Transcriptional profiling ofFrancisella tularensisinfected peripheral blood mononuclear cells: a predictive tool for tularemia

Abstract

In this study, we analyzed temporal gene expression patterns in human peripheral blood mononuclear cells (PBMCs) infected with the Francisella tularensis live vaccine strain from 1 to 24 h utilizing a whole human Affymetrix gene chip. We found that a considerable number of induced genes had similar expression patterns and functions as reported previously for gene expression profiling in patients with ulceroglandular tularemia. Among the six uniquely regulated genes reported for tularemia patients as being part of the alarm signal gene cluster, five, namely caspase 1, PSME2, TAP-1, GBP1, and GCH1, were induced in vitro. We also detected four out of the seven potential biomarkers reported in tularemia patients, namely TNFAIP6 at 4 h and STAT1, TNFSF10, and SECTM1 at 16 and 24 h. These observations underscore the value of using microarray expression profiling as an in vitro tool to identify potential biomarkers for human infection and disease. Our results indicate the potential involvement of several host pathways/processes in Francisella infection, notably those involved in calcium, zinc ion binding, PPAR signaling, and lipid metabolism, which further refines the current knowledge of F. tularensis infection and its effects on the human host. Ultimately, this study provides support for utilizing in vitro microarray gene expression profiling in human PBMCs to identify biomarkers of infection and predict in vivo immune responses to infectious agents.

Host Immune Response and Acute Disease in a Zebrafish Model ofFrancisellaPathogenesis

“…and persisting up to 1 week. These responses share many similarities with findings from studies of mice and humans (7,9,12,15,19,22,24,40,49,65), suggesting that zebrafish are a useful and relevant comparative model system to study hostpathogen interactions during Francisella infection.…”

“…However, in another study using a much lower multiplicity of infection to infect peripheral blood mononuclear cells, there was no downregulation of TNF-␣. Rather, a slight delay in induction was observed (49). The ability to suppress or delay the activation of very specific immune responses may be an important virulence mechanism utilized by Francisella (21).…”

“…IFN-␥ is produced in response to infection with Francisella in all vertebrate model systems (2,6,9,12,19,22,49,51), and IFN-␥ knockout mice and mice treated with anti-IFN-␥ antibodies succumb to normally sublethal doses of Francisella (22,32). In this study, although IFN-␥ was upregulated at early time points, the most significant upregulation occurred during the later phases of acute infection: 72 h and 7 days p.i.…”

Interleukin-17 Protects against the Francisella tularensis Live Vaccine Strain but Not against a Virulent F. tularensis Type A Strain

“…In this study, we investigated the role of IL-17 in tularemia due to findings by others that IL-17 and IL-23 (which can induce IL-17) are induced in vitro and in vivo following infection with attenuated strains of F. tularensis (16)(17)(18). Indeed, we did find that IL-17R␣ Ϫ/Ϫ mice were more susceptible to LVS infection; however, during the course of our work, several groups reported similar findings (19)(20)(21), but no efforts were made by these groups to study the role of IL-17 during virulent F. tularensis infections.…”

“…One study showed that IL-12p35-deficient mice, as well as wildtype mice, are capable of resolving infection; however, IL-12p40-deficient mice are much more susceptible to disease, suggesting that IL-23 (a heterodimer of IL-23p19 and IL-12p40), which can induce IL-17 production, is important in resolving F. tularensis infections (39). It was also shown that intranasal LVS infection leads to increased IL-17 expression in the bronchoalveolar lavage fluid of infected mice (16), and the infection of human peripheral blood mononuclear cells (PBMCs) with LVS in vitro also induces IL-17 responses (17). In addition, the infection of human PBMCs in vitro with either Francisella novicida or type A F. tularensis SchuS4 was shown to induce IL-23p19 mRNA (18).…”