A Transcriptomic Network Identified in Uninfected Macrophages Responding to Inflammation Controls Intracellular Pathogen Survival

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

doi:10.1016/j.chom.2013.08.004

John W.J Moore, Paul M Kaye + Show 5 more

Open Access

https://doi.org/10.1016/j.chom.2013.08.004

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Abstract

SummaryIntracellular 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.

Highlights

Intracellular pathogens have evolved over many millions of years to coexist in the face of a wide array of host defense mechanisms
We discovered that expression of an retinoid X receptor a (Rxra)-centered transcriptomic pathway, which is downregulated in Kupffer cells (KCs) in response to inflammation, is aberrantly maintained in infected cells
This study demonstrates that aberrant expression of the Rxra-centered transcriptional pathway in Leishmania-infected KCs favors parasite survival and validates the use of cells exposed to inflammation as a means to discover pathogen-regulated transcriptomic pathways in vivo

Summary

Introduction

Intracellular pathogens have evolved over many millions of years to coexist in the face of a wide array of host defense mechanisms. In vitro studies of the host-pathogen interaction exclude the inflammatory milieu, but a major challenge in studying the host response in vivo is dissecting pathogen-specific responses from the general inflammatory or common host response (Jenner and Young, 2005) that occurs as a result of tissue insult during the infectious process This latter response is in part driven by activation of components of the complement cascade (Ricklin et al, 2010), the coagulation pathway (Oikonomopoulou et al, 2012), and the acute phase response (Suffredini et al, 1999), which all come into play within minutes of infection, and is compounded by rapid changes to the inflammatory cytokine and chemokine environment (Oghumu et al, 2010; Sadik and Luster, 2012; Soehnlein and Lindbom, 2010). Transcriptomic networks restricted to uninfected cells would serve to identify responses potentially beneficial to the host, the lack of which (in infected cells) might favor pathogen survival

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