Coordination of transcriptional and translational regulations in human epithelial cells infected by Listeria monocytogenes

ABSTRACT

The invasion of mammalian cells by intracellular bacterial pathogens reshuffles their gene expression and functions; however, we lack dynamic insight into the distinct control levels that shape the host response. Here, we have addressed the respective contribution of transcriptional and translational regulations during a time-course of infection of human intestinal epithelial cells by an epidemic strain of Listeria monocytogenes, using transcriptome analysis paralleled with ribosome profiling. Upregulations were dominated by early transcriptional activation of pro-inflammatory genes, whereas translation inhibition appeared as the major driver of downregulations. Instead of a widespread but transient shutoff, translation inhibition affected specifically and durably transcripts encoding components of the translation machinery harbouring a 5ʹ-terminal oligopyrimidine motif. Pre-silencing the most repressed target gene (PABPC1) slowed down the intracellular multiplication of Listeria monocytogenes, suggesting that the infected host cell can benefit from the repression of genes involved in protein synthesis and thereby better control infection.

KEYWORDS:

• Listeria monocytogenes
• host–pathogen interactions
• translation
• 5ʹ-terminal oligopyrimidine motif
• poly(A)-binding proteins

Acknowledgments

We warmly thank Zhen Wang for sharing with us her optimized Ribo-seq protocol, and invaluable advice about how to best handle this technique. We are grateful to Caroline Peron-Cane, Chloé Connan, Morgane Corre and José-Carlos Fernandez for their precious experimental assistance and eagerness to help solve technical issues, as well as Morgane Thomas-Chollier for helpful discussion regarding data analysis. Last, we thank the IBENS genomics platform for their careful sequencing of all samples, patient assistance and dedication, as well as the Computational Biology Centre for maintaining access to the servers, and Imaging facility for maintaining access to microscopy equipment.

Author contributions

AL designed the project. VB and AL devised experiments and interpreted results. VB performed experiments with the help of SR for Lm genetics and FISH. FH, BN and VB analysed High-Seq data under supervision by AG and AL. AL and VB wrote the manuscript.

Disclosure statement

The authors declare no competing financial interests.

Supplementary material

Supplemental data for this article can be accessed here.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

Work in the group of AL has received support under the program ‘Investissements d’Avenir’ implemented by ANR MemoLife [ANR-10-LABX-54] and PSL University [ANR-10-IDEX-0001-02], Fondation pour la Recherche Médicale [FRM-AJE20131128944], Inserm ATIP-Avenir and Mairie de Paris Programme Émergences – Recherche médicale. SR benefitted from SNF Early Postdoc Mobility grant [P2BEP3_168721].