Inhibition of the master regulator of Listeria monocytogenes virulence enables bacterial clearance from spacious replication vacuoles in infected macrophages
Author(s)
Type
Journal Article
Abstract
<jats:p>A hallmark of<jats:italic>Listeria (L</jats:italic>.<jats:italic>) monocytogenes</jats:italic>pathogenesis is bacterial escape from maturing entry vacuoles, which is required for rapid bacterial replication in the host cell cytoplasm and cell-to-cell spread. The bacterial transcriptional activator PrfA controls expression of key virulence factors that enable exploitation of this intracellular niche. The transcriptional activity of PrfA within infected host cells is controlled by allosteric coactivation. Inhibitory occupation of the coactivator site has been shown to impair PrfA functions, but consequences of PrfA inhibition for<jats:italic>L</jats:italic>.<jats:italic>monocytogenes</jats:italic>infection and pathogenesis are unknown. Here we report the crystal structure of PrfA with a small molecule inhibitor occupying the coactivator site at 2.0 Å resolution. Using molecular imaging and infection studies in macrophages, we demonstrate that PrfA inhibition prevents the vacuolar escape of<jats:italic>L</jats:italic>.<jats:italic>monocytogenes</jats:italic>and enables extensive bacterial replication inside spacious vacuoles. In contrast to previously described spacious<jats:italic>Listeria</jats:italic>-containing vacuoles, which have been implicated in supporting chronic infection, PrfA inhibition facilitated progressive clearance of intracellular<jats:italic>L</jats:italic>.<jats:italic>monocytogenes</jats:italic>from spacious vacuoles through lysosomal degradation. Thus, inhibitory occupation of the PrfA coactivator site facilitates formation of a transient intravacuolar<jats:italic>L</jats:italic>.<jats:italic>monocytogenes</jats:italic>replication niche that licenses macrophages to effectively eliminate intracellular bacteria. Our findings encourage further exploration of PrfA as a potential target for antimicrobials and highlight that intra-vacuolar residence of<jats:italic>L</jats:italic>.<jats:italic>monocytogenes</jats:italic>in macrophages is not inevitably tied to bacterial persistence.</jats:p>
Editor(s)
Navarre, William
Date Issued
2022-01-01
Date Acceptance
2021-12-01
Citation
PLOS Pathogens, 2022, 18 (1), pp.e1010166-e1010166
ISSN
1553-7366
Publisher
Public Library of Science (PLoS)
Start Page
e1010166
End Page
e1010166
Journal / Book Title
PLOS Pathogens
Volume
18
Issue
1
Copyright Statement
© 2022 Tran et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/35007292
PII: PPATHOGENS-D-21-01898
Subjects
Animals
Female
Listeria monocytogenes
Listeriosis
Macrophages
Male
Mice
Mice, Inbred C57BL
Vacuoles
Virulence
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2022-01-10