Salmonella-driven polarization of granuloma macrophages antagonizes TNF-mediated pathogen restriction during persistent infection
File(s)Pham_et_al_2019_Final_unformatted_reducedsize.pdf (5.1 MB)
Accepted version
Author(s)
Type
Journal Article
Abstract
Many intracellular bacteria can establish chronic infection and persist in tissues within granulomas composed of macrophages. Granuloma macrophages exhibit heterogeneous polarization states, or phenotypes, that may be functionally distinct. Here, we elucidate a host-pathogen interaction that controls granuloma macrophage polarization and long-term pathogen persistence during Salmonella Typhimurium ( STm) infection. We show that STm persists within splenic granulomas that are densely populated by CD11b +CD11c +Ly6C + macrophages. STm preferentially persists in granuloma macrophages reprogrammed to an M2 state, in part through the activity of the effector SteE, which contributes to the establishment of persistent infection. We demonstrate that tumor necrosis factor (TNF) signaling limits M2 granuloma macrophage polarization, thereby restricting STm persistence. TNF neutralization shifts granuloma macrophages toward an M2 state and increases bacterial persistence, and these effects are partially dependent on SteE activity. Thus, manipulating granuloma macrophage polarization represents a strategy for intracellular bacteria to overcome host restriction during persistent infection.
Date Issued
2020-01-08
Date Acceptance
2019-11-20
Citation
Cell Host and Microbe, 2020, 27 (1), pp.54-67.E5
ISSN
1931-3128
Publisher
Elsevier (Cell Press)
Start Page
54
End Page
67.E5
Journal / Book Title
Cell Host and Microbe
Volume
27
Issue
1
Copyright Statement
© 2019 Elsevier Inc. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor
Medical Research Council (MRC)
Medical Research Council (MRC)
Lister Institute of Preventive Medicine
Biotechnology and Biological Sciences Research Council (BBSRC)
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000506213900009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
MR/M009629/1
MR/M009629/1
n/a
BB/R011834/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Microbiology
Parasitology
Virology
TUMOR-NECROSIS-FACTOR
NITRIC-OXIDE SYNTHASE
FACTOR-ALPHA
TUBERCULOSIS
NEUTRALIZATION
EXPRESSION
REGULATOR
IMMUNITY
GROWTH
Publication Status
Published
Date Publish Online
2019-12-26