Mario Philipp and Monica Embers (TNPRC)

Lyme disease, or Lyme borreliosis, is prevalent worldwide. In the U.S., where it is the most frequently reported vector-borne disease, the annual number of reported cases exceeds 30,000, and the CDC estimates that the true incidence of Lyme disease may be 10-fold larger. Its etiologic agent, the spirochete Borrelia burgdorferi (sensu lato), infects humans incidentally during a transmission cycle that involves ticks and rodents as the two main protagonists, and deer as the preferred hosts for the adult ticks. Following infection, spirochetes eventually disperse to multiple organs, including the skin, joints, heart,eyes, nerves, and brain. This remarkable organ pleiotropism by B. burgdorferi is probably the cause of the diverse manifestations of Lyme borreliosis. These include, among others, a skin rashcalled erythema migrans, acute or chronic arthritis, carditis, and neurological disease (neuroborreliosis). Lyme neuroborreliosis is arguably the most morbid manifestation of Lyme disease.

Nonhuman primate(NHP) studies are instrumental to address issues such as antibiotic treatment efficacy, diagnosis, and neuroborreliosis. The NHP is the only animal model to reproduce virtually all of the signs of Lyme disease, including neuroborreliosis(1,2) and, as with humans, it is an incidental host for B. burgdorferi. Mice, in contrast, do not exhibit skin rash or nervous system disease, and they are a natural (reservoir) host for the spirochete.

Early Lyme disease is treated successfully with antibiotics in the majority of the cases. The response to treatment by patients with late manifestations is typically slower, may take weeks or months and sometimes remain incomplete. This is why early and accurate diagnosis of Lyme borreliosis is crucial. A peptide-based ELISA denoted as the C6 test was developed following the discovery by investigators at the Tulane National Primate Research Center (TNPRC) of the C6 peptide as a diagnostic antigen(3). This diagnostic test, which was approved by the FDA and the USDA, has been shown to be as sensitive and specific as the CDC-recommended two-tier test, but entails only one step(4). Furthermore, it has been shown to have potential as a test for cure(5), and serves as the antigen in the most commonly used canine Lyme diagnostic test(6). Subsequent efforts have been focused on expanding the sensitivity of the C6 test by combining the peptide with other B. burgdorferi antigens in a Luminex®-based diagnostic assay.

About 10% of the patients treated for Lyme disease after physician-diagnosed erythema migrans have persistent or intermittently subjective musculoskeletal, cognitive, or fatigue complaints of mild to moderate intensity at 12 months of follow up. The underlying mechanism for these symptoms, collectively referred to as post-treatment Lyme disease (or post-Lyme disease) syndrome (PTLDS) is currently unknown and is the focus of intense controversy in the field of Lyme disease. Investigators at the TNPRC demonstrated the persistence of B. burgdorferi spirochetes in rhesus macaques following administration of standard antibiotic therapy. Among the techniques used to detect the low-level persistent spirochetes was xenodiagnosis, wherein intact B. burgdorferi were observed(7). These studies have prompted further inquiry into the cause of PTLDS and the potential need for more effective antibiotics.

In recent studies in rhesus macaques,TNPRC researchers demonstrated that inflammation is required for B. burgdorferi to cause signs of Lyme neuroborreliosis such as leptomeningitis, vasculitis, demyelination in the spinal roots, and neurodegeneration in the dorsal root ganglia (8). NHPs that were treated with a steroidal anti-inflammatory drug showed none of these signs. Investigators have, in addition, implicated the mitogen-activated protein kinase kinase (MAP2K or MEK) pathway as a major conduit for inflammation caused by B. burgdorferi in NHP microglia (9).These and other findings have helped to delineate the mechanisms that underlie Lyme neuroborreliosis. They will aid in directing therapy for affected individuals.

Article References

1. England JD, Bohm RP Jr, Roberts ED, Philipp MT. Mononeuropathy multiplex in rhesus monkeys with chronic Lyme disease. Ann Neurol. 1997 Mar;41(3):375-84. PubMed PMID: 9066359.

2. Roberts ED, Bohm RP, Jr., Lowrie RC, Jr., Habicht G, Katona L, Piesman J, Philipp MT. 1998. Pathogenesis of Lyme neuroborreliosis in the rhesus monkey: the early disseminated and chronic phases of disease in the peripheral nervous system. Journal of Infectious Diseases 178:722-732.

3. Liang FT, Alvarez AL, Gu Y, Nowling JM, Ramamoorthy R, Philipp MT. 1999. An immunodominant conserved region within the variable domain of VlsE, the variable surface antigen of Borrelia burgdorferi. Journal of Immunology 163:5566-5573.

4. Liang FT, Steere AC, Marques AR, Johnson BJ, Miller JN, Philipp MT. 1999. Sensitive and specific serodiagnosis of Lyme disease by enzyme-linked immunosorbent assay with a peptide based on an immunodominant conserved region of Borrelia burgdorferi VlsE. Journal of Clinical Microbiology 37:3990-3996. PubMed Central PMCID: PMC85863.

5. Philipp MT, Bowers LC, Fawcett PT, Jacobs MB, Liang FT, Marques AR, Mitchell PD, Purcell JE, Ratterree MS, Straubinger RK. 2001. Antibody response to IR6, a conserved immunodominant region of the VlsE lipoprotein, wanes rapidly after antibiotic treatment of Borrelia burgdorferi infection in experimental animals and in humans. Journal of Infectious Diseases 184:870-878.

6. Liang FT, Jacobson RH, Straubinger RK, Grooters A, Philipp MT. 2000. Characterization of a Borrelia burgdorferi VlsE invariable region useful in canine Lyme disease serodiagnosis by enzyme-linked immunosorbent assay. Journal of Clinical Microbiology 38:4160-4166. PubMed Central PMCID: PMC87557.

7. Embers ME, Barthold SW, Borda JT, Bowers L, Doyle L, Hodzic E, Jacobs MB, Hasenkampf NR, Martin DS, Narasimhan S, Phillippi-Falkenstein KM, Purcell JE, Ratterree MS, Philipp MT. 2012. Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated infection. PLoS ONE 7:e29914.PubMed Central PMCID: PMC3256191.

8. Ramesh G, Didier PJ, England JD, Santana-Gould L, Doyle-Meyers LA, Martin DS, Jacobs MB, Philipp MT. Inflammation in the pathogenesis of lyme neuroborreliosis. Am J Pathol. 2015. In press.

9. Parthasarathy G and Philipp MT.Inflammatory mediator release from primary rhesus microglia in response to Borrelia burgdorferi results from the activation of several receptors and pathways. J Neuroinflammation. 2015. In press.

NPRC Publications

There are currently 31 publications available for Lyme Disease.

2018

Blum LK, Adamska JZ, Martin DS, Rebman AW, Elliott SE, Cao RRL, Embers ME, Aucott JN, Soloski MJ, Robinson WH
Robust B Cell Responses Predict Rapid Resolution of Lyme Disease.
Frontiers in immunology 2018 08; 9(): 1634.

Parthasarathy G, Philipp MT
Intracellular TLR7 is activated in human oligodendrocytes in response to Borrelia burgdorferi exposure.
Neurosci. Lett. 2018 Feb; 671(): 38-42.

2017

Crossland NA, Alvarez X, Embers ME.
Late Disseminated Lyme Disease: Associated Pathology and Spirochete Persistence Posttreatment in Rhesus Macaques.
Am. J. Pathol. 2017 Dec; (): .

Embers ME, Hasenkampf NR, Jacobs MB, Tardo AC, Doyle-Meyers LA, Philipp MT, Hodzic E.
Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding.
PLoS ONE 2017 ; 12(12): e0189071.

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