In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 17, No. 7 ( 2021-7-15), p. e1009725-
Abstract:
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 Δ plzA 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 Δ plzA 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.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1009725
DOI:
10.1371/journal.ppat.1009725.g001
DOI:
10.1371/journal.ppat.1009725.g002
DOI:
10.1371/journal.ppat.1009725.g003
DOI:
10.1371/journal.ppat.1009725.g004
DOI:
10.1371/journal.ppat.1009725.g005
DOI:
10.1371/journal.ppat.1009725.g006
DOI:
10.1371/journal.ppat.1009725.g007
DOI:
10.1371/journal.ppat.1009725.g008
DOI:
10.1371/journal.ppat.1009725.t001
DOI:
10.1371/journal.ppat.1009725.t002
DOI:
10.1371/journal.ppat.1009725.t003
DOI:
10.1371/journal.ppat.1009725.s001
DOI:
10.1371/journal.ppat.1009725.s002
DOI:
10.1371/journal.ppat.1009725.s003
DOI:
10.1371/journal.ppat.1009725.s004
DOI:
10.1371/journal.ppat.1009725.s005
DOI:
10.1371/journal.ppat.1009725.s006
DOI:
10.1371/journal.ppat.1009725.s007
DOI:
10.1371/journal.ppat.1009725.s008
DOI:
10.1371/journal.ppat.1009725.s009
DOI:
10.1371/journal.ppat.1009725.s010
DOI:
10.1371/journal.ppat.1009725.s011
DOI:
10.1371/journal.ppat.1009725.s012
DOI:
10.1371/journal.ppat.1009725.s013
DOI:
10.1371/journal.ppat.1009725.s014
DOI:
10.1371/journal.ppat.1009725.s015
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2205412-1
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