The Lyme disease spirochete, Borrelia burgdorferi, as a model vector-borne pathogen: insights on regulation of gene and protein expression

Stevenson, Brian

doi:10.1016/j.mib.2023.102332

Cited by 12 publications

(6 citation statements)

References 59 publications

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“…1D ). These results further underscore the remarkable intricacies of borrelial gene regulation cascades, where the expression of many genes is interlinked, including genes that encode Osps, with possible relevance to spirochete adaptations in the infectious cycle ( 10 , 16 , 17 ).…”

Section: Observationmentioning

confidence: 65%

A systemic approach to identify non-abundant immunogenic proteins in Lyme disease pathogens

Yaş,

Coleman,

Lipman

et al. 2024

mSystems

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Borrelia burgdorferi , the pathogen of Lyme disease, differentially produces many outer surface proteins (Osp), some of which represent the most abundant membrane proteins, such as OspA, OspB, and OspC. In cultured bacteria, these proteins can account for a substantial fraction of the total cellular or membrane proteins, posing challenges to the identification and analysis of non-abundant proteins, which could serve as novel pathogen detection markers or as vaccine candidates. Herein, we introduced serial mutations to remove these abundant Osps and generated a B. burgdorferi mutant deficient in OspA, OspB, and OspC in an infectious 297-isolate background, designated as Osp ABC − mutant. Compared to parental isolate, the mutant did not reflect growth defects in the cultured medium but showed differential mRNA expression of representative tested genes, in addition to gross changes in cellular and membrane protein profiles. The analysis of differentially detectable protein contents of the Osp ABC − mutant, as compared to the wild type, by two-dimensional gel electrophoresis followed by liquid chromatography-mass spectrometry, identified several spirochete proteins that are dominated by proteins of unknown functions, as well as membrane transporters, chaperons, and metabolic enzymes. We produced recombinant forms of two of these represented proteins, BBA34 and BB0238, and showed that these proteins are detectable during spirochete infection in the tick-borne murine model of Lyme borreliosis and thus serve as potential antigenic markers of the infection. IMPORTANCE The present manuscript employed a systemic approach to identify non-abundant proteins in cultured Borrelia burgdorferi that are otherwise masked or hidden due to the overwhelming presence of abundant Osps like OspA, OspB, and OspC. As these Osps are either absent or transiently expressed in mammals, we performed a proof-of-concept study in which their removal allowed the analysis of otherwise less abundant antigens in OspABC-deficient mutants and identified several immunogenic proteins, including BBA34 and BB0238. These antigens could serve as novel vaccine candidates and/or genetic markers of Lyme borreliosis, promoting new research in the clinical diagnosis and prevention of Lyme disease.

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Section: Observationmentioning

confidence: 65%

A systemic approach to identify non-abundant immunogenic proteins in Lyme disease pathogens

Yaş,

Coleman,

Lipman

et al. 2024

mSystems

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“…Although several DNA-binding proteins have been previously described in B . burgdorferi , these proteins were cytoplasmic and are involved in gene expression regulation [ 10 ]. Of course, this is not possible for PFam12 surface/periplasm localized lipoproteins, which also do not have a transmembrane part, suggesting that the proteins could most likely be related to sensing or gathering the eDNA although the exact role of PFam12 in B .…”

Section: Resultsmentioning

confidence: 99%

“…Regardless of the pathogenic Borrelia species located in the infected tick, once the bacteria from the tick gut enter the mammalian host, they must be able to fight against the host’s immune system, attach to different host cells, and disseminate [ 6 ]. Therefore, to adjust to the specific requirements, Borrelia has managed to change the expression levels of various proteins depending on the environmental conditions [ 7 – 10 ]. To successfully infect the new host, surface-exposed outer surface lipoproteins potentially play the most important role, as they interact with the environment.…”

Section: Introductionmentioning

confidence: 99%

Members of the paralogous gene family 12 from the Lyme disease agent Borrelia burgdorferi are non-specific DNA-binding proteins

Brangulis,

Akopjana,

Drunka

et al. 2024

PLoS ONE

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Lyme disease is the most prevalent vector-borne infectious disease in Europe and the USA. Borrelia burgdorferi, as the causative agent of Lyme disease, is transmitted to the mammalian host during the tick blood meal. To adapt to the different encountered environments, Borrelia has adjusted the expression pattern of various, mostly outer surface proteins. The function of most B. burgdorferi outer surface proteins remains unknown. We determined the crystal structure of a previously uncharacterized B. burgdorferi outer surface protein BBK01, known to belong to the paralogous gene family 12 (PFam12) as one of its five members. PFam12 members are shown to be upregulated as the tick starts its blood meal. Structural analysis of BBK01 revealed similarity to the coiled coil domain of structural maintenance of chromosomes (SMC) protein family members, while functional studies indicated that all PFam12 members are non-specific DNA-binding proteins. The residues involved in DNA binding were identified and probed by site-directed mutagenesis. The combination of SMC-like proteins being attached to the outer membrane and exposed to the environment or located in the periplasm, as observed in the case of PFam12 members, and displaying the ability to bind DNA, represents a unique feature previously not observed in bacteria.

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“…This tick is considered endemic to several parts of USA including Midwest, Northeast, West, Southeast, and Southern USA and its distribution is dependent on the various ecological factors such as climates, vegetation, landscape and availability of host [1,2]. I. scapularis, which transmits 7 of 16 human tick borne disease (TBD) agents in the USA [2] including causative agents of anaplasmosis (Anaplasma phagocytophilum), babesiosis (Babesia microti), ehrlichiosis (Ehrlichia chaffeensis), hard Tick Relapsing Fever (Borrelia miyamotoi), Powassan encephalitis virus [3][4][5], is famously known for transmission of causative agents of Lyme disease (LD): Borrelia burgdorferi [6] and the recently described B. mayonii [7][8][9]. LD is among the most important human TBD with ≈476,000 diagnosed cases nationally per year and can cost up to $1 billion without including suspected, undiagnosed and nonacute cases.…”

Section: Introductionmentioning

confidence: 99%

<em>Ixodes scapularis</em> Calreticulin Binds Complement Proteins but Does Not Protect <em>Borrelia burgdorferi </em>from Complement Killing

Ansari,

Nguyen,

Kocurek

et al. 2024

Preprint

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Ixodes scapularis is a blood-feeding obligate ectoparasite responsible for transmitting the Lyme disease (LD) agent, Borrelia burgdorferi. During the feeding process, I. scapularis injects B. burgdorferi into the host along with its saliva, facilitating the transmission and colonization of the LD agent. Tick calreticulin (CRT) is one of the earliest tick saliva proteins identified and is currently utilized as a biomarker for tick bites. Our recent findings revealed elevated levels of CRT in the saliva proteome of B. burgdorferi-infected I. scapularis nymphs compared to uninfected ticks. Differential precipitation of proteins (DiffPOP) and LC-MS/MS analyses were used to identify the interactions between Ixs (I. scapularis) CRT and human plasma proteins and further exploring its potential role in shielding B. burgdorferi from complement killing. We observed that although yeast expressed recombinant (r) IxsCRT binds to the C1 complex (C1q, C1r, and C1s), the activator of complement via the classical cascade, it did not inhibit deposition of the membrane attack complex (MAC) via the classical pathway. Intriguingly, rIxsCRT binds intermediate complement proteins (C3, C5, and C9) and reduces MAC deposition through the lectin pathway. Despite inhibition of MAC deposition in the lectin pathway, rIxsCRT did not protect a serum sensitive B. burgdorferi strain (B314/pBBE22Luc) from complement-induced killing. As B. burgdorferi establishes a local dermal infection before disseminating to secondary organs, it is noteworthy that rIxsCRT promotes the replication of B. burgdorferi in culture. We hypothesize that rIxsCRT may contribute to the transmission and/or host colonization of B. burgdorferi by acting as a decoy activator of complement and by fostering B. burgdorferi replication at the transmission site.

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The Lyme disease spirochete, Borrelia burgdorferi, as a model vector-borne pathogen: insights on regulation of gene and protein expression

Cited by 12 publications

References 59 publications

A systemic approach to identify non-abundant immunogenic proteins in Lyme disease pathogens

A systemic approach to identify non-abundant immunogenic proteins in Lyme disease pathogens

Members of the paralogous gene family 12 from the Lyme disease agent Borrelia burgdorferi are non-specific DNA-binding proteins

<em>Ixodes scapularis</em> Calreticulin Binds Complement Proteins but Does Not Protect <em>Borrelia burgdorferi </em>from Complement Killing

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