A transcriptomic network identified in uninfected macrophages responding to inflammation controls intracellular pathogen survival

Lynette Beattie; Micely d'El-Rei Hermida; John W J Moore; Asher Maroof; Najmeeyah Brown; Dimitris Lagos; Paul M Kaye

doi:10.1016/j.chom.2013.08.004

A transcriptomic network identified in uninfected macrophages responding to inflammation controls intracellular pathogen survival

Lynette Beattie, Micely d'El-Rei Hermida, John W J Moore, Asher Maroof, Najmeeyah Brown, Dimitris Lagos, Paul M Kaye

Research output: Contribution to journal › Article › peer-review

Abstract

Intracellular pathogens modulate host cell function to promote their survival. However, in vitro infection studies do not account for the impact of host-derived inflammatory signals. Examining the response of liver-resident macrophages (Kupffer cells) in mice infected with the parasite Leishmania donovani, we identified a transcriptomic network operating in uninfected Kupffer cells exposed to inflammation but absent from Kupffer cells from the same animal that contained intracellular Leishmania. To test the hypothesis that regulated expression of genes within this transcriptomic network might impact parasite survival, we pharmacologically perturbed the activity of retinoid X receptor alpha (RXRα), a key hub within this network, and showed that this intervention enhanced the innate resistance of Kupffer cells to Leishmania infection. Our results illustrate a broadly applicable strategy for understanding the host response to infection in vivo and identify Rxra as the hub of a gene network controlling antileishmanial resistance.

Original language	English
Pages (from-to)	357-68
Number of pages	12
Journal	Cell Host & Microbe
Volume	14
Issue number	3
DOIs	https://doi.org/10.1016/j.chom.2013.08.004
Publication status	Published - 11 Sept 2013

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10.1016/j.chom.2013.08.004

http://www.sciencedirect.com/science/article/pii/S1931312813002862

Cite this

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title = "A transcriptomic network identified in uninfected macrophages responding to inflammation controls intracellular pathogen survival",

abstract = "Intracellular pathogens modulate host cell function to promote their survival. However, in vitro infection studies do not account for the impact of host-derived inflammatory signals. Examining the response of liver-resident macrophages (Kupffer cells) in mice infected with the parasite Leishmania donovani, we identified a transcriptomic network operating in uninfected Kupffer cells exposed to inflammation but absent from Kupffer cells from the same animal that contained intracellular Leishmania. To test the hypothesis that regulated expression of genes within this transcriptomic network might impact parasite survival, we pharmacologically perturbed the activity of retinoid X receptor alpha (RXRα), a key hub within this network, and showed that this intervention enhanced the innate resistance of Kupffer cells to Leishmania infection. Our results illustrate a broadly applicable strategy for understanding the host response to infection in vivo and identify Rxra as the hub of a gene network controlling antileishmanial resistance.",

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AU - Brown, Najmeeyah

AU - Lagos, Dimitris

AU - Kaye, Paul M

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