Structural Basis for Complement Evasion by Lyme Disease Pathogen Borrelia burgdorferi

Bhattacharjee, Arnab; Oeemig, Jesper S.; Kolodziejczyk, R.; Meri, Taru; Kajander, Tommi; Lehtinen, Markus J.; Iwaï, Hideo; Jokiranta, T. Sakari; Goldman, Adrian

doi:10.1074/jbc.m113.459040

Cited by 50 publications

(69 citation statements)

References 74 publications

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“…The outer surface protein E (OspE) of Lyme disease-causing Borrelia burgdorferi specifically binds the FH C terminus 44 . Notably, OspE binds FH via the W1183, S1196, E1198 and R1215 side chains, which also provide the most important interaction for 3′SL 38 , assuring that FH bound to B. burgdorferi adopts an orientation that resembles its host cell orientation.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for sialic acid–mediated self-recognition by complement factor H

et al. 2014

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The serum protein complement factor H (FH) ensures downregulation of the complement alternative pathway, a branch of innate immunity, upon interaction with specific glycans on host cell surfaces. Using ligand-based NMR, we screened a comprehensive set of sialylated glycans for binding to FH and solved the crystal structure of a ternary complex formed by the two C-terminal domains of FH, a sialylated trisaccharide and the complement C3b thioester-containing domain. Key residues in the sialic acid binding site are conserved from mice to men, and residues linked to atypical hemolytic uremic syndrome cluster within this binding site, suggesting a possible role for sialic acid as a host marker also in other mammals and a critical role in human renal complement homeostasis. Unexpectedly, the FH sialic acid binding site is structurally homologous to the binding sites of two evolutionarily unrelated proteins. The crystal structure also advances our understanding of bacterial immune evasion strategies.

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Section: Discussionmentioning

confidence: 99%

Structural basis for sialic acid–mediated self-recognition by complement factor H

et al. 2014

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“…Importantly, RNA-Seq, unlike 70-mer glass slide microarrays, enabled us to unambiguously distinguish between closely related paralogs within each lipoprotein family (77)(78)(79). Members of the OspE family, also referred to as BbCrasps, have been shown to inhibit complement-mediated lysis by binding complement factor H (CFH) and CFH-related proteins (1,80,81), while the functions of the OspF, Elp, and Mlp families remain to be determined. bb0323 encodes an OM-associated lipoprotein that interacts with peptidoglycan via a C-terminal LysM domain and is well expressed in feeding larvae and nymphs (82).…”

Section: Resultsmentioning

confidence: 99%

Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission

et al. 2015

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e Borrelia burgdorferi, the Lyme disease spirochete, couples environmental sensing and gene regulation primarily via the Hk1/ Rrp1 two-component system (TCS) and Rrp2/RpoN/RpoS pathways. Beginning with acquisition, we reevaluated the contribution of these pathways to spirochete survival and gene regulation throughout the enzootic cycle. Live imaging of B. burgdorferi caught in the act of being acquired revealed that the absence of RpoS and the consequent derepression of tick-phase genes impart a Stay signal required for midgut colonization. In addition to the behavioral changes brought on by the RpoS-off state, acquisition requires activation of cyclic di-GMP (c-di-GMP) synthesis by the Hk1/Rrp1 TCS; B. burgdorferi lacking either component is destroyed during the blood meal. Prior studies attributed this dramatic phenotype to a metabolic lesion stemming from reduced glycerol uptake and utilization. In a head-to-head comparison, however, the B. burgdorferi ⌬glp mutant had a markedly greater capacity to survive tick feeding than B. burgdorferi ⌬hk1 or ⌬rrp1 mutants, establishing unequivocally that glycerol metabolism is only one component of the protection afforded by c-di-GMP. Data presented herein suggest that the protective response mediated by c-di-GMP is multifactorial, involving chemotactic responses, utilization of alternate substrates for energy generation and intermediary metabolism, and remodeling of the cell envelope as a means of defending spirochetes against threats engendered during the blood meal. Expression profiling of c-di-GMP-regulated genes through the enzootic cycle supports our contention that the Hk1/Rrp1 TCS functions primarily, if not exclusively, in ticks. These data also raise the possibility that c-di-GMP enhances the expression of a subset of RpoS-dependent genes during nymphal transmission. Borrelia burgdorferi, the causative agent of Lyme disease, is maintained in nature within an enzootic cycle that involves an arthropod vector and vertebrate reservoir hosts, typically, small rodents and birds (1). In the northeastern United States, the primary vector for B. burgdorferi is the black-legged deer tick, Ixodes scapularis (2, 3). Because B. burgdorferi cannot be passaged transovarially, naive larvae acquire spirochetes by feeding on infected reservoir hosts. Successful colonization of the vector requires B. burgdorferi to establish an intimate association with rapidly differentiating, highly endocytic midgut epithelial cells (4-6). In order to accomplish this feat, spirochetes must resist deleterious substances within the midgut lumen, such as host-and tick-derived innate immune effector molecules, reactive oxygen species (ROS), and salivary enzymes imbibed from the feeding site (4, 7-11). At the same time, B. burgdorferi also must alter its metabolic machinery to exploit the availability of alternative carbon sources (e.g., glycerol, N-acetylglucosamine [GlcNAc], chitobiose) as the supply of ingested glucose diminishes (12-15). During nymphal transmission, spirochetes are almost certai...

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“…Depending on the genetic composition, individual Borrelia species can produce up to five different binding proteins; hence, various combinations of these molecules exist on the borrelial outer surface. CRASPs differ not only in their binding capabilities for distinct complement regulators and other serum proteins but also in their protein sequences and structures, gene locations, gene regulatory mechanisms, and expression patterns during the tick-mammal infection cycle (11,12,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30).…”

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confidence: 99%

Versatile Roles of CspA Orthologs in Complement Inactivation of Serum-Resistant Lyme Disease Spirochetes

et al. 2014

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Structural Basis for Complement Evasion by Lyme Disease Pathogen Borrelia burgdorferi

Cited by 50 publications

References 74 publications

Structural basis for sialic acid–mediated self-recognition by complement factor H

Structural basis for sialic acid–mediated self-recognition by complement factor H

Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission

Versatile Roles of CspA Orthologs in Complement Inactivation of Serum-Resistant Lyme Disease Spirochetes

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