Basic Science Archives - Global Lyme Alliance Basic Science Archives - Global Lyme Alliance

Antimicrobial action of calprotectin that does not involve metal withholding.

Metallomics doi: 10.1039c8mt00133b

YEAR: 2018 TOPICS: Basic Science, Treatment.

Heavy metals like iron, copper, manganese and zinc can be toxic in large amounts. But in low concentrations, they are essential micronutrients for humans as well as bacteria. As part of the defense against invasive microbes, our immune system exploits this property by starving bacteria of the metals they need to survive. One way of doing this is with calprotectin, an immune defense protein produced by neutrophils at the site of infections. Calprotectin depletes the local environment of metal nutrients, and can block Borrelia burgdorferi growth. The mechanism of how this works has now been explained in a newly published study, funded by GLA and led by Dr. Valeria Culotta.

Calprotectin was found in the dermal and epidermal layers of erythema migrans rashes of early Lyme disease patients. It is believed that epithelial keratinocytes in the skin produce calprotectin, which is more commonly associated with neutrophils, immune cells that are absent in this particular site. Surprisingly, calprotectin blocked B. burgdorferi growth not by depleting metals, as would be expected. Instead, it directly bound to the bacteria and changed their shape from spirochetes into a cyst-like form, when immersed in water. This differs from calprotectin’s mechanism of blocking another bacteria, E. coli, in which metal sequestration is essential to blocking bacterial replication. These findings suggest a unique new pathway that could be explored for a potential therapeutic that is specific to B. burgdorferi.

Borrelia burgdorferi bbk13 Is Critical for Spirochete Population Expansion in the Skin during Early Infection

George Aranjuez

YEAR: 2019 TOPICS: Basic Science.

Borrelia burgdorferi (Bb) enters the human body via the bite of an infected Ixodes tick. Lyme disease symptoms arise from the dissemination of Bb from the initial bite site to the distal tissues such as the heart, the joints, or the nervous system. We identified a novel Bb infectivity gene, bbk13, that is important for distal tissue colonization in a mouse model of infection. Detailed characterization of the infection kinetics showed that there is a critical Bb population expansion that occurs at the skin during early infection and that bbk13 is important for this process. This study highlights the significance of early spirochete expansion in the skin towards driving downstream events that lead to distal tissue colonization. Therapeutic approaches that limit the early, localized expansion in the skin may prevent the onset of disseminated Lyme disease symptoms.

Published in American Society for Microbiology:

Borrelia burgdorferi-Induced Changes in the Class II Self-Immunopeptidome Displayed on HLA-DR Molecules Expressed by Dendritic Cells

Maria G. Gutierrez-Hoffman, Robert N. O'Meally, Robert N. Cole, Eleni Tiniakou, Erika Darrah, Mark J. Soloski

YEAR: 2020 TOPICS: Basic Science.

Published in: Front Med (Lausanne) Sep 16;7:568. doi: 10.3389/fmed.2020.00568. eCollection 2020.

Botanical medicines Cryptolepsis sanguinolenta, Artemisia annua, Scutellaria baicalensis, Polygonum cuspidatum, and Alchornea cordifolia demonstrate inhibitory activity against Babesia duncani.

Yumin-Zhang, Hector S. Alvarez-Manzo, Jacob Leone, Sunjya Schweig, Ying Zhang

YEAR: 2021 TOPICS: Basic Science.

Published in: Frontiers in cellular and infection microbiology.

Doi: 10.3389/fcimb.2021.624645. 08 March 2021.

Brave new worlds: the expanding universe of Lyme disease

Vector-borne Zoo Dis 17:619

Brissette CA

YEAR: 2017 TOPICS: Basic Science, Tick Biology.

C-reactive protein response in patients with post-treatment Lyme disease symptoms versus those with myalgic encephalomyelitis/chronic fatigue syndrome

Clin Inf Dis. 67(8):1309–1310.

Alaedini A

YEAR: 2018 TOPICS: Basic Science, Diagnostics.

DksA Controls the Response of the Lyme Disease Spirochete Borrelia burgdorferi to Starvation

Ashley Groshong

YEAR: 2019 TOPICS: Basic Science.

The pathogenic spirochete Borrelia burgdorferi senses and responds to changes in the environment, including changes in nutrient availability, throughout its enzootic cycle in Ixodes ticks and vertebrate hosts. This study examined the role of DnaK suppressor protein (DksA) in the transcriptional response of B. burgdorferi to starvation.

Published in American Society for Microbiology–Journal of Bacteriology:

Evaluation of Disulfiram Drug Combinations and Identification of Other More Effective Combinations against Stationary Phase Borrelia burgdorferi

Yumin-Zhang, Hector S. Alvarez-Manzo, Wanliang Shi, Ying Zhang

YEAR: 2020 TOPICS: Basic Science, Treatment.

Published in: Antibiotics Aug 26;9(9):542.

doi: 10.3390/antibiotics9090542

Genomes, expression profiles, and diversity of mitochondria of the White-footed Deermouse Peromyscus leucopus, reservoir of Lyme disease and other zoonoses

Alan Barbour

YEAR: 2019 TOPICS: Basic Science.

Dr. Alan Barbour and his team have analyzed the mitochondrial DNA from wild white-footed mice, Peromyscus leucopus. These mice are the natural host for Lyme and other tickborne bacteria, and serve as a reservoir from which ticks acquire pathogens. However, the mice themselves do not become sick despite being infected. This work focuses on mitochondria, the organelle responsible for generating energy in living cells. By sequencing and analyzing mitochondrial DNA and its transcription, Dr. Barbour’s group has provided the groundwork to determine how mice can tolerate infection, compared to lab mice and humans who do suffer symptoms. In addition, because mitochondrial DNA is inherited directly from the mother, genetic studies to understand Peromyscus subspecies geographic distribution and vectorborne disease dynamics can now be undertaken.

Published in Nature:

Host-specific functional compartmentalization within the oligopeptide transporter during the Borrelia burgdorferi enzootic cycle

Ashley M. Groshong, Melissa A. McLain, Justin D. Radolf

YEAR: 2021 TOPICS: Basic Science.

Published in: PLos Pathogens, 2021 Jan 11;17(1):e1009180.

doi: 10.1371/journal.ppat.1009180. eCollection 2021 Jan

Identification of Essential Oils with Strong Activity against Stationary Phase Borrelia burgdorferi

Antibiotics 2018, 7(4), 89;

Ying Zhang

YEAR: 2019 TOPICS: Basic Science, Chronic Lyme.

Persister forms of Borrelia burgdorferi, the bacterium that causes Lyme disease, are dormant or slow-growing, and tolerant of antibiotic treatment. It’s not clear yet whether persister bacteria, immune dysfunction, or some combination of the two is responsible for post-treatment Lyme disease syndrome (PTLDS), in which patients treated with antibiotics continue to suffer symptoms.

The search for novel compounds to kill persister bacteria has led to the discovery that essential oils (EOs), aromatic compounds produced by plants, may be promising. In an article published in Antibiotics, a peer-reviewed journal, scientists led by Dr. Ying Zhang of Johns Hopkins University identified 10 EOs that have strong activity against stationary phase B. burgdorferi at a low concentration of 0.1%. The study, underwritten by GLA, found that of the 10 EOs, those of garlic, allspice, and Palmarosa were active at even at 0.05% concentration. In addition, cinnamaldehyde, a major ingredient isolated from cinnamon bark, was active against both stationary phase bacteria as well as replicating B. burgdorferi at a 0.02% concentration.

A stringent test of antimicrobial activity against stationary phase bacteria is the capacity to block subcultured bacteria from growing. This means that after killing bacteria in culture with the inhibitor, a small amount of that culture is transferred to fresh growth media that lacks the inhibitor. Any regrowth indicates that the inhibitor did not completely kill all bacteria from the original culture. Under these conditions, only garlic and cinnamaldehyde were effective against the regrowth of B. burgdorferi spirochetes subcultured for 21 days.

These results indicate that certain EOs or their ingredients are potent in eliminating persister B. burgdorferi, and should be studied in greater depth to analyze their utility as potential treatments.

Interactions Between Ticks and Lyme Disease Spirochetes.

Utpal Pal, Chrysoula Kitsou, Dan Drecktrah, Ozlam Buyuktanir Yas, Erol Fikrig

YEAR: 2020 TOPICS: Basic Science.

Published in: Curr Issues Mol Biol. 2020 Dec 8;42:113-144. doi: 10.21775/cimb.042.113.

Lymphatic Migration of Immune Cells

Henry Hampton

YEAR: 2019 TOPICS: Basic Science.

Lymphatic vessels collect interstitial fluid that has extravasated from blood vessels and return it to the circulatory system. Another important function of the lymphatic network is to facilitate immune cell migration and antigen transport from the periphery to draining lymph nodes. This migration plays a crucial role in immune surveillance, initiation of immune responses and tolerance.

Published in Frontiers in :

Metagenomic-based surveillance of Pacific coast tick Dermacentor occidentalis identifies two novel bunyaviruses and an emerging human ricksettsial pathogen

Sci Rep. 7:12234. doi:10.1038/s41598-017-12047-6

Chiu CY

YEAR: 2017 TOPICS: Basic Science, Tick Biology.

Pediatric Lyme Disease Biobank, United States, 2015–2020

Lise Nigrovic, Desire N. Neville, Fran Balamuth, Michael N. Levas, Jonathan E. Bennett, Anupam B. Kharbanda, Amy D. Thompson, John A. Branda, Aris C. Garro, Pedi Lyme Net Working Group

YEAR: 2020 TOPICS: Basic Science, Diagnostics, Patient Care.

Published in: Emerg Infect Dis. 2020 Dec; 26(12): 3099–3101.

doi: 10.3201/eid2612.200920

Short-chain fatty acids alter metabolic and virulence attributes of Borrelia burgdorferi

Infec Immun 86(9): pii e00217-18. doi: 10.1128/IAI.00217-18

Seshu J

YEAR: 2018 TOPICS: Basic Science.

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

Monica Embers, Ying Zhang

YEAR: 2019 TOPICS: Basic Science, Chronic Lyme, Treatment.

Although most patients with Lyme disease can be cured with a 2-4 week antibiotic therapy, about 10-20% of patients continue to suffer prolonged persistent symptoms, a condition called post-treatment Lyme disease syndrome (PTLDS). The cause for PTLDS is unclear and hotly debated. B. burgdorferi develops morphological variants under stress conditions but their significance is not clear. Here we isolated the biofilm-like microcolony (MC) and planktonic (spirochetal form and round body) (SP) variant forms from the stationary phase culture and showed that the MC and SP were not only more tolerant to the current Lyme antibiotics but also caused more severe arthritis in mice than the log phase spirochete form (LOG). We propose to divide the persistent Lyme disease into two categories: (1) early development of persistent disease from inoculation with persister/biofilm at the beginning of infection introduced by tick bites, or Type I persistent disease (i.e., PTLDS); and (2) late development of persistent disease due to initial infection not being diagnosed or treated in time such that the infection develops into late persistent disease, or Type II persistent disease. Importantly, we show that the murine infection caused by LOG could be eradicated by ceftriaxone whereas the persistent infection established with MC could not be eradicated by doxycycline (Doxy), ceftriaxone (CefT), or vancomycin (Van), or Doxy+CefT or Van+CefT, but could only be eradicated by the persister drug combination daptomycin+doxycycline+ceftriaxone. Our studies demonstrate that varying levels of persistence and pathologies of Borrelia infection can be established with heterogeneous inocula with different morphologies and have different treatment responses. These observations may have broad implications for understanding pathogenesis and treatment of not only persistent Lyme disease but also other persistent infections in general and call for treatment of persistent infections with persister drug combination regimens that are more effective than the current often single-antibiotic monotherapy treatment.

Published in Discovery Medicine: 

The Functional and Molecular Effects of Doxycycline Treatment on Borrelia burgdorferi Phenotype

Monica Embers

YEAR: 2019 TOPICS: Basic Science, Chronic Lyme, Treatment.

Recent studies have shown that Borrelia burgdorferi can form antibiotic-tolerant persisters in the presence of microbiostatic drugs such as doxycycline. Precisely how this occurs is yet unknown. The goal of this study was to examine gene transcription by B. burgdorferi following doxycycline treatment in an effort to identify both persister-associated genes and possible targets for antimicrobial intervention.

Published in Frontiers in Microbiology:

The RpoS Gatekeeper in Borrelia burgdorferi: An Invariant Regulatory Scheme That Promotes Spirochete Persistence in Reservoir Hosts and Niche Diversity

Ashley Groshong

YEAR: 2019 TOPICS: Basic Science, Chronic Lyme.

This team, based at University of Connecticut, studied genes controlled by the RpoS pathway, the regulatory system that facilitates transmission and mammalian infection by Borrelia burgdorferi. They were particularly interested in whether RpoS-controlled genes are needed for chronic infection. They were able to show, contrary to current hypotheses, that OspA was expressed on spirochetes delivered via tick, then quickly turned off via RpoS repression. OspA remains repressed until subsequent acquisition by feeding larvae. RpoS is known to be required for the early stages of infection. But it’s been hard to study RpoS during chronic infection, because mutant strains of bacteria that lack RpoS aren’t virulent. Using a creative approach, the team confirmed that expression of RpoS is required throughout infection. In support of these findings, they identified an RpoS-regulated protein that imports peptides, OppA5, that are required to maintain bacterial persistence during chronic infection. OppA5 has thus been deemed a “persistence” gene, validating the hypothesis that a specific subset of RpoS-regulated genes are essential for maintenance of chronic infection.

Published in Frontiers in Microbiology:

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