Cyclic di-GMP is Essential for the Survival of the Lyme Disease Spirochete in Ticks

PLoS Pathogens

Bryan Troxell¹  Ming He¹  Haijun Xu¹  Joseph Piesman¹  Mark Gomelsky²  Zhiming Ouyang²  X. Frank Yang³  Michael V. Norgard⁴  Akira Moh⁵ 

[1] Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America;Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, Unites States of America;Department of Molecular Biology, University of Wyoming, Laramie, Wyoming, United States of America;Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Fort Collins, Colorado, United States of America;Institute of Insect Science, Zhejiang University, Hangzhou, China

关键词: Borrelia burgdorferi;    Glycerol;    Spirochetes;    Ticks;    Gene expression;    Larvae;    Nymphs;    Polymerase chain reaction;   

DOI  :  10.1371/journal.ppat.1002133

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY