limits how you approach trying to solve that problem.

Robert Herriman: Okay. Well, for the audience if you haven’t seen any of this, I will put up a link to Dr. Sellati’s rebuttal on the website when I publish the podcast, and I’ll also put up a link to the IDSA letter, and you can read it, and you can judge for yourselves. Dr. Sellati, any final thoughts on any of these issues?

Timothy Sellati: Yes, I’m glad you asked. So there is one final thought. As far as the report is concerned, I think there was a very important section in the report titled, “Looking Forward,” and in my opinion, I think one of the most important take home messages from that section was the need to develop and disseminate more comprehensive clinical education that highlights the diversity of symptoms that Lyme and other tick-borne disease patients might present with, expand the geography of infecting tics, and also the limitations of the current testing procedures. So I think if we do a better job of communicating to clinicians, and maybe even at the level of medical school students, the complexity of Lyme disease, and what some of the true limitations are in terms of prevention, diagnosis, and treatment, they will be better prepared to take care of the diversity of patients that they see during their practice.

Robert Herriman: Well very good. Well, I wanted to thank you Dr. Timothy Sellati for joining me to discuss these very important issues, I appreciate it, sir.

Timothy Sellati: Thank you very much.

scientific advisory board

GLA Counters IDSA’s Criticisms of Tick-Borne Disease Working Group Report

GLA’s Chief Scientific Officer Provides Evidence-based Rebuttal of IDSA Letter to Head of HHS and Tick-Borne Disease Working Group Report

 

by Timothy J. Sellati, Chief Scientific Officer, Global Lyme Alliance

Last month, the Tick-Borne Disease Working Group (TBDWG) published its first report to the U.S. Congress, outlining an integrated, multi-pronged approach to the growing public health challenges posed by tick-borne diseases in the U.S. In response shortly thereafter, the Infectious Diseases Society of America (IDSA) sent a letter to to the Secretary of the U.S. Department of Health and Human Services (HHS) stating that if some key recommendations of the TBDWG are implemented, it “would cause significant harm to patients and public health.”

Below is a rebuttal to IDSA’s unfounded criticisms of the TBDWG, which we find hyperbolic in light of the hundreds of man hours worked on the part of dozens of stakeholders dedicated to collecting, collating, and drafting a roadmap to advance the prevention, diagnosis, and treatment of patients suffering from Lyme and other tick-borne diseases.

IDSA’s letter suggests that there are “significant concerns with the working group’s lack of transparency and minimal opportunities for meaningful public input.”

  • The basis for this concern is unclear given that a substantial effort was made to be inclusive of professionals within the academic research community, physicians at renowned academic institutions and in private practice, as well as members of the general public in the form of patients suffering from Lyme and other tick-borne diseases and their advocates. Through contacts with their colleagues and fellow patients sitting on the TBDWG a free flow of ideas and opinions has passed between various stakeholders not part of the working group as well as those on it. The more likely concern of the IDSA is that it could not control the working group’s deliberations and final report through which it means to ensure consistency with the society’s long-held, and some would argue entrenched, ideas about tick-borne disease. Paramount is IDSA’s long-held view that Lyme disease is easy to diagnose, easy to treat, and only very rarely results in lasting consequences of infection. On the contrary, the overwhelming consensus among tick-borne disease researchers is that Post Treatment Lyme disease Syndrome occurs in 10 to 20% of those who received early treatment.

 

IDSA’s letter also suggests that if implemented, some recommendations of the TBDWG “would cause significant harm to patients and public health.”

  • Besides IDSA’s having only very limited support in the peer-reviewed scientific and medical literature regarding unsafe alternative treatment options, this hyperbole seems intended to spread fear, especially when one takes into consideration tick-borne disease researchers’ ever-evolving clinical understanding of Lyme disease, as opposed to the IDSA’s obsolete mantra that Lyme is easy to diagnose, easy to treat and only rarely results in lasting consequences of infection.

 

We urge you to ensure that the federal government response to tick-borne diseases is solidly rooted in the best available scientific evidence.”

  • Any claim that the TBDWG is not solidly rooted in the best available scientific evidence is unfounded. TheTBDWG report draws from the efforts of subject-matter experts from such diverse organizations as Johns Hopkins University School of Medicine; Office of the Secretary, U.S. Department of HHS;Stanford University Lyme Disease Working Group; Deputy Director, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention (CDC); Chief, Bacteriology and Mycology Branch, National Institute of Allergy and Infectious Diseases (NIAID); Medicare Hospital Health and Safety Regulations, Centers for Medicare and Medicaid Services, U.S. Department of HHS; Population Health Sciences and Health Services Research Center of the Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital; Vector-Borne Disease Laboratory; and Maine Medical Center Research Institute, just to name a few.

 

IDSA suggests that the makeup of the TBDWG is “skewed to individuals with perspectives that do not align with the overwhelming majority of scientific evidence regarding the diagnosis and treatment of Lyme disease.”

  • Evidently, one organization’s definition of “skewed” is another group’s diverse voices, opinions, and peer-reviewed evidence. Ultimately it does not benefit the scientific and medical research enterprise nor the Lyme and other tick-borne disease patient community to hew to the notion IDSA promulgates, which is that “Lyme disease is easy to diagnose, easy to treat, and only very rarely results in lasting consequences of infection”. Moreover, one could effectively argue that at least a subset of IDSA members hold perspectives about the persistence of Lyme borreliosis despite initial antibiotic treatment and see the desperate need for alternative treatment strategies that “do not align” with current scientific evidence.

 

While IDSA acknowledges that the CDC case definition for Lyme disease is intended for use as an epidemiological tool, they suggest “it is it is incorrect to promulgate the notion that the components of the surveillance definition should not be used for clinical diagnosis”.

  • However, it is important to note as the CDC itself mentions throughout its webpage that the case definition provided is for purposes of surveillance. Nowhere is it mentioned that the case definition criteria listed should be used for clinical diagnostic purposes alone. The CDC goes on to state that “Surveillance case definitions establish uniform criteria for disease reporting and should not be used as the sole criteria for establishing clinical diagnoses, determining the standard of care necessary for a particular patient, setting guidelines for quality assurance, or providing standards for reimbursement.” Finally, the spurious nature of IDSA’s suggestion that components of the surveillance definition could or should be used for clinical diagnosis is evident in the fact that CDC research has confirmed that annual clinical case numbers for Lyme disease are approximately 10-fold higher than the number reported by the CDC. This upward revision of annual Lyme disease cases suggests that considerably more early Lyme diagnoses are being missed than are the result of inaccurate, ultimately non-Lyme, diagnoses being made.

 

IDSA acknowledges that “some patients who are successfully treated for Lyme disease continue to suffer from persistent symptoms after treatment”.

  • This statement is illogical, however, because a patient who continues to suffer from symptoms caused by infection cannot or should not be classified as successfully treated.

 

IDSA states that “There is clear, widely accepted scientific evidence indicating that a 10-28-day course of antibiotics, depending on the stage of Lyme disease, will kill the Lyme disease bacterium in humans in all but the rarest of cases”.

  • Unfortunately, IDSA refuses to acknowledge that there also is clear, widely accepted and compelling scientific evidence indicating that 10 to 20% of patients receiving a 10-28-day course of antibiotics progress to Post-Treatment Lyme Disease Syndrome, which has a clear clinical definition, or the more broadly clinically-defined state of chronic Lyme disease. If one considers the number of CDC-reportable cases for 2016 of 364,290 (based on surveillance case reporting to CDC multiplied by a 10-fold factor to account for estimated underreporting) then 36,429 to 72,858 patients annually progressing to PTLDS/chronic Lyme disease cannot reasonably be considered a rarity.

 

IDSA supports more research to improve diagnostic tools for Lyme disease and they correctly state that it is essential that clinical education is rooted in the best currently available evidence.

  • Yet it is unclear that medical school educators are explaining to students that the best currently available evidence suggests that a large percentage of patients suffer persistent symptomatology as a result of misdiagnosis of early Lyme disease due to deficiencies in the current two-tier test. It is also unknown whether students are instructed in the atypical size, shape and coloration of the erythema migrans (EM) rash, rather than the classic “bull’s-eye” rash, that can be observed in some, but not all Lyme patients. In fact, despite IDSA’s claims, according to the CDC only 70 to 80% of patients with Lyme disease reported to its surveillance system the presence of an EM rash.

 

IDSA supports increased federal funding for responses to tick-borne diseases and correctly notes that higher level funding should not come at the expense of funding for other diseases, including HIV. The IDSA letter goes on to state that “Pitting one disease against another, as suggested in the draft report, is counterproductive and costly.”

  • While everyone can agree with the former statement, the latter is a mischaracterization of the content and intention of the TBDWG report. Suggesting that the level of funding for Lyme and other tick-borne diseases should be commensurate with the case incidence rates is not pitting one infectious disease against another; it is, rather, a fair-minded plea for equitable distribution of limited funds based on current public infection risk. Making comparisons between Lyme disease and HIV merely highlights the disproportionate distribution of funding if one looks solely at case incidence rates for the two diseases.

 

Please reach out to [email protected] with any questions.


Click here for a list of GLA’s published research findings.
Click here to read GLA’s comprehensive Research Report.

timothy sellati

Meet the Researcher: Timothy J. Sellati, Ph.D.

Meet the Researcher is a blog series to introduce GLA-funded Lyme disease researchers, and in this case, GLA’s Chief Scientific Officer.


 

#Meettheresearcher

NAME: Timothy J. Sellati, Ph.D.
TITLE: Chief Scientific Officer

Dr. Sellati has more than 20 years of Lyme and tick-borne disease research experience. He has published more than 40 peer-reviewed infectious disease papers, nearly 20 of which are focused on Lyme disease. As GLA’s Chief Scientific Officer, he leads GLA’s research initiatives to accelerate the development of more effective methods of diagnosis, the treatment of Lyme and other tick-borne diseases, and the search for a cure. But what makes him tick?

GLA CEO Scott Santarella, GLA grantee Dr. Nicole Baumgarth, GLA CSO Dr. Timothy Sellati
Dr. Sellati, far right, with GLA CEO Scott Santarella and GLA grantee Dr. Nicole Baumgarth at GLA’s Lyme Disease Research Symposium 2018

WHAT MOTIVATED YOU TO FOCUS ON TICK-BORNE DISEASE RESEARCH?

When I began pursuing my Ph.D. from the State University of New York at Stony Brook, I thought I would focus on cancer biology and tumor cell metastasis. Through serendipity I instead found myself training with Martha Furie, Ph.D., a renowned cell biologist, and Jorge Benach, Ph.D., who along with Willy Burgdorfer, Ph.D., discovered that the causative agent of Lyme disease Borrelia burgdorferi  is a bacterial spirochete transmitted by the bite of a black-legged (“deer”) tick.. Although the study of bacteria entering and then escaping from the bloodstream after a tick bite sounds worlds away from studying tumor cell metastasis, there really are some remarkable similarities.

Timothy Sellati
Dr. Sellati served as Distinguished Fellow and Chair of the Department of Infectious Diseases in the Drug Discovery Division at Southern Research Institute

For instance, small cell lung cancers spread via the bloodstream to the liver, lung, bones and brain, but not to other organs that also receive blood. In a similar fashion, B. burgdorferi spirochetes leave the site of inoculation and travel to the joints, heart, and brain, but not to other organs also receiving blood. I wanted to explore and understand why that was so and what controlled where the spirochetes (like cancer cells) could and could not go in the body. I also wanted to determine why certain immune cells responsible for killing and clearing B. burgdorferi instead invade the joint while a different type of immune cell invades the spirochete-infected heart.

WHY DID YOU DECIDE TO MOVE FROM THE LAB TO GLOBAL LYME ALLIANCE?

Dr. Sellati with GLA grantee Dr. Lise Nigrovic at GLA’s Lyme Disease Research Symposium 2018

Joining GLA allows me to make a greater impact, beyond my own academic research program, in helping to solve the mystery of Lyme disease and better understand its impact on patients. I’m most excited about the opportunity to engage scientists and physicians willing to share and learn from one another, willing to approach their work in a cross-disciplinary, inter-departmental and cross-institutional manner and who are willing to alter their notion of “how the world works” when presented with experimental evidence that runs contrary to it. In essence, GLA enables me to serve as scientific ‘cupid,’ supporting young, mid-career, and senior research scientists and physicians who are inclined to “color outside the lines,” challenging conventional thinking and approaches and hopefully getting us to the finish line—preventing future cases of tick-borne illness and curing those individuals already infected.

What drew me to GLA was its reputation. Reviewing its roster of Scientific Advisory Board members, I saw many faces and names with whom I was familiar and had interacted with during my long research career. I was also excited to see the caliber of scientists and physicians whose research the organization had funded in the past or is currently funding.

WHAT IS YOUR VISION FOR GLA’S RESEARCH PROGRAM?

GLA’s goal is to impact patients, and I believe the best way to do that is through research. My strategic vision for GLA is to identify and help direct funds to projects that will drive the development of more accurate and accessible diagnostic tests, treatments for chronic, or persistent, Lyme disease, and a cure. I believe these goals are realistically attainable.

PUBLISHED RESEARCH

(a small sample)

Induction of Interleukin 10 by Borrelia burgdorferi Is Regulated by the Action of CD14-Dependent p38 Mitogen-Activated Protein Kinase and cAMP-Mediated Chromatin Remodeling.

Sahay B, Bashant K, Nelson NLJ, Patsey RL, Gadila SK, Boohaker R, Verma A, Strle K, Sellati TJ.  Infect Immun. 2018 Mar 22;86(4). pii: e00781-17. doi: 10.1128/IAI.00781-17. Print 2018 Apr. 

CD14 signaling restrains chronic inflammation through induction of p38-MAPK/SOCS-dependent tolerance.

Sahay B, Patsey RL, Eggers CH, Salazar JC, Radolf JD, Sellati TJ.  PLoS Pathog. 2009 Dec;5(12):e1000687. doi: 10.1371/journal.ppat.1000687. Epub 2009 Dec 11.

NKT cells prevent chronic joint inflammation after infection with Borrelia burgdorferi.

Tupin E, Benhnia MR, Kinjo Y, Patsey R, Lena CJ, Haller MC, Caimano MJ, Imamura M, Wong CH, Crotty S, Radolf JD, Sellati TJ, Kronenberg M. Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19863-8. doi: 10.1073/pnas.0810519105. Epub 2008 Dec 5.

Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria.

Kinjo Y, Tupin E, Wu D, Fujio M, Garcia-Navarro R, Benhnia MR, Zajonc DM, Ben-Menachem G, Ainge GD, Painter GF, Khurana A, Hoebe K, Behar SM, Beutler B, Wilson IA, Tsuji M, Sellati TJ, Wong CH, Kronenberg M. Nat Immunol. 2006 Sep;7(9):978-86. Epub 2006 Aug 20.

Toll-like receptor 2 functions as a pattern recognition receptor for diverse bacterial products.

Lien E, Sellati TJ, Yoshimura A, Flo TH, Rawadi G, Finberg RW, Carroll JD, Espevik T, Ingalls RR, Radolf JD, Golenbock DT. J Biol Chem. 1999 Nov 19;274(47):33419-25.


LEARN MORE ABOUT GLA’s RESEARCH INITIATIVES AND ACCOMPLISHMENTS:

Serodiagnostic Testing

GLA POV: Advances in Serodiagnostic Testing for Lyme Disease

by Timothy J. Sellati, Ph.D.
Chief Scientific Officer
Global Lyme Alliance

GLA Point of View on “Advances in Serodiagnostic Testing for Lyme Disease Are at Hand” published in Clinical Infectious Diseases

 

In 2016, a scientific conference was held at Cold Spring Harbor Laboratory’s Banbury Center to discuss the state of serodiagnostic testing for Lyme disease, from both a historical perspective as well as recent advances in the field. This conference was supported by a meeting grant from Global Lyme Alliance (GLA). GLA, as part of its support, also inspired the topic for the conference; to discuss the adequacy or inadequacies of the current Lyme disease diagnostic testing paradigm. The opinion of conference attendees was detailed in a recent publication by John A. Branda, M.D. of Harvard University, Steven E. Schutzer, M.D. of Rutgers University-New Jersey Medical School, and co-authors, in the peer-reviewed journal Clinical Infectious Diseases.

The article titled “Advances in Serodiagnostic Testing for Lyme Disease Are at Hand” clearly articulates the fact we are at a historic turning point where new diagnostic approaches can deliver better performance than the current two-tiered testing protocol that was established for Lyme disease serodiagnosis back in 1994. Issues with poor sensitivity, specificity, and reproducibility inherent in the two-tiered testing protocol, which relies on Western immunoblotting, makes it a suboptimal choice and yet, more than two decades later, this approach remains the standard for laboratory diagnosis of Lyme disease. Branda, Schutzer, and their colleagues highlight several exciting technical and conceptual advances in laboratory diagnostic testing that, if adopted, would significantly improve the accuracy of testing and ease with which physicians can diagnose patients, particularly those in the early stages of Lyme disease.

The article describes a new generation of enzyme-linked immunosorbent assays (EIAs, the first tier of the current testing protocol) that have emerged and offer superior specificity, reproducibility, and ease of interpretation of assay results. The authors suggest that adoption of such NextGen EIAs, as a replacement for second-tier Western immunoblotting, could eliminate or at least significantly reduce the rate of false-positive or false-negative results associated with the second tier of the current testing protocol. Furthermore, coupling the use of multiple NextGen EIAs that target different parts of Borrelia burgdorferi, the bacterial causative agent of Lyme disease, would provide greater specificity than would be obtained with individual EIAs. This well-accepted principle is applied in rapid testing for human immunodeficiency virus (HIV).

The time for the Lyme disease community to benefit from implementing a similar test strategy is long overdue. In fact, in a separate study published by Branda et al. in Clinical Infectious Diseases, it was demonstrated that a two-EIA protocol can be more sensitive in early Lyme disease than conventional two-tiered testing.  GLA has been focused on investing in direct and indirect diagnostic methods using the latest available technologies.

Other key points made at the Banbury Conference include the following:

  1. Beyond improved sensitivity, the two-EIA protocol offers several advantages compared with standard two-tiered testing. The results are obtained objectively by an instrument system, and the information provided to the clinician is straightforward (e., the patient is either seropositive or seronegative), with an interpretation that is less complex than immunoblotting.
  2. Improvements in serologic testing methods or protocols will not address their inability to differentiate active infection from past exposure. Ideally it will be addressed through improved direct detection methods, because direct detection of the microbe is strong evidence of an active rather than a past infection.
  3. Ultimately, it will be advantageous to have both direct and indirect tests available, with direct detection methods favored in the evaluation of patients who present soon after initial infection, or who have been exposed multiple times and have a persistent antibody response, and indirect tests favored when clinical presentation of the primary infection occurs weeks or months after tick exposure.
  4. Although several next-generation EIAs are FDA-cleared as first tier assays, none is currently cleared as a second-tier test in place of immunoblotting. Currently, the Centers for Disease Control and Prevention (CDC) recommends that only laboratory tests cleared or approved by FDA be used to aid in the routine serodiagnosis of Lyme disease. Thus, an important next step for widespread adoption will be for assay developers to provide performance data establishing that their assay is equivalent to, or better than, the current reference standard, which is the two-tiered testing with immunoblots.

timothy sellatiTimothy J. Sellati, Ph.D.
Chief Scientific Officer
Global Lyme Alliance

A noted immunologist and microbiologist, Dr. Sellati has more than 20 years of research experience with Lyme and other tick-borne diseases. 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.