Analysis of Transcriptional Signatures in Response to Listeria monocytogenes Infection Reveals Temporal Changes That Result from Type I Interferon Signaling

Abstract

Analysis of the mouse transcriptional response to Listeria monocytogenes infection reveals that a large set of genes are perturbed in both blood and tissue and that these transcriptional responses are enriched for pathways of the immune response. Further we identified enrichment for both type I and type II interferon (IFN) signaling molecules in the blood and tissues upon infection. Since type I IFN signaling has been reported widely to impair bacterial clearance we examined gene expression from blood and tissues of wild type (WT) and type I IFNαβ receptor-deficient (Ifnar1-/-) mice at the basal level and upon infection with L. monocytogenes. Measurement of the fold change response upon infection in the absence of type I IFN signaling demonstrated an upregulation of specific genes at day 1 post infection. A less marked reduction of the global gene expression signature in blood or tissues from infected Ifnar1-/- as compared to WT mice was observed at days 2 and 3 after infection, with marked reduction in key genes such as Oasg1 and Stat2. Moreover, on in depth analysis, changes in gene expression in uninfected mice of key IFN regulatory genes including Irf9, Irf7, Stat1 and others were identified, and although induced by an equivalent degree upon infection this resulted in significantly lower final gene expression levels upon infection of Ifnar1-/- mice. These data highlight how dysregulation of this network in the steady state and temporally upon infection may determine the outcome of this bacterial infection and how basal levels of type I IFN-inducible genes may perturb an optimal host immune response to control intracellular bacterial infections such as L. monocytogenes.

Neuroinvasive Listeria monocytogenes Infection Triggers IFN-Activation of Microglia and Upregulates Microglial miR-155

“…Strain 10403s appeared to be the more potent stimulator of miR-155, perhaps due to greater induction of Tnf (Figure 9D ). Genes strongly associated with Type I IFN-response in L. monocytogenes infected macrophages and mice, Ifit3 and Mx1 , were also upregulated in infected SIM-A9 cells (Figure 9E ) ( 59 , 62 ). These results show L. monocytogenes infection of microglia upregulates miR-155 and markers of Type I IFN activation that are also upregulated at 3 d p.i in vivo .…”

“…(Figure 5 ). Upregulation of Ifit3 and Oas1 show a key role for stimulation by Type I IFN ( 59 ). Numbers of expressed transcripts were largely similar in B6.WT and B6.miR-155 −/− mice at 3 d p.i.…”

“…show upregulation of IFN-related genes in microglia during the innate response to systemic infection. The gene expression profile at this time suggested microglia are primarily sensing Type I rather than Type II IFNs even though both are produced in the periphery at this time ( 59 , 72 ), and gene expression in whole brain specimens and recruitment of Ly6C high monocytes are notably impaired in IFN-γ −/− mice ( 46 , 73 ). Upregulation of miR-155 in microglia by Type I IFN in vitro found here and in bone marrow-derived macrophages contrasts with in vivo findings at 3 d p.i.…”

“…Systemic L. monocytogenes infection induces types I, II, and III IFNs resulting in a prominent IFN signature in blood, spleen, and liver during the first 3 days of infection ( 59 , 72 ). In accord, our results at 3 d p.i.…”

Rapid Remodeling of the Host Epithelial Cell Proteome by the Listeriolysin O (LLO) Pore-forming Toxin

“…Listeria is a facultative intracellular pathogen that can infect both phagocytic and nonphagocytic cells, such as epithelial cells. In contrast to the numerous reports of global transcriptional changes induced by Listeria in host cells during infection ( 7 – 14 ), only few studies reported post-transcriptional alterations of host protein abundance ( 15 – 19 ). These studies focused on specific host proteins ( i.e.…”