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Report of the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee to the Tick-Borne Disease Working Group

Background

An understanding of the pathogenesis and pathophysiology of Lyme disease is key to the ultimate care of patients with Lyme disease. It is apparent that a number of gaps exist in our understanding that are adversely impacting especially patients with persisting symptoms and signs of Lyme disease, both in patients previously treated with antibiotics and in those without any prior antibiotic treatment. To better understand the various mechanisms underlying the infection caused by Borrelia burgdorferi, the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee was formed to review what is currently known about the pathogenesis and pathophysiology of Lyme disease, from its inception, but also especially about its ability to persist in the host. To that end, the following experts were assembled to update our knowledge about the infectious process, identify the gaps that exist in our understanding of the process, and provide recommendations as to how to best approach solutions that could lead to a better means to manage patients with persistent Lyme disease (Table 1).

Table 1: Members of the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee

Members Type Stakeholder Group Expertise
Co-chair
Sam T. Donta, MD Senior Advisor, Learning and Diffusion Group, Innovation Center, Centers for Medi-care & Medicaid Services, Baltimore, MD
Public Health care provider Basic science and clinical experience with Lyme disease; member of the Pathogenesis, Transmission, and Treatment Subcommittee of the first Tick-Borne Disease Working Group

Co-chair
Leith Jason States, MD, MPH Chief Medical Officer (acting), Office of the Assistant Secretary for Health, U.S. Department of Health and Human Services, Washington, DC

Federal

Federal Employee provider

Public health and preventive medicine clinician with experience with population-based prevention of tick-borne diseases in military populations and diagnosis and treatment of Lyme disease

Wendy A. Adams, MBA Research Grant Director and Advisory Board Member, Bay Area Lyme Foundation; Board Member, Lyme Disease Biobank, Portola Valley, CA

Public

Patient advocate

Knowledge of patient and other issues concerning the diagnosis and treatment of Lyme disease; member of the first Tick-Borne Disease Working Group and its Pathogenesis, Transmission, and Treatment Subcommittee

Troy Bankhead, PhD Associate Professor, Department of Veterinary Microbiology and Pathology, Washington State University College of Veterinary Medicine, Pullman, WA

Public

Researcher

Expertise on the pathogenesis and persistence of Borrelia species

Nicole Baumgarth, DVM, PhD Professor, Center for Comparative Medicine, Department of Pathology, Microbiology & Immunology, University of California, Davis, School of Veterinary Medicine, Davis, CA

Public

Reasearcher

Knowledge of persistence of Borrelia burgdorferi and the role of the immune system; member of the first Tick-Borne Disease Working Group and its Pathogenesis, Transmission, and Treatment Subcommittee

Monica E. Embers, PhD Physician (specialty: infec-tious disease), Plymouth, MA

Public

Reasearcher

Leading researcher on the pathogenesis and persistence of Lyme disease in the nonhuman primate model; member of the Vaccine and Therapeutics Subcommittee of the first Tick-Borne Disease Working Group

Robert Lochhead, PhD Assistant Professor, Department of Microbiology & Immunology, The Medical College of Wisconsin, Milwaukee, WI

Public

Reasearcher

Leading researcher on the pathogenesis of Lyme arthritis and the role of peptidoglycan

Brian Stevenson, PhD Professor, Department of Microbiology, Immunology & Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY

Public

Reasearcher

Expert on the pathogenesis of Lyme disease and mentor for several subsequent researchers in the field; member of the Pathogenesis, Transmission, and Treatment Subcommittee to the first Tick-Borne Disease Working Group

Goals of the Subcommittee

The specific goal of the subcommittee was to address the following questions:

  1. What are the initial events and mechanisms involved in the entry of B. burgdorferi into host tissues?
  2. What are the events and pathophysiology involved following entry of B. burgdorferi into host tissues?
  3. What are the pathogenetic and pathophysiologic mechanisms involved in the development of symptoms and signs?
  4. What underlies the persistence of Borrelia in host tissues?
  5. Does immune evasion or suppression or autoimmunity contribute to the process of persistent symptoms?
  6. Is there a role for antibiotic tolerance in “resistance” to successful antibiotic treatment?

Methods

The subcommittee consisted of eight members, including one federal partner, representing public health, academia/research, patients, and clinical practice. Members’ areas of expertise are described in Table 1. The subcommittee met 14 times from July 16 through December 17, 2019. At the first meeting, the subcommittee co-chairs circulated several proposed topics, which were then discussed. Also discussed was the process by which the subcommittee would propose potential actions and how those suggestions would be presented to the Working Group. Through ongoing discussion, members proposed topics and potential presenters, including presentations from subcommittee members themselves, as well as from other leading experts in the field.

Presentations from members or invited guests focused on topics relevant to the goals of the subcommittee, covering a range of topics from Borrelia genomics through animal models and human clinical studies. Presentations were followed by a question-and-answer session with the presenter and subsequent discussion among the members alone. Information from these presentations often included unpublished work and brought new information and scientific data to the subcommittee’s discussion and recommendations. Table 2 gives an overview of the subcommittee’s meetings; Table 3 summarizes the presentations at each meeting. Appendix 1 provides the agenda and a brief summary of each meeting.

Subcommittee co-chairs drafted segments of the report and circulated them for review by the subcommittee. Members submitted comments by email and discussed the draft report briefly during meetings. The co-chairs revised the drafts according to the consensus of the group. At the final meeting, members voted on each section of the report and each proposed potential action (see Table 4). (Subcommittee members who were unable to attend the final meeting submitted their votes by email.)

Table 2: Overview of Pathogenesis and Pathophysiology of Lyme Disease Subcommittee Meetings

Meeting No. Data Presenter Topics Addressed
1 July 16, 2019 Sam T. Donta, MD, Co-Chair
Wendy A. Adams, MBA
Troy Bankhead, PhD
Nicole Baumgarth, DVM, PhD
Monica E. Embers, PhD
Robert Lochhead, PhD
Brian Stevenson, PhD
Introductions; topics for consideration; potential speakers for upcoming meetings.
2 July 30, 2019 Sam T. Donta, MD, Co-Chair
Leith Jason States, MD, MPH, Co-Chair
Wendy A. Adams, MBA
Monica E. Embers, PhD
Robert Lochhead, PhD
Presentation from Brandon L. Jutras, PhD, on the pathogenesis of Lyme arthritis; potential and confirmed speakers for upcoming meetings.
3 July 30, 2019 Sam T. Donta, MD, Co-Chair
Leith Jason States, MD, MPH, Co-Chair
Wendy A. Adams, MBA
Troy Bankhead, PhD
Monica E. Embers, PhD
Robert Lochhead, PhD
Brian Stevenson, PhD
Presentation from member Brian Stevenson, PhD, on Borrelia burgdorferi transmission and dissemination in the vertebrate host; potential and confirmed speakers for upcoming meetings.
4 August 27, 2019 Sam T. Donta, MD, Co-Chair
Wendy A. Adams, MBA
Troy Bankhead, PhD
Monica E. Embers, PhD
Robert Lochhead, PhD
Brian Stevenson, PhD
Presentation from Jenny A. Hyde, PhD, on genetic regulation of Lyme disease; potential and confirmed speakers for upcoming meetings.
5 September 10, 2019 Sam T. Donta, MD, Co-Chair
Leith Jason States, MD, MPH, Co-Chair
Wendy A. Adams, MBA
Nicole Baumgarth, DVM, PhD
Monica E. Embers, PhD
Robert Lochhead, PhD
Presentation from member Nicole Baumgarth, DVM, PhD, on B. burgdorferi infection-induced adaptive immune response evasion in a natural reservoir species, and from member Monica Embers, PhD, on adaptive immune response variation and suppression in Lyme borreliosis; review of slide presentation on backgrounds and methods for the Tick-Borne Disease Working Group September 12 meeting; potential and confirmed speakers for upcoming meetings.
6 September 24, 2019 Sam T. Donta, MD, Co-Chair
Leith Jason States, MD, MPH, Co-Chair
Wendy A. Adams, MBA
Troy Bankhead, PhD
Nicole Baumgarth, DVM, PhD
Monica E. Embers, PhD
Robert Lochhead, PhD
Brian Stevenson, PhD
Presentation from Mark Wooten, PhD, on the results of novel technology for real-time visualization of B. burgdorferi spirochetal motility; confirmed speakers for upcoming meetings; revision of meeting schedule.
7 October 1, 2019 Sam T. Donta, MD, Co-Chair
Wendy A. Adams, MBA
Robert Lochhead, PhD
Brian Stevenson, PhD
Review of timeline for subcommittee draft report; presentation from Michal “Mikki” Caspi Tal, PhD, on the hypothesis that B. burgdorferi has a mechanism for preventing immune system response in hosts; review of upcoming meetings and speakers.
8 October 8, 2019 Sam T. Donta, MD, Co-Chair
Leith Jason States, MD, MPH, Co-Chair
Wendy A. Adams, MBA
Troy Bankhead, PhD
Nicole Baumgarth, DVM, PhD
Monica E. Embers, PhD
Robert Lochhead, PhD
Brian Stevenson, PhD
Presentation from member Robert Lochhead, PhD, describing novel findings on the pathogenesis of postinfectious Lyme arthritis; review of upcoming meetings and speakers; overview of timeline for subcommittee draft report.
9 October 15, 2019 Sam T. Donta, MD, Co-Chair
Wendy A. Adams, MBA
Troy Bankhead, PhD
Nicole Baumgarth, DVM, PhD
Monica E. Embers, PhD
Brian Stevenson, PhD
Presentation from Emir Hodzic, DVM, MSc, PhD, on research findings suggesting the presence of persistent, viable but uncultivable B. burgdorferi spirochetes; discussion of subcommittee report to the Tick-Borne Diseases Working Group; review of upcoming meetings.
10 November 5, 2019 Sam T. Donta, MD, Co-Chair
Leith Jason States, MD, MPH, Co-Chair
Wendy A. Adams, MBA
Nicole Baumgarth, DVM, PhD
Monica E. Embers, PhD
Brian Stevenson, PhD
Presentation from Kim Lewis, PhD, on some promising approaches to targeted treatment of Lyme disease; discussion of subcommittee report to the Tick-Borne Diseases Working Group; review of upcoming meetings.
11 November 12, 2019 Sam T. Donta, MD, Co-Chair
Monica E. Embers, PhD
Brian Stevenson, PhD
Presentation from Catherine Brissette, PhD, on a murine model that demonstrates Borrelia infection of the dura mater that leads to inflammation in the central nervous system; discussion of subcommittee report to the Tick-Borne Diseases Working Group; review of upcoming meetings.
12 November 19, 2019 Sam T. Donta, MD, Co-Chair
Leith Jason States, MD, MPH, Co-Chair
Wendy A. Adams, MBA
Troy Bankhead, PhD
Nicole Baumgarth, DVM, PhD
Brian Stevenson, PhD
Presentation from member Troy Bankhead, PhD, explaining how the VlsE gene protects B. burgdorferi surface antigens from host antibodies; discussion of subcommittee report to the Tick-Borne Diseases Working Group; review of upcoming meetings.
13 December 3, 2019 Sam T. Donta, MD, Co-Chair
Wendy A. Adams, MBA
Troy Bankhead, PhD
Nicole Baumgarth, DVM, PhD
Robert Lochhead, PhD
Discussion of subcommittee report to the Tick-Borne Diseases Working Group; review of upcoming meetings
14 December 17, 2019 Sam T. Donta, MD, Co-Chair
Wendy A. Adams, MBA
Nicole Baumgarth, DVM, PhD
Monica E. Embers, PhD
Robert Lochhead, PhD
Brian Stevenson, PhD
Discussion of subcommittee report to the Tick-Borne Diseases Working Group and voting

It has been established that the causative organism of Lyme disease, B. burgdorferi, can persist in a number of animal models and human case studies following infection and treatment with a “standard” course of antibiotics. However, it is still unclear whether human patients with ongoing symptoms associated with Lyme disease continue to have an active infection following completion of seemingly appropriate antibiotic therapy and thus the extent to which unresolved infection or clearance of Borrelial antigens contributes to persistent Lyme disease symptoms. The mechanisms underlying the establishment and persistence of B. burgdorferi following experimental infection are beginning to be delineated, but gaps still exist in our understanding of this process, which gaps of information contribute to problems in the care of patients with persistent Lyme disease. By hearing from subcommittee members and outside experts on this topic, it is hoped that the process will be better understood and that an increased understanding of these processes will translate into improved patient care. (See Table 3 for the list of presentations to the subcommittee.)

Table 3: Presenters to the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee

Meeting No. Presenter(s) Topics Addressed Ok to Share?
1 None n/a n/a
2 Brandon L. Jutras, PhD, Assistant Professor, Department of Biochemistry, Fralin Life Sciences (affiliated faculty), Molecular and Cellular Biology (affiliated faculty), Virginia PolyTechnic Institute and State University Unraveling the mysteries of Lyme disease (pathogenesis of Lyme arthritis) No
3 Brian Stevenson, PhD, Professor, Department of Microbiology, Immunology & Molecular Genetics, University of Kentucky College of Medicine Borrelia burgdorferi transmission and dissemination in the vertebrate host Yes
4 Jenny A. Hyde, PhD, Assistant Professor, Department of Microbial Pathogenesis and Immunology, Texas A&M University College of Medicine Genetic regulation of Lyme disease No
5 Nicole Baumgarth, DVM, PhD, Professor, Center for Comparative Medicine, Department of Pathology, Microbiology & Immunology, University of California, Davis, School of Veterinary Medicine Infection of animals with B. burgdorferi and dysregulation of the host immune response No
Monica E. Embers, PhD, Associate Professor, Director, Vector-Borne Diseases Core, Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University School of Medicine Adaptive immune response variation and suppression in Lyme borreliosis No
6 R. Mark Wooten, PhD, Professor and Institutional Biosafety Committee Chair, Department of Medical Microbiology and Immunology, University of Toledo College of Medicine Results of novel technology for real-time visualization of B. burgdorferi spirochetal motility No
7 Michal “Mikki” Caspi Tal, PhD, Instructor, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University Exploration of the hypothesis that a B. burgdorferi mechanism prevents immune system response in hosts No
8 Robert Lochhead, PhD, Assistant Professor, Department of Microbiology & Immunology, The Medical College of Wisconsin Pathogenesis of postinfectious Lyme arthritis No
9 Emir Hodzic, DVM, MSc, PhD, Director, Real-Time PCR Research and Diagnostics Core Facility, School of Veterinary Medicine, University of California, Davis Persistence of different B. burgdorferi strains after antimicrobial treatment in two mouse models Yes
10 Kim Lewis, PhD, Professor of Biology, Director, Antimicrobial Discovery Center, Northeastern University Developing targeted treatments for Lyme disease No
11 Catherine Brissette, PhD, Associate Professor, Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences A murine model of Lyme disease demonstrates that Borrelia species colonize the dura mater and induce inflammation in the central nervous system No
12 Troy Bankhead, PhD, Associate Professor, Washington State University College of Veterinary Medicine VlsE-mediated immune protection by the Lyme disease pathogen No

Table 4: Votes Taken by the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee

Meeting Number or Date Motion Result Minority Response

14

Approve the Background section

Motion passed
8 in favor, 0 opposed, 0 abstained, 0 absent

No

14

Approve the Methods section, pending elaboration on how the report was drafted and how decisions were made

Motion passed
8 in favor, 0 opposed, 0 abstained, 0 absent

No

14

Approve Priority 1

Motion passed
8 in favor, 0 opposed, 0 abstained, 0 absent

No

14

Approve Priority 2

Motion passed
8 in favor, 0 opposed, 0 abstained, 0 absent

No

14

Approve Priority 3

Motion passed
8 in favor, 0 opposed, 0 abstained, 0 absent

No

14

Approve Priority 4

Motion passed
8 in favor, 0 opposed, 0 abstained, 0 absent

No

Results and Potential Actions

For consideration by the Tick-Borne Disease Working Group, the Pathogenesis and Physiology of Lyme Disease Subcommittee has identified four major priorities and 13 potential actions to achieve them.

Priority 1: Determine the mechanisms underlying the persistence of B. burgdorferi in the host.

To better understand the pathogenesis and pathophysiology of Lyme disease, especially in its ability to establish persistence in vertebrate species, including humans, the progression of B. burgdorferi from its reservoir in the Ixodes tick to transmission into the vertebrate host and to its localization and persistence in neural and other tissues are key steps towards eventually finding means to intervene and resolve the infection. The following are descriptions of what is known about these various components of the pathogenesis and pathophysiology of Lyme disease and its persistence, along with identification of the gaps that exist that need to be addressed in order to eventually resolve the infection.

Transmission and Dissemination of B. burgdorferi in the Vertebrate Host

In the midgut of a molted, unfed tick, B. burgdorferi's survival in a dormant state requires only a small amount of energy, because little to no bacterial replication occurs. Outer surface proteins (Osps) facilitate the pathogen’s adhesion to midgut tissue. A tick’s ingestion of blood provides B. burgdorferi with copious nutrition, resulting in rapid bacterial replication. In turn, B. burgdorferi stops producing tick-specific adhesins and starts producing OspC, a lipoprotein known as VlsE, and other factors required for transmission of the pathogen to vertebrates. After a blood meal, the infected tick’s midgut swells, and the junctions between midgut cells become thinner. B. burgdorferi then penetrates those junctions and enters the tick’s salivary glands and salivary ducts, thereby setting the stage for its transmission to a vertebrate via tick bite. Upon injection into the vertebrate, the bacteria adhere to tissue at the bite site and replicate (Radolf, Camaino, Stevenson, & Hu, 2012; Stevenson & Seshu, 2018).

Dissemination of B. burgdorferi throughout the vertebrate host involves migration through solid tissue as well as transport via the bloodstream, resulting in a brief period of bacteremia. There are a number of questions meriting additional investigation, including processes occurring inside the tick, as well as the processes of initial entry and dissemination, such as the following:

  • How does B. burgdorferi sense its location in the tick-mammal infectious cycle, then use that information to regulate production of its proteins and other factors?
  • What are the signals that “tell” B. burgdorferi that a vector tick is feeding and that it is time to transmit out of the tick?
  • How does B. burgdorferi get into the tick’s salivary glands and salivary ducts?
  • How does B. burgdorferi control production of host-specific proteins?
  • When bacteria adhere to host tissues at the tick’s bite site and then replicate, to what kinds of tissues do they adhere? What types of proteins is B. burgdorferi making to facilitate adherence?
  • Upon infection of a human, how does B. burgdorferi spread? It is known to migrate through skin and other solid tissue, but does it go through the lymphatic system or attach to nerve endings? Does it localize in sensory ganglia? What is the role of adhesins in dissemination throughout the vertebrate host? Are there particular host tissues that attract B. burgdorferi?

Gene Regulation of B. burgdorferi During Colonization, Dissemination, and Tissue-Specific Infection in Mice

B. burgdorferi can sense whether it is located in a tick or mammal and adapt its response to environmental signals, such as temperature, pH, oxygen levels, carbon dioxide levels, nutrient availability, and reactive oxygen species. The rate of bacterial replication has effects on expression levels of numerous infection-associated genes and proteins. Carbon dioxide is important in determining the virulence of B. burgdorferi in mice. Borrelial oxidative stress regulator plays a pivotal role in establishing mammalian infection. B. burgdorferi can grow and survive without iron; genes generate an oxidative stress response that is involved in the transport of manganese and other metals within B. burgdorferi-infected mice. The use of bioluminescent Borrelial as a tool for studies in mice allows visualization of the kinetics of infection with different strains of the pathogen and enables real-time evaluation of gene expression in the skin, heart, and joints of a mammal infected with B. burgdorferi. Notably, localized infection with Borrelial becomes more difficult to detect as the pathogen disseminates throughout the mouse. An important gap here is that it is yet to be determined which genes are required for dissemination of Borrelial and its colonization of tissues during later stages of infection (Arnold et al., 2016; Jutras, Chenail, & Stevenson, 2013; Stevenson & Seshu, 2018).

Role of the Immune System in Response to B. burgdorferi

Immunocompetent mice establish persistent and non-resolving infection (Tracey & Baumgarth, 2017). In these species, there is no correlation between the load of B. burgdorferi and clinical signs of disease. Immunoglobulin (Ig) G but not IgM antibodies control B. burgdorferi tissue load, but cannot clear the infection, even when the antibodies are able to passively protect from infection of a new host. Data suggest that B. burgdorferi suppresses effective adaptive immunity and, therefore, that the immune system is key to understanding persistence of Lyme disease. B-cell responses in these reservoir species are characterized by a lack of continued antibody affinity maturation and the development of long-lived responses due to the rapid collapse of germinal centers. B. burgdorferi infection appears to suppress the adaptive immune response, as indicated by the reduced immune response to influenza vaccine in mice infected with B. burgdorferi (Eisner et al., 2015). Ongoing work suggests that B. burgdorferi also prevents CD4 T cells from mounting an effective immune response to infection, potentially dysregulating effector immune responses in tissues and failing to suppress persistent infection of the host. Data were presented to the subcommittee to support the hypothesis that B. burgdorferi suppresses and subverts adaptive humoral and cellular immunity to itself and to other antigens. The gaps in knowledge to be addressed here are the precise mechanisms of Borrelia-induced immune suppression. Identifying host immune targets of Borrelia-mediated immune suppression might result in the development of approaches that enhance host immunity to this pathogen in a manner similar to strategies that are currently being explored in anti-tumor immunity.

Notably, mice never clear B. burgdorferi infection without antibiotic treatment; humans and nonhuman primates appear to harbor low-level, persistent B. burgdorferi infection as well. Persistence appears to be a function of active immune suppression and immune evasion tactics. An assay that was developed to detect antibody responses to five antigens of B. burgdorferi infection following antibiotic treatment (Embers et al., 2016) showed that most rhesus macaques infected with B. burgdorferi generated responses to most of the antigens, but two showed no specific antibody responses to these antigens (Embers et al., 2017). Evaluation of serum samples from human patients with Lyme disease demonstrated that this assay had higher sensitivity than the standard two-tier test approved by the Centers for Disease Control and Prevention and good specificity. In another study in humans, patients who returned to health after antibiotic treatment generated the strongest antibody response (Blum et al., 2018), while those with persisting symptoms had weak responses to antigens or had an anti-oligopeptide permease A2 titer that did not decline. The reasons that patients had a good antibody response remain to be determined, but might be attributed to host differences in the ability to generate humoral responses to B. burgdorferi or to differences in the infecting strains of B. burgdorferi.

Further studies of immune function in monkeys previously vaccinated with B. burgdorferi found that IgM-producing cells were more frequent and persistent in B. burgdorferi-infected primates, results similar to those observed in human patients with persistent Lyme disease as well as in mice. Memory B cells and plasmablasts are reduced in B. burgdorferi-infected, unvaccinated macaques compared with vaccinated macaques; whereas CD4 T-cell memory populations appeared similar among groups, activation of T cells was somewhat dampened in the B. burgdorferi-infected primates. Areas for future research include determining how long B. burgdorferi-induced immune suppression lasts and the impact of persistent infection on effectiveness of vaccines.

Chemotaxis, Motility, and Immune Evasion as Key Factors in B. burgdorferi Spirochete Persistence

Most spirochetes use flagellin proteins as “motors,” with which they move back and forth whenever they encounter an obstacle until they eventually push through the obstacle. This movement can now be tracked in real time in mice with the use of multiphoton/confocal microscopy and fluorescently labeled B. burgdorferi. Ongoing studies showed that, independent of the initial infections of BB. burgdorferi, imaging analysis revealed that the number of spirochetes peaked at similar levels around 7–10 days after infection (R.M. Wooten, personal communication [presentation to subcommittee], September 24, 2019). This peak was followed by a dramatic drop in spirochete numbers, again, to the same levels, where they persisted for the duration of the experiment. Spirochetes often tend to reside in the dermis. Of the various resident immune response cells, Langerhans cells are not as effective as are macrophages, other dendritic cells, and neutrophils in phagocytosing the bacteria, as spirochetes move up to 80 times faster than any of the immune response cells. Neutrophils respond the fastest, but after a certain point, they stop responding, even though the spirochetes remain. The gap here is a lack of understanding of the signals involved in this apparent suppression of neutrophil responses. Interleukin 10, an anti-inflammatory cytokine that may inhibit immune responses to B. burgdorferi, is initially downregulated by B. burgdorferi. However, this appeared to be a temporary response. The innate immune response is important for controlling early infection, independent of the presence of T and B cells. In contrast, antibody responses control the levels of Borrelia load later in infection. Greater understanding is needed regarding the different roles the innate and adaptive arms of the immune system play in regulating immunity to the spirochetes.

Role of CD47 and the Immune Response to B. burgdorferi

It was observed that when CD47, a relatively conserved “marker of self,” expressed on cells, binds to signal regulatory protein alpha (SIRP-alpha), this inhibits macrophages from phagocytosing those cells. Anti-CD47 antibodies are currently under evaluation in clinical trials for cancer treatment (Willingham et al., 2012). It is hypothesized that B. burgdorferi (among other pathogens) can mimic CD47 and thus prevent macrophages from destroying Borrelia via phagocytosis (van der Burg, Arens, & Melief, 2011). Imaging studies of the immune response to B. burgdorferi shows that macrophages can send out a “lasso” that wraps around B. burgdorferi spirochetes and draws them into the macrophage, usually the first step in the process of phagocytosis. In a few cases, however, the spirochetes sit inside the macrophage but never appear to reach the lysosome, which is where bacterial destruction usually occurs. In donor sera, the addition of the SIRP-alpha binding domains of its receptor CV1G4 in vitro sometimes results in increased phagocytosis, presumably by blocking serum-derived SIRP-alpha to CD47-like molecules on the spirochete. To understand why the response is more efficient in some settings, the genetic sequences of CD47 and SIRP-alpha were studied, and it was found that SIRP-alpha is highly polymorphic (Weiskopf et al., 2013). Evolutionarily, there has been long-term balancing selection, which ensures that proteins that are vital to the immune response are maintained with maximum diversity, perhaps because the pathogens see some types of SIRP-alpha as beneficial to them. By using mass spectrometry and CV1G4 as a binder, a known Borrelia protein was identified as a CD47-like anti-phagocytic signal. In the absence of this protein, macrophages were more effective in clearing cells. Further research is needed to identify the underlying mechanisms involved in this process. Whether B. burgdorferi can survive by inhibiting phagolysosome fusion, as is the case with a number of other known persistent pathogens, is currently unknown.

VlsE Protein-Mediated Immune Evasion

VlsE is a surface-expressed protein able to undergo extensive antigenic variation (Norris, 2006). Its expression and ability to undergo antigenic variation is required for B. burgdorferi survival and persistence in the presence of a host humoral antibody response targeted against VlsE (Bankhead & Chaconas, 2007), but also against other surface proteins. A longstanding question has been how B. burgdorferi immune escape is accomplished through sequence variation of this single lipoprotein, despite the presence of a substantial number of additional antigens residing on the bacterial surface. A function for VlsE other than its antigenic variation, and thus constant evasion from the humoral antibody response, is not currently known to exist. Although other forms of immune evasion have been proposed, antigenic variation occurs even in antibody-deficient severe combined immunodeficient mice. Among the several models that have been suggested, one scenario proposes that VlsE may act as a shield to obscure the epitopes of other surface antigens (Bankhead, 2016).

One example of this is the immunogenic Arp protein of B. burgdorferi, which is responsible for joint inflammation during infection. Despite Arp eliciting a strong humoral response, antibodies fail to clear the infection. Subsequent studies revealed that VlsE seems to prevent binding of Arp-specific antibodies to the surface of B. burgdorferi, thereby providing a possible explanation for the failure of Arp antisera to clear the infection. However, other surface-expressed proteins of B. burgdorferi do not seem to be blocked by expression of VlsE, and Arp remains highly immunogenic. Thus, VlsE does not appear to be a universal protector of all B. burgdorferi cell surface antigens. Therefore, other, as-of-yet-unknown mechanisms of immune evasion from antibody-mediated Borrelia clearance may exist.

From the above findings, it appears that B. burgdorferi utilizes multiple immune evasion mechanisms to establish persistent infection in its natural vertebrate hosts. These findings raise additional questions:

  • What are the precise mechanisms by which B. burgdorferi evades, alters, or suppresses immune responses? Which of these mechanisms may lead to enhanced persistence in human patients and/or alterations in the immune system that could explain some of the ongoing symptoms of Lyme disease?
  • Does B. burgdorferi infection cause altered immune responses and, if so, how?
  • Are immune evasion mechanisms useful targets for therapeutic intervention?
  • Will a better understanding of the mechanisms of immune evasion by B. burgdorferi be helpful in the design of vaccines directed at inducing strong anti-Borrelia immunity?

Evidence that Persisting B. burgdorferi Are Metabolically Active and Induce Host Gene Expressions

Evidence now exists, from the results of experiments in both murine and nonhuman primate models, that persisting B. burgdorferi can be metabolically active, expressing certain bacterial genes and inducing gene expression changes in the infected host, despite being non-culturable following antibiotic treatment (Greenmyer et al., 2018). In one model, the spirochetes localized to the dura mater of the brain, associated with large-scale changes in gene expression of pro-inflammatory cytokines and chemokines (Divan et al., 2018). Although there was no evidence of direct infection of the brain itself in this model, certain brain tissues expressed genes related to interferon (IFN) signaling pathways. Gene expression of other brain functions—for example, glutamate receptors—has not yet been studied. These results, then, provide support for the hypothesis and the likelihood that it is persistent infection that is the cause of persisting symptoms in patients with persistent Lyme disease.

Possible Opportunities

Based on the information presented, a sound foundation has been laid upon which support for future research should result in a clearer understanding of the pathogenesis and pathophysiology of persistent Lyme disease, which would ultimately translate into improved care of patients who have been adversely impacted by this disease. Of particular importance is support of research that builds on research that has demonstrated that persistent B. burgdorferi are metabolically active in neurologic and other tissues and induce brain and other tissues to respond in turn in an attempt to limit or resolve the persistent infection. Support of further research, targeting neural and other tissue responses, has the opportunity of finding means to intervene in the persistent process, leading to resolution of symptoms and signs of persistent Lyme disease.

Threats or Challenges

Without further research to identify targets of intervention in the progression of Lyme disease from its initial entry into the host to its persistence, patients with persistent Lyme disease will be faced with continued, often disabling symptoms and signs that affect not only those afflicted by the disease but also family members and society in general.

One of the greatest challenges is to actually find means to intervene in the infectious process, especially if no specific markers can be found because of low infectious load or if organisms are in locations inaccessible to diagnostic methods. Whether different antibiotic regimens can be found to eliminate the persistent state is another challenge that it is hoped can be met with additional targeted research.

In consideration of the possible opportunities and challenges, the subcommittee discussed the following potential actions and is proposing them to the Working Group.

Priority 1 Potential Actions

Potential Action 1.1:Support targeted funding of research that aims to better understand the initial events and mechanisms involved in the entry of B. burgdorferi into the host.

Vote on Potential Action 1.1

Number in Favor Number Opposed Number Abstained Number Absent
8 0 0 0

Potential Action 1.2a: Support targeted funding of research that aims to better understand the mechanisms involved in the establishment of infection and its persistence in host tissues.

Vote on Potential Action 1.2

Number in Favor Number Opposed Number Abstained Number Absent
8 0 0 0

Potential Action 1.3: Support targeted funding of research that aims to better understand the interactions between B. burgdorferi and host immune systems and development of more efficient tools to characterize host-pathogen interaction and facilitate approaches to genetically manipulate B. burgdorferi.

Vote on Potential Action 1.3

Number in Favor Number Opposed Number Abstained Number Absent
8 0 0 0

Potential Action 1.4: Support targeted funding to develop and assess animal models of neuroborreliosis and human studies to better understand the molecular mechanisms involved in the pathogenesis of neuroborreliosis.

Vote on Potential Action 1.4

Number in Favor Number Opposed Number Abstained Number Absent
8 0 0 0

Potential Action 1.5: Support targeted funding of research that aims to determine the potential roles of antibiotic tolerance and immunomodulation in the persistence of B. burgdorferi despite antibiotic treatment.

Vote on Potential Action 1.5

Number in Favor Number Opposed Number Abstained Number Absent
8 0 0 0

Potential Action 1.6:Support targeted opportunities for graduate students and postdoctoral researchers (for example, through National Institutes of Health F and K awards) and junior and senior investigators (for example, through National Institutes of Health R03 and R21 awards) to become involved in research that addresses the gaps in our understanding of the pathogenesis and pathophysiology of Lyme disease, including studies of Borrelia persistence. Support targeted clinical studies and the analysis of veterinary clinical data on Lyme disease in dogs, horses, and other species.

Vote on Potential Action 1.6

Number in Favor Number Opposed Number Abstained Number Absent
8 0 0 0

Priority 2: Determine the role of persistence of Borrelial or its components in the pathogenesis of Lyme arthritis and persistent Lyme disease.

One of the objective signs of Lyme disease that can occur months after the initial infection with Borrelial is arthritis. This manifestation usually involves a single joint, commonly the knee, but can involve other articular tissues as well. The results of recent research are leading to a better understanding of the pathogenesis and pathophysiology of Lyme arthritis, as is described in the following review, but important gaps continue to exist that need to be addressed to improve the diagnosis and management of this manifestation of Lyme disease.

Role of B. burgdorferi Peptidoglycan in the Pathogenesis and Persistence of Lyme Arthritis

B. burgdorferi peptidoglycan, the primary component of the bacterial cell wall, has a unique composition and plays an important role in bacterial physiology and host immune responses. B. burgdorferi lack the molecular machinery required for recycling of peptidoglycan during cell replication, and the bacteria shed copious amounts of peptidoglycan fragments (Jutras et al., 2019). These fragments are recognized by a host pathogen recognition receptor, NOD2, and cells stimulated with peptidoglycan fragments produce high levels of pro-inflammatory cytokines. Synovial fluid from some human patients with Lyme arthritis, many of whom had received 1–3 months of antibiotic therapy, had high levels of detectible peptidoglycan, as well as anti-peptidoglycan antibodies, despite lack of any evidence of ongoing infection after antibiotic therapy (Jutras et al., 2019). Thus, it appears that B. burgdorferi peptidoglycan might be a persistent antigen in Lyme arthritis (Jutras et al., 2019). Ongoing research is being conducted to determine whether B. burgdorferi peptidoglycan plays a role in the pathogenesis and pathophysiology of neuroborreliosis or of persistent Lyme disease other than previously treated Lyme arthritis.

Pathogenesis and Pathophysiology of Lyme Arthritis

Approximately 60% of untreated individuals with Lyme disease in the United States develop Lyme arthritis. Although most patients with Lyme arthritis respond favorably to 1–3 months of antibiotic therapy, about 10–20% of patients have persistent arthritis after treatment (Arvikar & Steere, 2015). A number of genetic and environmental factors contribute to persistent Lyme arthritis, such as infection by certain arthritogenic strains of B. burgdorferi, retained spirochetal antigens (for example, peptidoglycans), genetic risk factors, and evidence of prior joint trauma (Arvikar & Steere, 2015; Jutras et al., 2019). As in rheumatoid arthritis, the prototypical autoimmune joint disease, Lyme arthritis is frequently accompanied by autoimmune T- and B-cell responses to self-antigens (Arvikar & Steere, 2015). These unresolved inflammatory and autoimmune responses may contribute to ongoing arthritis, despite months of antibiotic therapy. Consistent with this hypothesis, nearly all patients with persistent Lyme arthritis experience resolution of arthritis when treated with immunosuppressive drugs, including non-steroidal anti-inflammatory drugs, corticosteroids, and other antirheumatic drugs, such as methotrexate or tumor necrosis factor-alpha inhibitors. Cellular analysis of the arthritic joint has shown that large numbers of IFN-gamma-positive lymphocytes are present in inflamed tissue and surrounding fluid (Lochhead, Arvikar, et al., 2019). Synovial fibroblasts, the most abundant cell type in synovial tissue, show evidence of immune activation and express major histocompatibility complex (MHC) class II molecules and other immune factors associated with inflammation and lymphocyte activation (Lochhead, Ordonez, et al., 2019).

Several self-peptides are immunogenic in Lyme disease patients, so there seems to be a breakdown in immune tolerance to self during B. burgdorferi infection. Autoimmune B-cell responses (but not T-cell responses) can be detected early in infection in patients with erythema migrans, but these early autoimmune responses appear to be self-limiting and non-pathogenic. T-cell autoimmunity accompanies B-cell autoimmunity later in disease, such as during Lyme arthritis. In late-stage disease, Lyme-disease-associated autoantibodies correlate with clinical features of arthritis, suggesting that autoimmunity in Lyme disease may become pathogenic over time. Lyme arthritis progresses from early invasion of synovial tissue to early inflammatory responses to later inflammatory responses, and then to late tissue repair and wound healing (Lochhead, Arvikar, et al., 2019; Lochhead, Ordonez, et al., 2019). The role of infection as an autoimmune trigger in Lyme disease is poorly understood, leading to the following questions:

  • What are the mechanisms by which B. burgdorferi infection causes ongoing arthritic joint disease in a subset of patients?
  • Are ongoing disease symptoms caused by the presence of Borrelia antigens (such as peptidoglycans) rather than active infection and, if so, why are they not cleared from the host?
  • Does Borrelia infection lead to the induction of novel autoantigens?

Questions remain regarding the role of immunosuppressive treatments versus differing antibiotic treatment regimens for persistent Lyme arthritis if peptidoglycan is an inflammatory agent and persists despite 1–3 months of antibiotic therapy. It was also noted that patients who have persistent Lyme arthritis may represent a different condition than do people with other Lyme disease syndromes.

Possible Opportunities

The identification of the role of B. burgdorferi peptidoglycan in the pathogenesis of Lyme arthritis is an important beginning of how to better address the diagnosis and treatment of this manifestation of Lyme disease. Support of further research into the mechanisms underlying the role of this bacterial product, as well as the potential role of other bacterial products in the persistence of arthritis, should lead to means to intervene in the process and resolve the arthritis.

Threats or Challenges

It is currently unknown whether there are persistent B. burgdorferi organisms that continue to produce peptidoglycan or other bacterial products that contribute to the pathogenesis and pathophysiology of Lyme arthritis. If there are no persisting organisms, but peptidoglycan and/or other bacterial products persist and cannot be cleared by the host, it might not be possible to resolve the arthritis using antibiotic or immunotherapeutic interventions. To attempt to address these challenges, the subcommittee discussed the following potential actions and is proposing them to the Working Group.

Priority 2 Potential Actions

Potential Action 2.1: Support targeted funding opportunities for research to better understand the role of bacterial antigens, including peptidoglycan, and the host immune response in the persistence of ongoing symptoms of Lyme disease, including Lyme arthritis.

Number in Favor Number Opposed Number Abstained Number Absent
8 0 0 0

Potential Action 2.2a: Support targeted funding opportunities for research that determines whether different antibiotic regimens from those previously reported would be effective in resolving Lyme disease.

Vote on Potential Action 2.2a

Number in Favor Number Opposed Number Abstained Number Absent
8 0 0 0

Potential Action 2.2b:

Support targeted funding opportunities for research to determine whether the use of targeted immunomodulatory medications are effective in resolving Lyme arthritis and/or other residual Lyme disease symptoms that are not responsive to standardly recommended therapeutics.

Vote on Potential Action 2.2b

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8 0 0 0

Priority 3: Determine the pathogenesis, pathophysiology, and effective treatment of Lyme carditis.

Although the subcommittee did not review what is known and not known about the pathogenesis and pathophysiology of Lyme carditis, Lyme carditis is a priority focus for further study, as it is a particularly critical condition of Lyme disease that can result directly in the death of patients with Lyme disease whose electrical conduction system of the heart may be affected, especially within the first few months of the infection.

Possible Opportunities

With the support of additional research into the mechanisms underlying the effects of B. burgdorferi on the conduction system of the heart, it should be possible to find earlier means to identify and intervene in patients with Lyme carditis, thus preventing the unacceptable risk of sudden death.

Threats or Challenges

It is all too frequent a scenario that patients with Lyme disease are not identified as being at risk for the development of Lyme carditis, with sudden death being the ultimate catastrophic result. By supporting additional research into the pathogenesis and pathophysiology of Lyme carditis, it should be possible to find means to avert this potentially catastrophic result. To that end, the subcommittee discussed the following potential actions and is proposing them to the Working Group.

Priority 3 Potential Actions

Potential Action 3.1:

Support targeted funding opportunities for research to develop an animal model of Lyme carditis.

Vote on Potential Action 3.1

Number in Favor Number Opposed Number Abstained Number Absent
8 0 0 0

Potential Action 3.2: Establish a clinical network to study patients with Lyme carditis and its treatment.

Vote on Potential Action 3.2

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8 0 0 0

Priority 4: Develop targeted treatments for Lyme disease.

Whereas prompt treatment of early Lyme disease using antibiotics of differing mechanisms of action is effective in prevention of persistence of B. burgdorferi and persistent Lyme disease, similar antibiotic treatments for persistent B. burgdorferi in animal models and in patients with persistent Lyme disease appear to be ineffective. The reasons for this difference are unclear, but may be due to a number of possible mechanisms:

  • The bacteria may be dormant or incapable of replication, yet there may be the presence of residual antigens or the periodic release of antigens, to which the host responds to produce the symptoms associated with persistent Lyme disease.
  • The bacteria may be entrenched in areas either inaccessible to certain classes of antibiotics (for example, poorly vascularized connective tissue, intracellular compartments), or higher doses of antibiotics are needed to achieve levels that impede metabolic activity.
  • The bacteria may become antibiotic-tolerant, requiring repeated courses of antibiotic treatment or periods of treatment alternating with periods of no treatment.

There are indications, however, that certain other treatment regimens (for example, tetracycline instead of doxycycline, the combination of a macrolide antibiotic and an alkalinizing agent) are effective in treating the persistent state if given over longer durations of time rather than the usual 2–4-week periods. There is ongoing research as well, some in the discovery phase, using novel compounds to treat persisting organisms. There is also some indication that the intestinal microbiota may play an important role in the persistence or ability to eradicate persisting organisms.

Possible Opportunities

The study of the potential for antibiotic and non-antibiotic treatments in animal models to prevent the development of the persistent state of B. burgdorferi and for its treatment once established are key approaches for the eventual goal to prevent and treat persistent Lyme disease in patients.

Threats or Challenges

Finding antibiotic and non-antibiotic treatments that are effective in animal models may not readily translate into the application of these findings in human patients with Lyme disease. But, without further research that is more easily conducted and controlled in animal models, it may not be possible to conduct additional controlled treatment trials, especially in patients with persistent Lyme disease, or to recommend any such results of treatment studies in animal models for use in patients. The subcommittee discussed the following potential actions and is proposing them to the Working Group to address this important gap in the management of such patients.

Priority 4 Potential Actions

Potential Action 4.1: Support targeted funding toward a better understanding of the persistent state of B. burgdorferi, especially whether antibiotic tolerance and/or immunomodulation plays a role in persistence.

Vote on Potential Action 4.1

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8 0 0 0

Potential Action 4.2: Support targeted funding exploring the use of novel compounds or combinations of antibiotics in both preventing and resolving the persisting state.

Vote on Potential Action 4.2

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8 0 0 0

Summary

The results of studies into the pathogenesis and pathophysiology of Lyme disease, with the focus on the persistent state of the causative organism, B. burgdorferi, have begun to elucidate the mechanisms underlying the process by which the persistent state occurs. However, important gaps exist into how the process develops, from the organism’s existence in the Ixodes tick, to its entry into the host, to its effects on the immune system, to its distribution and ability to persist in certain tissues, to its ability to persist despite innate and other host immune system responses, and to its ability to persist despite certain antibiotic treatments. But there is reason for optimism that additional research into the pathogenetic and pathophysiologic mechanisms will lead to a better understanding of the processes involved and ultimately to a better means of preventing and treating patients with persistent Lyme disease. Increased funding of targeted research into the pathogenesis and pathophysiology of Lyme disease is key to achieving that goal.

Acknowledgements

The following people assisted in the writing of this report:

Name Type Expertise

Christina Li, MPH Kauffman & Associates, Inc., Washington, DC

Contractor support

Science writer

Katie Terra Kauffman & Associates, Inc.,
Washington, DC

Contractor support

Technical writer

Dana Trevas, Kauffman & Associates, Inc., Washington, DC

Contractor support

Science Writer

References

Arnold, W. K., Savage, C. R., Brissette, C. A., Seshu, J., Livny, J., & Stevenson, B. (2016). RNA-Seq of Borrelia burgdorferi in multiple phases of growth reveals insights into the dynamics of gene expression, transcriptome architecture, and noncoding RNAs. PLoS One, 11: e016416.

Arvikar, S. L., & Steere, A. C. (2015). Diagnosis and treatment of Lyme arthritis. Infectious Disease Clinics of North America, 29(2): 269–280.

Bankhead, T. (2016). Role of the VlsE lipoprotein in immune avoidance by the Lyme disease spirochete Borrelia burgdorferi. Forum on Immunopathological Diseases and Therapeutics, 7(3-4): 191–204.

Bankhead, T., & Chaconas, G. (2007). The role of VlsE antigenic variation in the Lyme disease spirochete: Persistence through a mechanism that differs from other pathogens. Molecular Microbiology, 65(6): 1547–1558.

Blum, L. K., Adamska, J. Z., Martin, D. S., Rebman, A. W., Elliott, S. E., Cao, R. R. L., … Robinson, W. H. (2018). Robust B cell responses predict rapid resolution of Lyme disease. Frontiers in Immunology, 9: 1634.

Divan, A., Casselli, T., Narayanan, S. A., Mukherjee, S., Zawieja, D. C., Watt, J. 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.

Eisner, R. A., Hasley, C. J., Olsen, K. J., & Baumgarth, N. (2015). Suppression of long-lived humoral immunity following Borrelia burgdorferi infection. PLoS Pathogens, 11(7): e1004976.

Embers, M. E., Hasenkampf, N. R., Barnes, M. B., Didiere, E. S., Phillipp, M. T., & Tardo, A. C. (2016). A five-antigen fluorescent bead-based assay for diagnosis of Lyme disease. Clinical and Vaccine Immunology, 23(4): 294–303.

Embers, M. E., Hasenkampf, N. R., Jacobs, M. B., Tardo, A. C., Doyle-Meyers, L. A. Phillipp, M. T., & Hodzic, E. (2017). Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding. PLoS ONE, 12(12): e0189071.

Greenmyer, J. R., Gaultney, R. A., Brissette, C. A., & Watt, J. A. (2018). Primary human microglia are phagocytically active and respond to Borrelia burgdorferi with upregulation of chemokines and cytokines. Frontiers in Microbiology, 9: 811. doi:10.3389/fmicb.2018.00811.

Jutras, B. L., Chenail, A. M., & Stevenson, B. (2013). Changes in bacterial growth rate govern expression of the Borrelia burgdorferi OspC and Erp infection-associated surface proteins. Journal of Bacteriology, 195(4): 757–764.

Jutras, B. L., Lochhead, R. B., Kloos, Z. A., Biboy, J., Strle, K., Booth, C. J., … Jacobs-Wagner, C. (2019). Borrelia burgdorferi peptidoglycan is a persistent antigen in patients with Lyme arthritis. Proceedings of the National Academy of Sciences of the USA, 116(27): 13498–13507.

Lochhead, R. B., Arvikar, S. L., Aversa, J. M., Sadreyev, R. I., Strle, K., & Steere, A. C. (2019). Robust interferon signature and suppressed tissue repair gene expression in synovial tissue from patients with postinfectious, Borrelia burgdorferi-induced Lyme arthritis. Cellular Microbiology, 21(2): e12954.

Lochhead, R. B., Ordoñez, D., Arvikar, S. L., Aversa, J. M., Oh, L. S., Heyworth, B., … Strle, K. (2019). Interferon-gamma production in Lyme arthritis synovial tissue promotes differentiation of fibroblast-like synoviocytes into immune effector cells. Cellular Microbiology, 21(2): e12992.

Norris, S. J. (2006). Antigenic variation with a twist—the Borrelia story. Molecular Microbiology, 60(6): 1319–1322.

Radolf, J. D., Caimano, M., Stevenson, B., & Hu, L. (2012) Of ticks, mice and men: Understanding the dual-host lifestyle of Lyme disease spirochaetes. Nature Reviews. Microbiology, 10(2): 87–99.

Stevenson, B., & Seshu, J. (2018) Regulation of gene and protein expression in the Lyme disease spirochete. In B. Adler (Ed.), Spirochete biology: The post genomic era (pp. 83­–112). Heidelberg: Springer Nature.

Tracey, K. E., & Baumgarth, N. (2017). Borrelia burgdorferi manipulates innate and adaptive immunity to establish persistence in rodent reservoir hosts. Frontiers in Immunology, 8: 116.

van der Burg, S. H., Arens, R., & Melief, C. J. M. (2011). Immunotherapy for persistent viral infections and associated disease. Trends in Immunology, 32(3): 97–103.

Weiskopf, K., Ring, A. M., Ho, C. C., Volkmer, J. P., Levin, A. M., … Garcia, K. C. (2013). Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies. Science, 341(6141): 88–91.

Willingham, S. B., Volkmer, J. P., Gentles, A. J., Sahoo, D., Dalerba, P., Mitra, S., … Weissman, I.L. (2012). The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proceedings of the National Academy of Sciences of the USA, 109(17): 6662–6667.

Appendix 1: Pathogenesis and Pathophysiology of Lyme Disease Subcommittee Agendas and Brief Meeting Overview

Meeting 1, July 16, 2019

Agenda

  1. Roll call
  2. Introduction of subcommittee members
  3. Review of milestones and deliverables
  4. Discussion of proposed topics to be addressed, including potential speakers
  5. Plans for next meeting

Overview

The subcommittee identified topics for consideration and some potential guest presenters.

Meeting 2, July 30, 2019

Agenda

  1. Roll call
  2. Presentation: Unraveling the mysteries of Lyme disease (pathogenesis of Borrelia burgdorferi)
  3. Discussion
  4. Plans for next meeting

Overview

The subcommittee heard a presentation on the pathogenesis of B. burgdorferi.

Meeting 3, August 13, 2019

Agenda

  1. Roll call
  2. Presentation: B. burgdorferi transmission and dissemination in the vertebrate host
  3. Discussion
  4. Plans for next meeting

Overview

The subcommittee heard a presentation on transmission and dissemination of B. burgdorferi in the vertebrate host.

Meeting 4, August 27, 2019

Agenda

  1. Roll call
  2. Presentation: Genetic regulation of Lyme disease
  3. Discussion
  4. Plans for next meeting

Overview

The subcommittee heard a presentation on genetic regulation of Lyme disease.

Meeting 5, September 10, 2019

Agenda

  1. Roll call
  2. Presentation: Nicole Baumgarth: Infection of animals with B. burgdorferi
  3. Presentation: Monica Embers: Adaptive immune response variation and suppression in Lyme borreliosis
  4. Slide deck for Working Group meeting
  5. Upcoming meetings

Overview

The subcommittee heard presentations from members Nicole Baumgarth, DVM, PhD, and Monica E. Embers, PhD, on immune response and immunosuppression in response to B. burgdorferi infection in animals and discussed the implications of the research findings.

Meeting 6, September 24, 2019

Agenda

  1. Roll call
  2. Presentation: R. Mark Wooten, PhD: B. burgdorferi spirochetal motility
  3. Discussion
  4. Upcoming meetings

Overview

The subcommittee heard a presentation from R. Mark Wooten, PhD, of the University of Toledo College of Medicine describing the results of novel technology for real-time visualization of Borrelia burgdorferi spirochetal motility and discussed the implications of the research findings.

Meeting 7, October 1, 2019

Agenda

  1. Roll call
  2. Subcommittee report to the Tick-Borne Diseases Working Group
  3. Presentation: Michal “Mikki” Caspi Tal, PhD: CD47 and immune response to B. burgdorferi
  4. Discussion
  5. Upcoming meetings

Overview

The subcommittee heard a presentation from Michal “Mikki” Caspi Tal, PhD, of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University on the hypothesis that B. burgdorferi has a mechanism for preventing immune system response in hosts and discussed the implications of the research findings.

Meeting 8, October 8, 2019

Agenda

  1. Roll call
  2. Presentation: Robert Lochhead, PhD: From infection to autoimmunity: The pathogenesis of Lyme arthritis
  3. Discussion
  4. Upcoming meetings
  5. Subcommittee report to the Tick-Borne Diseases Working Group

Overview

The subcommittee heard a presentation from member Robert Lochhead, PhD, describing novel findings on the pathogenesis of post-infectious Lyme arthritis and discussed the implications of the research findings.

Meeting 9, October 15, 2019

Agenda

  1. Roll call
  2. Discussion of subcommittee report to the Tick-Borne Diseases Working Group
  3. Discussion of upcoming meetings
  4. Presentation: Emir Hodzic, DVM, MSc, PhD: Persistence of B. burgdorferi after antimicrobial treatment
  5. Adjournment

Overview

The subcommittee heard a presentation from Emir Hodzic, DVM, MSc, PhD, on his research findings, which suggest the presence of persistent, viable but uncultivable B. burgdorferi spirochetes and discussed the implications of the research findings.

Meeting 10, November 5, 2019

Agenda

  1. Roll call
  2. Discussion of subcommittee report to the Tick-Borne Diseases Working Group
  3. Presentation: Kim Lewis, PhD: Developing targeted treatments for Lyme disease
  4. Discussion of upcoming meetings and adjournment

Overview

The subcommittee heard a presentation from Kim Lewis, PhD, on some promising approaches to targeted treatment of Lyme disease and discussed the implications of the research findings.

Meeting 11, November 12, 2019

Agenda

  1. Roll call
  2. Reminder: Subcommittee report to the Tick-Borne Diseases Working Group
  3. Presentation: Catherine Brissette, PhD: A murine model of Lyme disease demonstrates that Borrelia species colonize the dura mater and induce inflammation in the central nervous system
  4. Upcoming meetings and adjournment

Overview

The subcommittee heard a presentation from Catherine Brissette, PhD, on a murine model that demonstrates Borrelia infection of the dura mater that leads to inflammation in the central nervous system and discussed the implications of the research findings.

Meeting 12, November 19, 2019

Agenda

  1. Roll call
  2. Presentation: Troy Bankhead, PhD: VlsE-mediated immune protection by the Lyme disease pathogen
  3. Reminder: Subcommittee report to the Tick-Borne Diseases Working Group
  4. Upcoming meetings and adjournment

Overview

The subcommittee heard a presentation from member Troy Bankhead, PhD, explaining how the VlsE gene protects B. burgdorferi surface antigens from host antibodies. Members discussed the implications of the research findings.

Meeting 13, December 3, 2019

Agenda

  1. Roll call
  2. Review of subcommittee report to the Tick-Borne Diseases Working Group
  3. Upcoming meetings and adjournment

Overview

The subcommittee reviewed its draft report to the Working Group and suggested revisions.

Meeting 14, December 17, 2019

Agenda

  1. Roll call
  2. Review of subcommittee report to the Tick-Borne Diseases Working Group and voting
  3. Next steps

Overview

The subcommittee reviewed its draft report to the Working Group and suggested revisions and voted on the contents of the report.

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Content last reviewed on January 23, 2020