<i>Borrelia burgdorferi</i>
            Lacking BBK32, a Fibronectin-Binding Protein, Retains Full Pathogenicity

Li, Xin; Liu, Xianzhong; Beck, Deborah S.; Kantor, Fred S.; Fikrig, Erol

doi:10.1128/iai.02035-05

Cited by 90 publications

(99 citation statements)

References 62 publications

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“…Previous studies have identified several important virulence determinants, such as OspA, OspC, DbpB, DbpA, and BBK32 (19,31,39,54,60,67). For instance, B. burgdorferi strictly requires OspC to establish an infection in mice.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of bb0184 , Which Encodes Carbon Storage Regulator A, Represses the Infectivity of Borrelia burgdorferi

Sze

2011

Infect Immun

106

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The genome of Borrelia burgdorferi, the Lyme disease spirochete, encodes a homolog (the bb0184 gene product) of the carbon storage regulator A protein (CsrA Bb ); recent studies reported that CsrA Bb is involved in the regulation of several infectivity factors of B. burgdorferi. However, the mechanism involved remains unknown. In this report, a csrA Bb mutant was constructed and complemented in an infectious B31A3 strain. Subsequent animal studies showed that the mutant failed to establish an infection in mice, highlighting that CsrA Bb is required for the infectivity of B. burgdorferi. Western blot analyses revealed that the virulenceassociated factors OspC, DbpB, and DbpA were attenuated in the csrA Bb mutant. The Rrp2-RpoN-RpoS pathway ( 54 -S sigma factor cascade) is a central regulon that governs the expression of ospC, dbpB, and dbpA. Further analyses found that the level of RpoS was significantly decreased in the mutant, while the level of Rrp2 remained unchanged. A recent study reported that the overexpression of BB0589, a phosphate acetyl-transferase (Pta) that converts acetyl-phosphate to acetyl-coenzyme A (CoA), led to the inhibition of RpoS and OspC expression, suggesting that acetyl-phosphate is an activator of Rrp2. Along with this report, we found that CsrA Bb binds to the leader sequence of the bb0589 transcript and that the intracellular level of acetyl-CoA in the csrA Bb mutant was significantly increased compared to that of the wild type, suggesting that more acetyl-phosphate was being converted to acetyl-CoA in the mutant. Collectively, these results suggest that CsrA Bb may influence the infectivity of B. burgdorferi via regulation of acetate metabolism and subsequent activation of the Rrp2-RpoN-RpoS pathway.Borrelia burgdorferi, the causative agent of Lyme borreliosis, has a complex natural enzootic life cycle-transmitting between Ixodes tick vectors and mammals (56, 57). As such, differential gene expression plays an important role in its adaptation to diverse host environments (10, 45). To date, a limited number of regulatory pathways have been identified in B. burgdorferi (13,16,23,34,38,46,66). Among these identified regulatory factors, the Rrp2-RpoN-RpoS pathway is a central regulatory network of B. burgdorferi, which consists of a two-component response regulator, Rrp2, and two alternative sigma factors, RpoN ( 54 ) and RpoS ( S

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Section: Discussionmentioning

confidence: 99%

Inactivation of bb0184 , Which Encodes Carbon Storage Regulator A, Represses the Infectivity of Borrelia burgdorferi

Sze

2011

Infect Immun

106

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“…This may therefore translate into a lack of attenuation of infectivity following short-or long-term infection. Inactivation of proteins in B. burgdorferi that serve as adhesins, such as BBK32 (38,61) and Bgp (49), has resulted in either partial or no attenuation of infectivity, suggesting the role of multiple borrelial determinants in initiation and maintenance of infection. Hence, it is interesting to speculate that infectivity analysis of a BBA64/ BBA65/BBA66-negative triple mt will help further characterize the role of a subset of pgf 54 family members in the colonization and dissemination of B. burgdorferi within the mammalian host.…”

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confidence: 99%

Role of the BBA64 Locus of Borrelia burgdorferi in Early Stages of Infectivity in a Murine Model of Lyme Disease

et al. 2008

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Borrelia burgdorferi, the causative agent of Lyme disease, undergoes rapid adaptive gene expression in response to environmental signals encountered during different stages of its life cycle in the arthropod vector or the mammalian host. Among all the plasmid-encoded genes of B. burgdorferi, several linear plasmid 54 (lp54)-encoded open reading frames (ORFs) exhibit the greatest differential expression in response to mammalian host-specific temperature, pH, and other uncharacterized signals. These ORFs include members of the paralogous gene family 54 (pgf 54), such as BBA64, BBA65, and BBA66, present on lp54. In an attempt to correlate transcriptional up-regulation of these pgf 54 members to their role in infectivity, we inactivated BBA64 and characterized the phenotype of this mutant both in vitro and in vivo. There were no major differences in the protein profiles between the BBA64 mutant and the control strains, while immunoblot analysis indicated that inactivation of BBA64 resulted in increased levels of BBA65. Moreover, there was no significant difference in the ability of the BBA64 mutant to infect C3H/HeN mice compared to that of its parental or complemented control strains as determined by culturing of viable spirochetes from infected tissues. However, enumeration of spirochetes using quantitative real-time PCR revealed tissue-specific differences, suggesting a minimal role for BBA64 in the survival of B. burgdorferi in select tissues. Infectivity analysis of the BBA64 mutant suggests that B. burgdorferi may utilize multiple determinants to establish infection in mammalian hosts.Lyme disease is the most prevalent arthropod-borne infection in the United States and remains a significant public health issue in certain geographic loci (3,46). It is a multiphasic disorder with clinical symptoms involving the cutaneous, musculoskeletal, cardiovascular, and nervous systems (62). Borrelia burgdorferi, the causative agent of Lyme disease, is transmitted to several vertebrate hosts, including humans, by the bite of infected Ixodes ticks. When ticks consume a blood meal from mammalian hosts, there is a rapid alteration of gene expression in B. burgdorferi, facilitating adaptation of the spirochetes to the highly disparate environmental conditions that exist between the tick vector and the vertebrate host (4, 9, 10, 15, 29, 30-32, 44, 53, 57-59, 63, 67). This adaptive gene expression may aid in the efficient trafficking of the spirochetes from the tick vector to the mammalian host and subsequently facilitate dissemination and colonization of various host tissues (16,22).Whole-genome transcriptional analyses using B. burgdorferi, propagated under in vitro growth conditions that mimic either the tick vector or mammalian host environment, have revealed preferential expression of plasmid-encoded genes (4,44,53,66). Among the several linear and circular plasmids present in B. burgdorferi, linear plasmid 54 (lp54) encodes the largest number of open reading frames (ORFs) that exhibit differential gene expression in respon...

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“…The current results demonstrate that not all genes whose expression is coordinately regulated with those required for virulence are themselves necessary for that process. It should be noted that there are numerous contradictory reports about the roles of other RpoS-dependent genes (e.g., dbpA, bbk32, and bba64) in mammalian infection, although these discrepancies may depend on the experimental mode of infection (3,20,31,34,35,(42)(43)(44)(45). Our findings underscore the necessity to demonstrate required protein function by mutagenesis experiments, rather than reliance on correlative data alone.…”

Section: Discussionmentioning

confidence: 69%

BB0844, an RpoS-Regulated Protein, Is Dispensable for Borrelia burgdorferi Infectivity and Maintenance in the Mouse-Tick Infectious Cycle

et al. 2011

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The genome of Borrelia burgdorferi, the causative agent of Lyme disease, is comprised of a large linear chromosome and numerous smaller linear and circular plasmids. B. burgdorferi exhibits substantial genomic variation, and previous studies revealed genotype-specific variation at the right chromosomal telomere. A correlation has also been established between genotype and invasiveness. The correlation between chromosome length and genotype and between genotype and invasiveness suggested that a gene(s) at the right chromosome telomere may be required for virulence. Of particular interest was bb0844, an RpoS-regulated gene at the right telomere, the expression of which is induced when the spirochete undergoes adaptation to the mammalian host. The structure of the right chromosomal telomere was examined in 53 B. burgdorferi clinical isolates of various genotypes. Four distinct patterns were observed for bb0844: (i) chromosomal localization, (ii) plasmid localization, (iii) presence on both chromosome and plasmid, and (iv) complete absence. These patterns correlated with the B. burgdorferi genotype. On the basis of available sequence data, we propose a mechanism for the genomic rearrangements that accounts for the variability in bb0844 genomic localization. To further explore the role of BB0844 in the spirochete life cycle, a bb0844 deletion mutant was constructed by allelic exchange, and the viability of wild-type and bb0844 deletion mutants was examined in an experimental mouse-tick infection model. The bb0844 mutant was fully infectious in C3H/HeJ mice by either needle inoculation or tick transmission with B. burgdorferi-infected Ixodes scapularis larvae. Naïve larval ticks acquired both wild-type and mutant spirochetes with equal efficiency from B. burgdorferi-infected mice. The results demonstrate that BB0844 is not required for spirochete viability, pathogenicity, or maintenance in the tick vector or the mammalian host. At present, a defined role for BB0844 in B. burgdorferi cannot be ascertained.Borrelia burgdorferi, the Lyme disease pathogen, has a complex life cycle in nature which involves an arthropod vector and diverse mammalian hosts (6, 46). The type strain, B31, has a complex genome comprised of a linear chromosome and at least 21 linear and circular plasmids (12,19). The linear replicons have covalently closed hairpin telomeric ends (11, 24). The chromosome of B. burgdorferi strain B31 is 910,725 bp long and includes 853 putative open reading frames (ORFs) (19). A majority of the chromosomal sequence and gene order is conserved among B. burgdorferi strains; however, the chromosomes vary in length. These differences were shown to be the result of variability in the right telomeric region (10, 11) and have been confirmed by sequencing of additional B. burgdorferi genomes (40). It has been proposed that linear plasmid fragments were added to the right chromosomal telomere by means of nonhomologous recombination, after which portions of the transposed plasmid sequences underwent mutational decay (12,13,2...

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Borrelia burgdorferi Lacking BBK32, a Fibronectin-Binding Protein, Retains Full Pathogenicity

Cited by 90 publications

References 62 publications

Inactivation of bb0184 , Which Encodes Carbon Storage Regulator A, Represses the Infectivity of Borrelia burgdorferi

Inactivation of bb0184 , Which Encodes Carbon Storage Regulator A, Represses the Infectivity of Borrelia burgdorferi

Role of the BBA64 Locus of Borrelia burgdorferi in Early Stages of Infectivity in a Murine Model of Lyme Disease

BB0844, an RpoS-Regulated Protein, Is Dispensable for Borrelia burgdorferi Infectivity and Maintenance in the Mouse-Tick Infectious Cycle

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