PlzA is a bifunctional c-di-GMP biosensor that promotes tick and mammalian host-adaptation of Borrelia burgdorferi
| العنوان: | PlzA is a bifunctional c-di-GMP biosensor that promotes tick and mammalian host-adaptation of Borrelia burgdorferi |
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| المؤلفون: | André Alex Grassmann, Anthony A. Provatas, Melissa J. Caimano, Amit Luthra, Justin D. Radolf, Ashley M. Groshong, Melissa A. McLain |
| المصدر: | PLoS Pathogens, Vol 17, Iss 7, p e1009725 (2021) PLoS Pathogens |
| بيانات النشر: | Public Library of Science (PLoS), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Bacterial Diseases, Life Cycles, Physiology, Pathology and Laboratory Medicine, Mice, Larvae, Medical Conditions, Medicine and Health Sciences, Biology (General), Cyclic GMP, Gel Electrophoresis, Infectivity, Mammals, Staining, 0303 health sciences, Lyme Disease, Spirochetes, Virulence, Effector, Eukaryota, Adaptation, Physiological, Cell biology, Bacterial Pathogens, Body Fluids, Infectious Diseases, Blood, Medical Microbiology, Vertebrates, Host-Pathogen Interactions, Female, Pathogens, Anatomy, Research Article, Pathogen Motility, Silver Staining, Borrelia Burgdorferi, Virulence Factors, QH301-705.5, Immunology, Heterologous, Biology, Electrophoretic Staining, Research and Analysis Methods, Microbiology, 03 medical and health sciences, Electrophoretic Techniques, Bacterial Proteins, Virology, Borrelia, Genetics, Animals, Borrelia burgdorferi, Molecular Biology, Microbial Pathogens, 030304 developmental biology, Immune Evasion, Bacteria, Ixodes, 030306 microbiology, Organisms, Biology and Life Sciences, RC581-607, biology.organism_classification, Borrelia Infection, Specimen Preparation and Treatment, Amniotes, biology.protein, Parasitology, Diguanylate cyclase, Immunologic diseases. Allergy, rpoS, Zoology, Developmental Biology |
| الوصف: | In this study, we examined the relationship between c-di-GMP and its only known effector protein, PlzA, in Borrelia burgdorferi during the arthropod and mammalian phases of the enzootic cycle. Using a B. burgdorferi strain expressing a plzA point mutant (plzA-R145D) unable to bind c-di-GMP, we confirmed that the protective function of PlzA in ticks is c-di-GMP-dependent. Unlike ΔplzA spirochetes, which are severely attenuated in mice, the plzA-R145D strain was fully infectious, firmly establishing that PlzA serves a c-di-GMP-independent function in mammals. Contrary to prior reports, loss of PlzA did not affect expression of RpoS or RpoS-dependent genes, which are essential for transmission, mammalian host-adaptation and murine infection. To ascertain the nature of PlzA’s c-di-GMP-independent function(s), we employed infection models using (i) host-adapted mutant spirochetes for needle inoculation of immunocompetent mice and (ii) infection of scid mice with in vitro-grown organisms. Both approaches substantially restored ΔplzA infectivity, suggesting that PlzA enables B. burgdorferi to overcome an early bottleneck to infection. Furthermore, using a Borrelia strain expressing a heterologous, constitutively active diguanylate cyclase, we demonstrate that ‘ectopic’ production of c-di-GMP in mammals abrogates spirochete virulence and interferes with RpoS function at the post-translational level in a PlzA-dependent manner. Structural modeling and SAXS analysis of liganded- and unliganded-PlzA revealed marked conformational changes that underlie its biphasic functionality. This structural plasticity likely enables PlzA to serve as a c-di-GMP biosensor that in its respective liganded and unliganded states promote vector- and host-adaptation by the Lyme disease spirochete. Author summary Herein, we examined the roles of c-di-GMP and PlzA throughout the Borrelia burgdorferi lifecycle. Using a plzA point mutant that is unable to bind c-di-GMP, we confirmed that the protective function(s) of PlzA in feeding ticks and mammals are c-di-GMP-dependent and -independent, respectively. Contrary to previous studies, loss of PlzA did not affect expression of rpoS or RpoS-dependent genes, which are important for host-adaptation and persistence in the mammal. Host-adaptation prior to needle-inoculation of C3H mice or infection of scid mice substantially restored infectivity in the absence of PlzA. Using a Borrelia strain that synthesizes c-di-GMP constitutively, this secondary messenger was shown to be tick-phase specific and detrimental to host-adaptation via PlzA-mediated antagonism of RpoS function. Structural modeling and SAXS analysis of liganded- and unliganded-PlzA provide insight into the dramatic conformational changes upon c-di-GMP binding that likely underlie its differential function: liganded-PlzA supports survival within feeding ticks, while unliganded-PlzA promotes an RpoS-independent facet of host adaptation, enabling spirochetes to evade early immune clearance by the host. |
| اللغة: | English |
| تدمد: | 1553-7374 1553-7366 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c56c80e64e328ddd92a97935c2822a6eTest https://doaj.org/article/ecf504a6e74e4a17837c52e966c55a6aTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c56c80e64e328ddd92a97935c2822a6e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537374 15537366 |
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