Changing of the guard: How the Lyme disease spirochete subverts the host immune response.
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ABSTRACT:
SUBMITTER: Chaconas G
PROVIDER: S-EPMC6956529 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Many pathogens make use of antigenic variation as a way to evade the host immune response. A key mechanism for immune evasion and persistent infection by the Lyme disease spirochete, Borrelia burgdorferi, is antigenic variation of the VlsE surface protein. Recombination results in changes in the VlsE surface protein that prevent recognition by VlsE-specific antibodies in the infected host. Despite the presence of a substantial number of additional proteins residing on the bacterial surface, VlsE is the only known antigen that exhibits ongoing variation of its surface epitopes. This suggests that B. burgdorferi may utilize a VlsE-mediated system for immune avoidance of its surface antigens. To address this, the requirement of VlsE for host reinfection by the Lyme disease pathogen was investigated. Host-adapted wild type and VlsE mutant spirochetes were used to reinfect immunocompetent mice that had naturally cleared an infection with a VlsE-deficient clone. Our results demonstrate that variable VlsE is necessary for reinfection by B. burgdorferi, and this ability is directly related to evasion of the host antibody response. Moreover, the data presented here raise the possibility that VlsE prevents recognition of B. burgdorferi surface antigens from host antibodies. Overall, our findings represent a significant advance in our knowledge of immune evasion by B. burgdorferi, and provide insight to the possible mechanisms involved in VlsE-mediated immune avoidance.
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Project description:In nature, mixed Borrelia burgdorferi infections are common and possibly can be acquired by either superinfection or coinfection. Superinfection by heterologous B. burgdorferi strains has been established experimentally, although the ability of homologous B. burgdorferi clones to superinfect a host has not been studied in detail. Information regarding any potential immune barriers to secondary infection also currently is unavailable. In the present study, the ability to superinfect various mouse models by homologous wild-type clones was examined and compared to superinfection by heterologous strains. To assess the ability of homologous B. burgdorferi clones to successfully superinfect a mouse host, primary- and secondary-infecting spirochetes were recovered via in vitro cultivation of collected blood or tissue samples. This was accomplished by generating two different antibiotic-resistant versions of the wild-type B31-A3 clone in order to distinguish superinfecting B. burgdorferi from primary-infecting spirochetes. The data demonstrate an inability of homologous B. burgdorferi to superinfect immunocompetent mice as opposed to heterologous strains. Attempts to superinfect different types of immunodeficient mice with homologous B. burgdorferi indicate that the murine innate immune system represents a major barrier to intrastrain superinfection. Consequently, the possibility of innate immunity as a driving force for B. burgdorferi heterogeneity during the enzootic cycle is discussed.
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Project description: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. Wild-type and dksA mutant B. burgdorferi strains were subjected to starvation by shifting cultures grown in rich complete medium, Barbour-Stoenner-Kelly II (BSK II) medium, to a defined mammalian tissue culture medium, RPMI 1640, for 6?h under microaerobic conditions (5% CO2, 3% O2). Microarray analyses of wild-type B. burgdorferi revealed that genes encoding flagellar components, ribosomal proteins, and DNA replication machinery were downregulated in response to starvation. DksA mediated transcriptomic responses to starvation in B. burgdorferi, as the dksA-deficient strain differentially expressed only 47 genes in response to starvation compared to the 500 genes differentially expressed in wild-type strains. Consistent with a role for DksA in the starvation response of B. burgdorferi, fewer CFU of dksA mutants were observed after prolonged starvation in RPMI 1640 medium than CFU of wild-type B. burgdorferi spirochetes. Transcriptomic analyses revealed a partial overlap between the DksA regulon and the regulon of RelBbu, the guanosine tetraphosphate and guanosine pentaphosphate [(p)ppGpp] synthetase that controls the stringent response; the DksA regulon also included many plasmid-borne genes. Additionally, the dksA mutant exhibited constitutively elevated (p)ppGpp levels compared to those of the wild-type strain, implying a regulatory relationship between DksA and (p)ppGpp. Together, these data indicate that DksA, along with (p)ppGpp, directs the stringent response to effect B. burgdorferi adaptation to its environment.IMPORTANCE The Lyme disease bacterium Borrelia burgdorferi survives diverse environmental challenges as it cycles between its tick vectors and various vertebrate hosts. B. burgdorferi must withstand prolonged periods of starvation while it resides in unfed Ixodes ticks. In this study, the regulatory protein DksA is shown to play a pivotal role controlling the transcriptional responses of B. burgdorferi to starvation. The results suggest that DksA gene regulatory activity impacts B. burgdorferi metabolism, virulence gene expression, and the ability of this bacterium to complete its natural life cycle.
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Project description:Lyme disease is a tick-borne bacterial illness that occurs in areas of North America, Europe, and Asia. Early infection typically presents as generalized symptoms with an erythema migrans (EM) skin lesion. Dissemination of the pathogen Borrelia burgdorferi can result in multiple EM skin lesions or in extracutaneous manifestations such as Lyme neuroborreliosis. Metabolic biosignatures of patients with early Lyme disease can potentially provide diagnostic targets as well as highlight metabolic pathways that contribute to pathogenesis. Sera from well-characterized patients diagnosed with either early localized Lyme disease (ELL) or early disseminated Lyme disease (EDL), plus healthy controls (HC), from the United States were analyzed by liquid chromatography-mass spectrometry (LC-MS). Comparative analyses were performed between ELL, or EDL, or ELL combined with EDL, and the HC to develop biosignatures present in early Lyme disease. A direct comparison between ELL and EDL was also performed to develop a biosignature for stages of early Lyme disease. Metabolic pathway analysis and chemical identification of metabolites with LC-tandem mass spectrometry (LC-MS/MS) demonstrated alterations of eicosanoid, bile acid, sphingolipid, glycerophospholipid, and acylcarnitine metabolic pathways during early Lyme disease. These metabolic alterations were confirmed using a separate set of serum samples for validation. The findings demonstrated that infection of humans with B. burgdorferi alters defined metabolic pathways that are associated with inflammatory responses, liver function, lipid metabolism, and mitochondrial function. Additionally, the data provide evidence that metabolic pathways can be used to mark the progression of early Lyme disease.
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Project description:Borrelia burgdorferi, the agent of Lyme disease, spreads from the site of the tick bite to tissues such as heart, joints and the nervous tissues. Host glycosaminoglycans, highly modified repeating disaccharides that are present on cell surfaces and in extracellular matrix, are common targets of microbial pathogens during tissue colonization. While several dermatan sulfate-binding B. burgdorferi adhesins have been identified, B. burgdorferi adhesins documented to promote spirochetal binding to heparan sulfate have not yet been identified. OspEF-related proteins (Erps), a large family of plasmid-encoded surface lipoproteins that are produced in the mammalian host, can be divided into the OspF-related, OspEF-leader peptide (Elp) and OspE-related subfamilies. We show here that a member of the OspF-related subfamily, ErpG, binds to heparan sulfate and when produced on the surface of an otherwise non-adherent B. burgdorferi strain, ErpG promotes heparan sulfate-mediated bacterial attachment to the glial but not the endothelial, synovial or respiratory epithelial cells. Six other OspF-related proteins were capable of binding heparan sulfate, whereas representative OspE-related and Elp proteins lacked this activity. These results indicate that OspF-related proteins are heparan sulfate-binding adhesins, at least one of which promotes bacterial attachment to glial cells.
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Project description:In order to clear the body of infecting spirochetes, phagocytic cells must be able to get hold of them. In real-time phase-contrast videomicroscopy we were able to measure the speed of Borrelia burgdorferi (Bb), the Lyme spirochete, moving back and forth across a platelet to which it was tethered. Its mean crossing speed was 1,636 microm/min (N = 28), maximum, 2800 microm/min (N = 3). This is the fastest speed recorded for a spirochete, and upward of two orders of magnitude above the speed of a human neutrophil, the fastest cell in the body. This alacrity and its interpretation, in an organism with bidirectional motor capacity, may well contribute to difficulties in spirochete clearance by the host.
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Project description:The pathogenic spirochete Borrelia burgdorferi senses and responds to diverse environmental challenges, including changes in nutrient availability, throughout its natural infectious cycle in Ixodes spp. ticks and mammalian hosts. This study examined the role of the putative DnaK suppressor protein (DksA) in the transcriptional response of B. burgdorferi to starvation. Wild-type and dksA-deficient B. burgdorferi strains were subjected to starvation by shifting mid-logarithmic cultures grown in BSK-II medium to serum-free RPMI medium for six hours under microaerobic conditions (5% CO2, 3% O2). Microarray analyses of wild-type B. burgdorferi revealed that genes encoding flagellar components, ribosomal proteins, and DNA replication machinery were downregulated in response to starvation. DksA mediated transcriptomic responses to starvation in B. burgdorferi as the dksA-deficient B. burgdorferi strain differentially expressed only 47 genes in response to starvation compared to the 500 genes differentially expressed by wild-type strains. Consistent with a role for DksA in the starvation response of B. burgdorferi, fewer CFUs were observed for dksA-deficient spirochetes after prolonged starvation in RPMI medium compared to wild-type B. burgdorferi. Transcriptomic analyses revealed a partial overlap between the DksA regulon and the regulon of the guanosine tetraphosphate and guanosine pentaphosphate [(p)ppGpp] synthase RelBbu, while the DksA regulon also included many plasmid-borne genes. Corresponding to a DksA-(p)ppGpp regulatory relationship, (p)ppGpp levels were constitutively elevated in the dksA-deficient strain compared to the wild-type strain. Together, these data indicate that DksA directs the stringent response with a regulatory interplay with (p)ppGpp that is fundamental to B. burgdorferi responses to the environment.
2018-12-18 | GSE119023 | GEO
Project description:Transmission of Borrelia burgdorferi from its tick vector to a vertebrate host requires extensive reprogramming of gene expression. Small regulatory RNAs (sRNA) have emerged in the last decade as important regulators of bacterial gene expression. Despite the widespread observation of sRNA-mediated gene regulation, only one sRNA has been characterized in the Lyme disease spirochete B. burgdorferi. We employed an sRNA-specific deep-sequencing approach to identify the small RNA transcriptome of B. burgdorferi at both 23 °C and 37 °C, which mimics in vitro the transmission from the tick vector to the mammalian host.We identified over 1000 sRNAs in B. burgdorferi revealing large amounts of antisense and intragenic sRNAs, as well as characteristic intergenic and 5' UTR-associated sRNAs. A large fraction of the novel sRNAs (43%) are temperature-dependent and differentially expressed at the two temperatures, suggesting a role in gene regulation for adaptation during transmission. In addition, many genes important for maintenance of Borrelia during its enzootic cycle are associated with antisense RNAs or 5' UTR sRNAs. RNA-seq data were validated for twenty-two of the sRNAs via Northern blot analyses.Our study demonstrates that sRNAs are abundant and differentially expressed by environmental conditions suggesting that gene regulation via sRNAs is a common mechanism utilized in B. burgdorferi. In addition, the identification of antisense and intragenic sRNAs impacts the broadly used loss-of-function genetic approach used to study gene function and increases the coding potential of a small genome. To facilitate access to the analyzed RNA-seq data we have set-up a website at http://www.cibiv.at/~niko/bbdb/ that includes a UCSC browser track hub. By clicking on the respective link, researchers can interactively inspect the data in the UCSC genome browser (Kent et al., Genome Res 12:996-1006, 2002).
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Project description:6S RNA binds to RNA polymerase and regulates gene expression, contributing to bacterial adaptation to environmental stresses. In this study, we examined the role of 6S RNA in murine infectivity and tick persistence of the Lyme disease spirochete Borrelia (Borreliella) burgdorferi. B. burgdorferi 6S RNA (Bb6S RNA) binds to RNA polymerase, is expressed independent of growth phase or nutrient stress in culture, and is processed by RNase Y. We found that rny (bb0504), the gene encoding RNase Y, is essential for B. burgdorferi growth, while ssrS, the gene encoding 6S RNA, is not essential, indicating a broader role for RNase Y activity in the spirochete. Bb6S RNA regulates expression of the ospC and dbpA genes encoding outer surface protein C and decorin binding protein A, respectively, which are lipoproteins important for host infection. The highest levels of Bb6S RNA are found when the spirochete resides in unfed nymphs. ssrS mutants lacking Bb6S RNA were compromised for infectivity by needle inoculation, but injected mice seroconverted, indicating an ability to activate the adaptive immune response. ssrS mutants were successfully acquired by larval ticks and persisted through fed nymphs. Bb6S RNA is one of the first regulatory RNAs identified in B. burgdorferi that controls the expression of lipoproteins involved in host infectivity.
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Project description:To determine whether the Lyme disease spirochete Borrelia lusitaniae is associated with lizards, we compared the prevalence and genospecies of spirochetes present in rodent- and lizard-associated ticks at a site where this spirochete frequently infects questing ticks. Whereas questing nymphal Ixodes ricinus ticks were infected mainly by Borrelia afzelii, one-half of the infected adult ticks harbored B. lusitaniae at our study site. Lyme disease spirochetes were more prevalent in sand lizards (Lacerta agilis) and common wall lizards (Podarcis muralis) than in small rodents. Although subadult ticks feeding on rodents acquired mainly B. afzelii, subadult ticks feeding on lizards became infected by B. lusitaniae. Genetic analysis confirmed that the spirochetes isolated from ticks feeding on lizards are members of the B. lusitaniae genospecies and resemble type strain PotiB2. At our central European study site, lizards, which were previously considered zooprophylactic for the agent of Lyme disease, appear to perpetuate B. lusitaniae.
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