DhhP, a Cyclic di-AMP Phosphodiesterase of Borrelia burgdorferi, Is Essential for Cell Growth and Virulence

Ye, Meiping; Zhang, Jun Jie; Fang, Xin; Lawlis, Gavin B.; Troxell, Bryan; Zhou, Yan; Gomelsky, Mark; Lou, Yongliang; Yang, Xiaofeng

doi:10.1128/iai.00030-14

Cited by 75 publications

(125 citation statements)

References 78 publications

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“…Several studies have established that c-di-AMP depletion increases bacterial susceptibility to cell wall antibiotics, cell lysis, and is lethal for many species (5). Conversely, c-di-AMP elevation also appears to be similarly detrimental, affecting growth, division, peptidoglycan synthesis, and virulence (6,8,9,13). Here, we observed that the ΔpdeA ΔpgpH mutant was considerably attenuated in a murine infection model.…”

Section: Discussionsupporting

confidence: 52%

“…Listeria species encode a stand-alone DHH-DHHA1 protein, Lmo1575, homologous to other DHH-DHHA1 proteins that are reported to degrade c-di-AMP (9,12,13). Although PgpH is the only 7TMR_HD protein found in L. monocytogenes, seven other proteins of the HD superfamily (Pfam PF01966) are also present within the genome.…”

Section: Discussionmentioning

confidence: 99%

“…The first family comprises homologs of membrane-bound GdpP proteins, which contain a PAS domain, a degenerate GGDEF domain, and a catalytic DHH-DHHA1 domain (11). The second family comprises soluble, stand-alone DHH-DHHA1 domains (9,12,13).…”

mentioning

confidence: 99%

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An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence

Huynh

Luo

Pensinger

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

174

252

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The nucleotide cyclic di-3′,5′- adenosine monophosphate (c-di-AMP) was recently identified as an essential and widespread second messenger in bacterial signaling. Among c-di-AMP–producing bacteria, altered nucleotide levels result in several physiological defects and attenuated virulence. Thus, a detailed molecular understanding of c-di-AMP metabolism is of both fundamental and practical interest. Currently, c-di-AMP degradation is recognized solely among DHH-DHHA1 domain-containing phosphodiesterases. Using chemical proteomics, we identified the Listeria monocytogenes protein PgpH as a molecular target of c-di-AMP. Biochemical and structural studies revealed that the PgpH His-Asp (HD) domain bound c-di-AMP with high affinity and specifically hydrolyzed this nucleotide to 5′-pApA. PgpH hydrolysis activity was inhibited by ppGpp, indicating a cross-talk between c-di-AMP signaling and the stringent response. Genetic analyses supported coordinated regulation of c-di-AMP levels in and out of the host. Intriguingly, a L. monocytogenes mutant that lacks c-di-AMP phosphodiesterases exhibited elevated c-di-AMP levels, hyperinduced a host type-I IFN response, and was significantly attenuated for infection. Furthermore, PgpH homologs, which belong to the 7TMR-HD family, are widespread among hundreds of c-di-AMP synthesizing microorganisms. Thus, PgpH represents a broadly conserved class of c-di-AMP phosphodiesterase with possibly other physiological functions in this crucial signaling network.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

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An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence

Huynh

Luo

Pensinger

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

174

252

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“…SDS-PAGE and immunoblotting were performed as previously described (41). Monoclonal antibodies directed against OspC, OspA, and the loading control FlaB were described previously (42), and dilutions of 1:2,000, 1:2,000, and 1:500, respectively, were used in this study.…”

Section: Methodsmentioning

confidence: 99%

Outer Surface Protein OspC Is an Antiphagocytic Factor That Protects Borrelia burgdorferi from Phagocytosis by Macrophages

et al. 2015

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cOuter surface protein C (OspC) is one of the major lipoproteins expressed on the surface of Borrelia burgdorferi during tick feeding and the early phase of mammalian infection. OspC is required for B. burgdorferi to establish infection in both immunocompetent and SCID mice and has been proposed to facilitate evasion of innate immune defenses. However, the exact biological function of OspC remains elusive. In this study, we showed that the ospC-deficient spirochete could not establish infection in NOD-scid IL2r␥ null mice that lack B cells, T cells, NK cells, and lytic complement. The ospC mutant also could not establish infection in anti-Ly6G-treated SCID and C3H/HeN mice (depletion of neutrophils). However, depletion of mononuclear phagocytes at the skin site of inoculation in SCID and C3H/HeN mice allowed the ospC mutant to establish infection in vivo. In phagocyte-depleted mice, the ospC mutant was able to colonize the joints and triggered neutrophilia during dissemination. Furthermore, we found that phagocytosis of green fluorescent protein (GFP)-expressing ospC mutant spirochetes by murine peritoneal macrophages and human THP-1 macrophage-like cells, but not in PMN-HL60, was significantly higher than parental wild-type B. burgdorferi strains, suggesting that OspC has an antiphagocytic property. In addition, overproduction of OspC in spirochetes also decreased the uptake of spirochetes by murine peritoneal macrophages. Together, our findings provide evidence that mononuclear phagocytes play a key role in clearance of the ospC mutant and that OspC promotes spirochetes' evasion of macrophages during early Lyme borreliosis. L yme disease, the most prevalent vector-borne illness in the United States (1), is a multisystem inflammatory disorder caused by infection with the spirochete Borrelia burgdorferi (2, 3). This spirochete is maintained in nature through a complex enzootic cycle involving Ixodes ticks and various small-mammal hosts. Humans, as accidental hosts, become infected after B. burgdorferiinfected ticks feed on them (4). Spirochetes replicate in the skin, spread locally, and induce an inflammatory response with a symptom known as erythema migrans, observed in most patients (2, 4). During disseminated infection, B. burgdorferi colonizes multiple tissues, leading to different clinical manifestations, including arthritis, myocarditis, and neurological and/or cutaneous abnormalities (2, 4). This acute, disseminated stage of human Lyme disease is largely recapitulated using inbred mouse strains which are susceptible to B. burgdorferi infection and develop carditis and subacute arthritis (5). Thus, the murine model provides a powerful tool to elucidate the role of spirochete virulence factors and host immunological responses during Lyme disease pathogenesis (4).The B. burgdorferi genome encodes a large number of surface lipoproteins, many of which are expressed during mammalian infection (4, 6, 7). One of these lipoproteins is the major outer surface protein C (OspC), whose production is induced within inf...

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“…However, our understanding of how cyclicdi-AMP functions in regulating cell physiology is far less advanced. Studies of several systems have demonstrated that dysregulation of cyclic-di-AMP signaling (either overproduction or underproduction) leads to pleiotropic phenotypes, including altered sensitivity to osmotic stress, cell wall defects, and antibiotic sensitivity (11,12,15,16). Most dramatically, in several systems bacteria are unable to grow in the complete absence of cyclic-di-AMP (1), implying a role in one or more essential functions.…”

Section: Looking Forward: Effects Of Cyclic-di-amp On Cell Physiologymentioning

confidence: 99%

Chemical proteomics reveals a second family of cyclic-di-AMP hydrolases

Helmann¹

2015

Proc. Natl. Acad. Sci. U.S.A.

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DhhP, a Cyclic di-AMP Phosphodiesterase of Borrelia burgdorferi, Is Essential for Cell Growth and Virulence

Cited by 75 publications

References 78 publications

An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence

An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence

Outer Surface Protein OspC Is an Antiphagocytic Factor That Protects Borrelia burgdorferi from Phagocytosis by Macrophages

Chemical proteomics reveals a second family of cyclic-di-AMP hydrolases

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