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Most of work on c-di-AMP signaling has been done in Gram-positive bacteria, firmicutes, and actinobacteria, where c-di-AMP signaling pathways affect potassium transport, cell wall structure, and antibiotic resistance. Little is known about c-di-AMP signaling in other bacteria.<jats:named-content content-type=\"genus-species\">Borrelia burgdorferi<\/jats:named-content>, the causative agent of Lyme disease, is a spirochete that has a Gram-negative dual membrane. In this study, we demonstrated that<jats:named-content content-type=\"genus-species\">B. burgdorferi<\/jats:named-content>BB0619, a<jats:underline>DHH<\/jats:underline>-DHHA1 domain<jats:underline>p<\/jats:underline>rotein (herein designated DhhP), functions as c-di-AMP phosphodiesterase. Recombinant DhhP hydrolyzed c-di-AMP to pApA in a Mn<jats:sup>2+<\/jats:sup>- or Mg<jats:sup>2+<\/jats:sup>-dependent manner. In contrast to c-di-AMP phosphodiesterases reported thus far, DhhP appears to be essential for<jats:named-content content-type=\"genus-species\">B. burgdorferi<\/jats:named-content>growth both<jats:italic>in vitro<\/jats:italic>and in the mammalian host. Inactivation of the chromosomal<jats:italic>dhhP<\/jats:italic>gene could be achieved only in the presence of a plasmid-encoded inducible<jats:italic>dhhP<\/jats:italic>gene. The conditional<jats:italic>dhhP<\/jats:italic>mutant had a dramatic increase in intracellular c-di-AMP level in comparison to the isogenic wild-type strain. Unlike what has been observed in Gram-positive bacteria, elevated cellular c-di-AMP in<jats:named-content content-type=\"genus-species\">B. burgdorferi<\/jats:named-content>did not result in an increased resistance to \u03b2-lactamase antibiotics, suggesting that c-di-AMP's functions in spirochetes differ from those in Gram-positive bacteria. In addition, the<jats:italic>dhhP<\/jats:italic>mutant was defective in induction of the \u03c3<jats:sup>S<\/jats:sup>factor, RpoS, and the RpoS-dependent outer membrane virulence factor OspC, which uncovers an important role of c-di-AMP in<jats:named-content content-type=\"genus-species\">B. burgdorferi<\/jats:named-content>virulence.<\/jats:p>","DOI":"10.1128\/iai.00030-14","type":"journal-article","created":{"date-parts":[[2014,2,25]],"date-time":"2014-02-25T07:09:34Z","timestamp":1393312174000},"page":"1840-1849","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":84,"title":["DhhP, a Cyclic di-AMP Phosphodiesterase of Borrelia burgdorferi, Is Essential for Cell Growth and Virulence"],"prefix":"10.1128","volume":"82","author":[{"given":"Meiping","family":"Ye","sequence":"first","affiliation":[{"name":"School of Laboratory Medicine, Wenzhou Medical University, Zhejiang, China"},{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA"},{"name":"Environmental Microbiology Group, Key Laboratory of Agricultural and Environmental Microbiology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Wyoming, Laramie, Wyoming, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin B.","family":"Lawlis","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Wyoming, Laramie, Wyoming, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Troxell","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine, Wenzhou Medical University, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Gomelsky","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Wyoming, Laramie, Wyoming, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongliang","family":"Lou","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine, Wenzhou Medical University, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X. 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