Salmonella persisters undermine host immune defenses during antibiotic treatment
Actively persistent Salmonella
A proportion of Salmonella cells can enter a reversible state of growth arrest, which allows them to tolerate environmental stress such as antibiotics. Stapels et al. found that these cells are not dormant but are actively modulating their environment. Salmonella within their host macrophage niche deployed a specialized type 3 secretory system called SPI-2 to deliver virulence factors, including SteE, into host cells. SteE changed the cytokine profile of the infected macrophages to reprogram them into a noninflammatory and infection-permissive state. Thus, when antibiotics were removed, the Salmonella could reemerge and cause disease.
Science, this issue p. 1156
Abstract
Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters. In vitro, persister cells appear to be dormant. After uptake of Salmonella species by macrophages, nongrowing persisters also occur, but their physiological state is poorly understood. In this work, we show that Salmonella persisters arising during macrophage infection maintain a metabolically active state. Persisters reprogram macrophages by means of effectors secreted by the Salmonella pathogenicity island 2 type 3 secretion system. These effectors dampened proinflammatory innate immune responses and induced anti-inflammatory macrophage polarization. Such reprogramming allowed nongrowing Salmonella cells to survive for extended periods in their host. Persisters undermining host immune defenses might confer an advantage to the pathogen during relapse once antibiotic pressure is relieved.
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Supplementary Material
Summary
Materials and Methods
Figs. S1 to S10
Tables S1 to S9
Resources
File (aat7148_stapels_sm.pdf)
File (aat7148_table_s1.xlsx)
File (aat7148_table_s2.xlsx)
File (aat7148_table_s3.xlsx)
File (aat7148_table_s4.xlsx)
File (aat7148_table_s5.xlsx)
File (aat7148_table_s6.xlsx)
File (aat7148_table_s7.xlsx)
File (aat7148_table_s8.xlsx)
File (aat7148_table_s9.xlsx)
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Information & Authors
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Published In
Science
Volume 362 | Issue 6419
7 December 2018
7 December 2018
Copyright
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
This is an article distributed under the terms of the Science Journals Default License.
Submission history
Received: 28 March 2018
Accepted: 31 October 2018
Published in print: 7 December 2018
Acknowledgments
We thank members from the Holden and Helaine labs for sharing constructs and protocols and scientific discussions; I. Glegola-Madejska for help with the animal experiments; and D. Holden for careful reading of the manuscript. Funding: This research was supported by an MRC Career Development Award (MR/M009629/1) from the Medical Research Council (UK) and Lister Institute Research Prize 2017 to S.H., an EMBO long-term fellowship (ALTF 441-2015) to D.A.C.S., and an Elite Advancement Ph.D. stipend from the Universität Bayern e.V., Germany, to A.J.W. Author contributions: S.H. and J.V. outlined the study; D.A.C.S., P.W.S.H., A.J.W., R.F., I.B., and S.H. performed experiments; P.W.S.H. conducted the bioinformatic analysis; D.A.C.S., P.W.S.H., A.J.W., R.F., I.B., A.-E.S., and T.L.T. analyzed the data; D.A.C.S., P.W.S.H., A.J.W., and S.H. interpreted data; and D.A.C.S., P.W.S.H., and S.H. wrote the manuscript with contributions of other authors. Competing interests: We declare no competing interests. Data and materials availability: The dual RNA-seq data are summarized in table S1; results of analyses are in tables S2 to S5, S8, and S9; and the data are archived on GEO (accession: GSE104785).
Authors
Funding Information
EMBO: ALTF 441-2015
Medical Research Council (UK): MR/M009629/1
Universität Bayern e.V.: Elite Advancement Ph.D. stipend
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