In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 19, No. 3 ( 2023-3-20), p. e1011259-
Abstract:
The TprK protein of the syphilis agent, Treponema pallidum subsp. pallidum ( T . pallidum ), undergoes antigenic variation in seven discrete variable (V) regions via non-reciprocal segmental gene conversion. These recombination events transfer information from a repertoire of 53 silent chromosomal donor cassettes (DCs) into the single tprK expression site to continually generate TprK variants. Several lines of research developed over the last two decades support the theory that this mechanism is central to T . pallidum ’s ability for immune avoidance and persistence in the host. Structural and modeling data, for example, identify TprK as an integral outer membrane porin with the V regions exposed on the pathogen’s surface. Furthermore, infection-induced antibodies preferentially target the V regions rather than the predicted β-barrel scaffolding, and sequence variation abrogates the binding of antibodies elicited by antigenically different V regions. Here, we engineered a T . pallidum strain to impair its ability to vary TprK and assessed its virulence in the rabbit model of syphilis. Principal findings A suicide vector was transformed into the wild-type (WT) SS14 T . pallidum isolate to eliminate 96% of its tprK DCs. The resulting SS14-DC KO strain exhibited an in vitro growth rate identical to the untransformed strain, supporting that the elimination of the DCs did not affect strain viability in absence of immune pressure. In rabbits injected intradermally with the SS14-DC KO strain, generation of new TprK sequences was impaired, and the animals developed attenuated lesions with a significantly reduced treponemal burden compared to control animals. During infection, clearance of V region variants originally in the inoculum mirrored the generation of antibodies to these variants, although no new variants were generated in the SS14-DC KO strain to overcome immune pressure. Naïve rabbits that received lymph node extracts from animals infected with the SS14-DC KO strain remained uninfected. Conclusion These data further support the critical role of TprK in T . pallidum virulence and persistence during infection.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1011259
DOI:
10.1371/journal.ppat.1011259.g001
DOI:
10.1371/journal.ppat.1011259.g002
DOI:
10.1371/journal.ppat.1011259.g003
DOI:
10.1371/journal.ppat.1011259.g004
DOI:
10.1371/journal.ppat.1011259.g005
DOI:
10.1371/journal.ppat.1011259.g006
DOI:
10.1371/journal.ppat.1011259.g007
DOI:
10.1371/journal.ppat.1011259.t001
DOI:
10.1371/journal.ppat.1011259.t002
DOI:
10.1371/journal.ppat.1011259.t003
DOI:
10.1371/journal.ppat.1011259.s001
DOI:
10.1371/journal.ppat.1011259.s002
DOI:
10.1371/journal.ppat.1011259.s003
DOI:
10.1371/journal.ppat.1011259.s004
DOI:
10.1371/journal.ppat.1011259.s005
DOI:
10.1371/journal.ppat.1011259.s006
DOI:
10.1371/journal.ppat.1011259.s007
DOI:
10.1371/journal.ppat.1011259.s008
DOI:
10.1371/journal.ppat.1011259.s009
DOI:
10.1371/journal.ppat.1011259.s010
DOI:
10.1371/journal.ppat.1011259.s011
DOI:
10.1371/journal.ppat.1011259.s012
DOI:
10.1371/journal.ppat.1011259.r001
DOI:
10.1371/journal.ppat.1011259.r002
DOI:
10.1371/journal.ppat.1011259.r003
DOI:
10.1371/journal.ppat.1011259.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2205412-1
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