The timing of IFNβ production affects early innate responses to Listeria monocytogenes and determines the overall outcome of lethal infection

PLoS One. 2012;7(8):e43455. doi: 10.1371/journal.pone.0043455. Epub 2012 Aug 17.

Abstract

Dendritic cells (DCs) and natural killer (NK) cells are essential components of the innate immunity and play a crucial role in the first phase of host defense against infections and tumors. Listeria monocytogenes (Lm) is an intracellular pathogen that colonizes the cytosol of eukaryotic cells. Recent findings have shown Lm specifically in splenic CD8a(+) DCs shortly after intravenous infection. We examined gene expression profiles of mouse DCs exposed to Lm to elucidate the molecular mechanisms underlying DCs interaction with Lm. Using a functional genomics approach, we found that Lm infection induced a cluster of late response genes including type I IFNs and interferon responsive genes (IRGs) in DCs. Type I INFs were produced at the maximal level only at 24 h post infection indicating that the regulation of IFNs in the context of Lm infection is delayed compared to the rapid response observed with viral pathogens. We showed that during Lm infection, IFNγ production and cytotoxic activity were severely impaired in NK cells compared to E. coli infection. These defects were restored by providing an exogenous source of IFNβ during the initial phase of bacterial challenge. Moreover, when treated with IFNβ during early infection, NK cells were able to reduce bacterial titer in the spleen and significantly improve survival of infected mice. These findings show that the timing of IFNβ production is fundamental to the efficient control of the bacterium during the early innate phase of Lm infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / genetics
  • Cell Survival / immunology
  • Cells, Cultured
  • Coculture Techniques
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dendritic Cells / microbiology
  • Female
  • Gene Expression Profiling
  • Host-Pathogen Interactions / immunology
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology*
  • Interferon-beta / genetics
  • Interferon-beta / immunology*
  • Interferon-beta / metabolism
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / microbiology
  • Listeria monocytogenes / immunology*
  • Listeria monocytogenes / physiology
  • Listeriosis / genetics
  • Listeriosis / immunology*
  • Listeriosis / microbiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oligonucleotide Array Sequence Analysis
  • Prognosis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spleen / immunology
  • Spleen / metabolism
  • Spleen / microbiology
  • Survival Analysis
  • Time Factors

Substances

  • Interferon-beta

Grant support

This work was supported by the Italian Ministry of Education and Research (COFIN 2009), by grants from the European Union FP7 Program (TOLERAGE: HEALTH-F4-2008-202156; FIGHT-MG: Health-2009-242210). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.