Immune responses to intracellular pathogens depend largely upon the activation of T helper type 1-dependent mechanisms. The contribution of B cells to establishing protective immunity has long been underestimated. Francisella tularensis, including a number of subspecies, provides a suitable model for the study of immune responses against intracellular bacterial pathogens. We previously demonstrated that Francisella infects B cells and activates B-cell subtypes to produce a number of cytokines and express the activation markers. Recently, we documented the early production of natural antibodies as a consequence of Francisella infection in mice. Here, we summarize current knowledge on the innate and acquired humoral immune responses initiated by Francisella infection and their relationships with the immune defense systems.

• Keywords
• B cells, Francisella tularensis, intracellular pathogen, natural antibodies, natural immunity,
• Publication type
• Journal Article MeSH
• Review MeSH

There remains to this day a great gap in understanding as to the role of B cells and their products-antibodies and cytokines-in mediating the protective response to Francisella tularensis, a Gram-negative coccobacillus belonging to the group of facultative intracellular bacterial pathogens. We previously have demonstrated that Francisella interacts directly with peritoneal B-1a cells. Here, we demonstrate that, as early as 12 h postinfection, germ-free mice infected with Francisella tularensis produce infection-induced antibody clones reacting with Francisella tularensis proteins having orthologs or analogs in eukaryotic cells. Production of some individual clones was limited in time and was influenced by virulence of the Francisella strain used. The phylogenetically stabilized defense mechanism can utilize these early infection-induced antibodies both to recognize components of the invading pathogens and to eliminate molecular residues of infection-damaged self cells.

• MeSH
• B-Lymphocytes immunology   metabolism   MeSH
• Cytokines metabolism   MeSH
• Francisella tularensis pathogenicity   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred BALB C MeSH
• Mice MeSH
• Tularemia immunology   microbiology   MeSH
• Antibody Formation MeSH
• Virulence MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cytokines MeSH

Primary interaction of an intracellular bacterium with its host cell is initiated by activation of multiple signaling pathways in response to bacterium recognition itself or as cellular responses to stress induced by the bacterium. The leading molecules in these processes are cell surface membrane receptors as well as cytosolic pattern recognition receptors recognizing pathogen-associated molecular patterns or damage-associated molecular patterns induced by the invading bacterium. In this review, we demonstrate possible sequences of events leading to recognition of Francisella tularensis, present findings on known mechanisms for manipulating cell responses to protect Francisella from being killed, and discuss newly published data from the perspective of early stages of host-pathogen interaction.

• Keywords
• Francisella tularensis, innate immune recognition, intracellular replication, phagocytosis, signaling pathways,
• MeSH
• Alarmins genetics   immunology   MeSH
• Bacterial Proteins genetics   immunology   MeSH
• Phagocytosis genetics   MeSH
• Francisella tularensis genetics   immunology   pathogenicity   MeSH
• Host-Pathogen Interactions genetics   immunology   MeSH
• Humans MeSH
• Macrophages immunology   microbiology   MeSH
• Pathogen-Associated Molecular Pattern Molecules immunology   metabolism   MeSH
• Immunity, Innate * MeSH
• Receptors, Cell Surface genetics   immunology   MeSH
• Receptors, Pattern Recognition genetics   immunology   MeSH
• Gene Expression Regulation MeSH
• Signal Transduction MeSH
• Tularemia genetics   immunology   microbiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Alarmins MeSH
• Bacterial Proteins MeSH
• Pathogen-Associated Molecular Pattern Molecules MeSH
• Receptors, Cell Surface MeSH
• Receptors, Pattern Recognition MeSH

Francisella tularensis, the etiological agent of tularemia, is an intracellular pathogen that dominantly infects and proliferates inside phagocytic cells but can be seen also in non-phagocytic cells, including B cells. Although protective immunity is known to be almost exclusively associated with the type 1 pathway of cellular immunity, a significant role of B cells in immune responses already has been demonstrated. Whether their role is associated with antibody-dependent or antibody-independent B cell functions is not yet fully understood. The character of early events during B cell-pathogen interaction may determine the type of B cell response regulating the induction of adaptive immunity. We used fluorescence microscopy and flow cytometry to identify the basic requirements for the entry of F. tularensis into B cells within in vivo and in vitro infection models. Here, we present data showing that Francisella tularensis subsp. holarctica strain LVS significantly infects individual subsets of murine peritoneal B cells early after infection. Depending on a given B cell subset, uptake of Francisella into B cells is mediated by B cell receptors (BCRs) with or without complement receptor CR1/2. However, F. tularensis strain FSC200 ΔiglC and ΔftdsbA deletion mutants are defective in the ability to enter B cells. Once internalized into B cells, F. tularensis LVS intracellular trafficking occurs along the endosomal pathway, albeit without significant multiplication. The results strongly suggest that BCRs alone within the B-1a subset can ensure the internalization process while the BCRs on B-1b and B-2 cells need co-signaling from the co receptor containing CR1/2 to initiate F. tularensis engulfment. In this case, fluidity of the surface cell membrane is a prerequisite for the bacteria's internalization. The results substantially underline the functional heterogeneity of B cell subsets in relation to F. tularensis.

• MeSH
• B-Lymphocytes metabolism   microbiology   MeSH
• Genes, Bacterial MeSH
• Biological Transport MeSH
• Cell Line MeSH
• Francisella tularensis physiology   MeSH
• Host-Pathogen Interactions MeSH
• Membrane Microdomains metabolism   MeSH
• Microbial Viability MeSH
• Mice, Inbred BALB C MeSH
• Receptors, Antigen, B-Cell metabolism   MeSH
• Receptors, IgG metabolism   MeSH
• Receptors, Complement metabolism   MeSH
• Sequence Deletion MeSH
• Tularemia microbiology   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
• Receptors, Antigen, B-Cell MeSH
• Receptors, IgG MeSH
• Receptors, Complement MeSH