Global analysis of gene expression reveals mRNA superinduction is required for the inducible immune response to a bacterial pathogen

  1. Kevin C Barry
  2. Nicholas T Ingolia  Is a corresponding author
  3. Russell E Vance  Is a corresponding author
  1. University of California, Berkeley, United States

Abstract

The inducible innate immune response to infection requires a concerted process of gene expression that is regulated at multiple levels. Most global analyses of the innate immune response have focused on transcription induced by defined immunostimulatory ligands, such as lipopolysaccharide. However, the response to pathogens involves additional complexity, as pathogens interfere with virtually every step of gene expression. How cells respond to pathogen-mediated disruption of gene expression to nevertheless initiate protective responses remains unclear. We previously discovered that a pathogen-mediated blockade of host protein synthesis provokes the production of specific pro-inflammatory cytokines. It remains unclear how these cytokines are produced despite the global pathogen-induced block of translation. We addressed this question by using parallel RNAseq and ribosome profiling to characterize the response of macrophages to infection with the intracellular bacterial pathogen Legionella pneumophila. Our results reveal that mRNA superinduction is required for the inducible immune response to a bacterial pathogen.

Data availability

The following data sets were generated

Article and author information

Author details

  1. Kevin C Barry

    Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1064-5964
  2. Nicholas T Ingolia

    Division of Biochemistry, Biophysics and Structural Biology, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    ingolia@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.
  3. Russell E Vance

    Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    rvance@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6686-3912

Funding

Howard Hughes Medical Institute

  • Russell E Vance

National Institutes of Health (AI075039 AI063302)

  • Nicholas T Ingolia
  • Russell E Vance

Cancer Research Institute

  • Kevin C Barry
  • Russell E Vance

Burroughs Wellcome Fund

  • Russell E Vance

Fibrolamellar Cancer Foundation

  • Kevin C Barry

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: These studies were carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Animal Care and Use Committee at the University of California, Berkeley.

Copyright

© 2017, Barry et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,268
    views
  • 712
    downloads
  • 45
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Kevin C Barry
  2. Nicholas T Ingolia
  3. Russell E Vance
(2017)
Global analysis of gene expression reveals mRNA superinduction is required for the inducible immune response to a bacterial pathogen
eLife 6:e22707.
https://doi.org/10.7554/eLife.22707

Share this article

https://doi.org/10.7554/eLife.22707

Further reading

    1. Immunology and Inflammation
    Denise M Monack
    Insight

    Macrophages control intracellular pathogens like Salmonella by using two caspase enzymes at different times during infection.

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Ainhoa Arbués, Sarah Schmidiger ... Damien Portevin
    Research Article

    The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise 10 phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human in vitro granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets—a phenotype associated with dormancy—that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B, and TNF. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.