title: Cyclic di-GMP is essential for the survival of the lyme disease spirochete in ticks.
abstract: Cyclic dimeric GMP (c-di-GMP) is a bacterial second messenger that modulates many biological processes. Although its role in bacterial pathogenesis during mammalian infection has been documented, the role of c-di-GMP in a pathogen's life cycle within a vector host is less understood. The enzootic cycle of the Lyme disease pathogen Borrelia burgdorferi involves both a mammalian host and an Ixodes tick vector. The B. burgdorferi genome encodes a single copy of the diguanylate cyclase gene (rrp1), which is responsible for c-di-GMP synthesis. To determine the role of c-di-GMP in the life cycle of B. burgdorferi, an Rrp1-deficient B. burgdorferi strain was generated. The rrp1 mutant remains infectious in the mammalian host but cannot survive in the tick vector. Microarray analyses revealed that expression of a four-gene operon involved in glycerol transport and metabolism, bb0240-bb0243, was significantly downregulated by abrogation of Rrp1. In vitro, the rrp1 mutant is impaired in growth in the media containing glycerol as the carbon source (BSK-glycerol). To determine the contribution of the glycerol metabolic pathway to the rrp1 mutant phenotype, a glp mutant, in which the entire bb0240-bb0243 operon is not expressed, was generated. Similar to the rrp1 mutant, the glp mutant has a growth defect in BSK-glycerol medium. In vivo, the glp mutant is also infectious in mice but has reduced survival in ticks. Constitutive expression of the bb0240-bb0243 operon in the rrp1 mutant fully rescues the growth defect in BSK-glycerol medium and partially restores survival of the rrp1 mutant in ticks. Thus, c-di-GMP appears to govern a catabolic switch in B. burgdorferi and plays a vital role in the tick part of the spirochetal enzootic cycle. This work provides the first evidence that c-di-GMP is essential for a pathogen's survival in its vector host.
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors: Ming
authors: M
authors: He
authors: Zhiming
authors: Z
authors: Ouyang
authors: Bryan
authors: B
authors: Troxell
authors: Haijun
authors: H
authors: Xu
authors: Akira
authors: A
authors: Moh
authors: Joseph
authors: J
authors: Piesman
authors: Michael V
authors: MV
authors: Norgard
authors: Mark
authors: M
authors: Gomelsky
authors: X Frank
authors: XF
authors: Yang
mesh_terms: D000818:Animals; D015748:Borrelia burgdorferi Group / Q000235:genetics; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D004199:Disease Vectors; D029968:Escherichia coli Proteins / Q000235:genetics; D055786:Gene Knockout Techniques; D005990:Glycerol / Q000378:metabolism; D018884:Ixodes / Q000378:metabolism* / Q000382:microbiology; D008193:Lyme Disease / Q000382:microbiology / Q000635:transmission*; D051379:Mice; D008809:Mice, Inbred C3H; D046228:Microarray Analysis; D019761:Phosphorus-Oxygen Lyases / Q000235:genetics; D016133:Polymerase Chain Reaction; D017384:Sequence Deletion
chemical_list: D029968:Escherichia coli Proteins; C062025:bis(3',5')-cyclic diguanylic acid; D019761:Phosphorus-Oxygen Lyases; C060720:diguanylate cyclase; D006152:Cyclic GMP; D005990:Glycerol