Dendritic cells (DCs) infected by Francisella tularensis are poorly activated and do not undergo classical maturation process. Although reasons of such unresponsiveness are not fully understood, their impact on the priming of immunity is well appreciated. Previous attempts to explain the behavior of Francisella-infected DCs were hypothesis-driven and focused on events at later stages of infection. Here, we took an alternative unbiased approach by applying methods of global phosphoproteomics to analyze the dynamics of cell signaling in primary DCs during the first hour of infection by Francisella tularensis Presented results show that the early response of DCs to Francisella occurs in phases and that ERK and p38 signaling modules induced at the later stage are differentially regulated by virulent and attenuated ΔdsbA strain. These findings imply that the temporal orchestration of host proinflammatory pathways represents the integral part of Francisella life-cycle inside hijacked DCs.

‖Department of Microbiology Faculty of Medicine University of Rijeka 51000 Rijeka Croatia

§Institute of Molecular Genetics ASCR v v i Microscopy Centre Electron Microscopy Core Facility 142 20 Prague 4 Czech Republic

§Institute of Molecular Genetics ASCR v v i Microscopy Centre Electron Microscopy Core Facility 142 20 Prague 4 Czech Republic ¶Institute of Molecular Genetics ASCR v v i Department of Biology of the Cell Nucleus 142 20 Prague 4 Czech Republic

From the ‡Department of Molecular Pathology and Biology Faculty of Military Health Sciences University of Defence 500 01 Hradec Kralove Czech Republic

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