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

被引:99
作者
He, Ming [1 ]
Ouyang, Zhiming [2 ]
Troxell, Bryan [1 ]
Xu, Haijun [1 ,3 ]
Moh, Akira [1 ]
Piesman, Joseph [4 ]
Norgard, Michael V. [2 ]
Gomelsky, Mark [5 ]
Yang, X. Frank [1 ]
机构
[1] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA
[2] Univ Texas SW Med Ctr, Dept Microbiol, Dallas, TX USA
[3] Zhejiang Univ, Inst Insect Sci, Hangzhou 310003, Zhejiang, Peoples R China
[4] Ctr Dis Control & Prevent, Natl Ctr Emerging & Zoonot Infect Dis, Div Vector Borne Dis, Ft Collins, CO USA
[5] Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA
关键词
REGULATES BIOFILM FORMATION; BORRELIA-BURGDORFERI; VIBRIO-CHOLERAE; RESPONSE REGULATOR; YERSINIA-PESTIS; PSEUDOMONAS-AERUGINOSA; BINDING-PROTEIN; DOMAIN PROTEIN; MAMMALIAN INFECTION; ESCHERICHIA-COLI;
D O I
10.1371/journal.ppat.1002133
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
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.
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页数:15
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