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.

• MeSH
• Cell Line MeSH
• Dendritic Cells metabolism   microbiology   MeSH
• Extracellular Signal-Regulated MAP Kinases metabolism   MeSH
• Phosphorylation MeSH
• Francisella tularensis * MeSH
• p38 Mitogen-Activated Protein Kinases metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Tularemia metabolism   MeSH
• Animals MeSH
• Check Tag
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Extracellular Signal-Regulated MAP Kinases MeSH
• p38 Mitogen-Activated Protein Kinases MeSH

Francisella tularensis is the causative agent of the potentially lethal disease tularemia. Due to a low infectious dose and ease of airborne transmission, Francisella is classified as a category A biological agent. Despite the possible risk to public health, there is no safe and fully licensed vaccine. A potential vaccine candidate, an attenuated live vaccine strain, does not fulfil the criteria for general use. In this review, we will summarize existing and new candidates for live attenuated and subunit vaccines.

• MeSH
• Bacterial Vaccines immunology   MeSH
• Francisella tularensis immunology   MeSH
• Humans MeSH
• Drug Discovery trends   MeSH
• Tularemia immunology   prevention & control   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Bacterial Vaccines MeSH

Francisella tularensis subspecies tularensis is a highly virulent intracellular bacterial pathogen, causing the disease tularemia. However, a safe and effective vaccine for routine application against F. tularensis has not yet been developed. We have recently constructed the deletion mutants for the DsbA homolog protein (ΔdsbA/FSC200) and a hypothetical protein IglH (ΔiglH/FSC200) in the type B F. tularensis subsp. holarctica FSC200 strain, which exerted different protection capacity against parental virulent strain. In this study, we further investigated the immunological correlates for these different levels of protection provided by ΔdsbA/FSC200 and ΔiglH/FSC200 mutants. Our results show that ΔdsbA/FSC200 mutant, but not ΔiglH/FSC200 mutant, induces an early innate inflammatory response leading to strong Th1-like antibody response. Furthermore, vaccination with ΔdsbA/FSC200 mutant, but not with ΔiglH/FSC200, elicited protection against the subsequent challenge with type A SCHU S4 strain in mice. An immunoproteomic approach was used to map a spectrum of antigens targeted by Th1-like specific antibodies, and more than 80 bacterial antigens, including novel ones, were identified. Comparison of tularemic antigens recognized by the ΔdsbA/FSC200 post-vaccination and the SCHU S4 post-challenge sera then revealed the existence of 22 novel SCHU S4 specific antibody clones.

• Keywords
• antibody response, cytokines, immunoproteomics, protection, tularemia,
• MeSH
• Vaccines, Attenuated administration & dosage   genetics   immunology   MeSH
• Bacterial Vaccines administration & dosage   genetics   immunology   MeSH
• Cytokines metabolism   MeSH
• Virulence Factors deficiency   MeSH
• Francisella tularensis classification   enzymology   immunology   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred BALB C MeSH
• Protein Disulfide-Isomerases deficiency   MeSH
• Th1 Cells immunology   MeSH
• Tularemia immunology   prevention & control   MeSH
• Antibody Formation * MeSH
• Cross Protection * MeSH
• Animals MeSH
• Check Tag
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Vaccines, Attenuated MeSH
• Bacterial Vaccines MeSH
• Cytokines MeSH
• Virulence Factors MeSH
• Protein Disulfide-Isomerases MeSH

Francisella tularensis is a highly infectious bacterium that causes the potentially lethal disease tularemia. This extremely virulent bacterium is able to replicate in the cytosolic compartments of infected macrophages. To invade macrophages and to cope with their intracellular environment, Francisella requires multiple virulence factors, which are still being identified. Proteins containing tetratricopeptide repeat (TPR)-like domains seem to be promising targets to investigate, since these proteins have been reported to be directly involved in virulence-associated functions of bacterial pathogens. Here, we studied the role of the FTS_0201, FTS_0778, and FTS_1680 genes, which encode putative TPR-like proteins in Francisella tularensis subsp. holarctica FSC200. Mutants defective in protein expression were prepared by TargeTron insertion mutagenesis. We found that the locus FTS_1680 and its ortholog FTT_0166c in the highly virulent Francisella tularensis type A strain SchuS4 are required for proper intracellular replication, full virulence in mice, and heat stress tolerance. Additionally, the FTS_1680-encoded protein was identified as a membrane-associated protein required for full cytopathogenicity in macrophages. Our study thus identifies FTS_1680/FTT_0166c as a new virulence factor in Francisella tularensis.

• MeSH
• Bacterial Proteins genetics   metabolism   MeSH
• Cytosol microbiology   MeSH
• Virulence Factors genetics   metabolism   MeSH
• Francisella tularensis genetics   growth & development   physiology   MeSH
• Genetic Loci * MeSH
• Gene Knockout Techniques MeSH
• Mutagenesis, Insertional MeSH
• Macrophages microbiology   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred BALB C MeSH
• Tularemia microbiology   pathology   MeSH
• Virulence MeSH
• Animals MeSH
• Check Tag
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Bacterial Proteins MeSH
• Virulence Factors MeSH