Immunity to Francisella

Center for Biologics Evaluation and Research, U.S. Food and Drug Administration Bethesda, MD, USA.
Frontiers in Microbiology (Impact Factor: 3.99). 02/2011; 2:26. DOI: 10.3389/fmicb.2011.00026
Source: PubMed


In recent years, studies on the intracellular pathogen Francisella tularensis have greatly intensified, generating a wealth of new information on the interaction of this organism with the immune system. Here we review the basic elements of the innate and adaptive immune responses that contribute to protective immunity against Francisella species, with special emphasis on new data that has emerged in the last 5 years. Most studies have utilized the mouse model of infection, although there has been an expansion of work on human cells and other new animal models. In mice, basic immune parameters that operate in defense against other intracellular pathogen infections, such as interferon gamma, TNF-α, and reactive nitrogen intermediates, are central for control of Francisella infection. However, new important immune mediators have been revealed, including IL-17A, Toll-like receptor 2, and the inflammasome. Further, a variety of cell types in addition to macrophages are now recognized to support Francisella growth, including epithelial cells and dendritic cells. CD4(+) and CD8(+) T cells are clearly important for control of primary infection and vaccine-induced protection, but new T cell subpopulations and the mechanisms employed by T cells are only beginning to be defined. A significant role for B cells and specific antibodies has been established, although their contribution varies greatly between bacterial strains of lower and higher virulence. Overall, recent data profile a pathogen that is adept at subverting host immune responses, but susceptible to many elements of the immune system's antimicrobial arsenal.

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Available from: Siobhán C Cowley
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    • "Whereas, F. tularensis is a significant pathogen based on high morbidity and mortality rates, it also is an extremely interesting pathogen due its complicated intracellular lifestyle, ability to infect a wide variety of host cell types, persistence in the environment, and lack of classical bacterial virulence factors such as exotoxins or a Type III secretion system (Celli and Zahrt, 2013). Many excellent reviews previously have characterized F. tularensis as a " stealth " pathogen, which first evades host immune detection (Sjöstedt, 2006;Jones et al., 2014), but subsequently induces a cytokine storm that causes host death (Cowley, 2009;Cowley and Elkins, 2011). In addition, the metabolic pathways and nutrient requirements of F. tularensis promoting survival inside host cells also have been elegantly outlined (Barel and Charbit, 2013;Barel et al., 2015). "
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    ABSTRACT: Francisella tularensis is a highly-infectious bacterium that causes the rapid, and often lethal disease, tularemia. Many studies have been performed to identify and characterize the virulence factors that F. tularensis uses to infect a wide variety of hosts and host cell types, evade immune defenses, and induce severe disease and death. This review focuses on the virulence factors that are present in the F. tularensis envelope, including capsule, LPS, outer membrane, periplasm, inner membrane, secretion systems, and various molecules in each of aforementioned sub-compartments. Whereas no single bacterial molecule or molecular complex single-handedly controls F. tularensis virulence, we review here how diverse bacterial systems work in conjunction to subvert the immune system, attach to and invade host cells, alter phagosome/lysosome maturation pathways, replicate in host cells without being detected, inhibit apoptosis, and induce host cell death for bacterial release and infection of adjacent cells. Given that the F. tularensis envelope is the outermost layer of the bacterium, we highlight herein how many of these molecules directly interact with the host to promote infection and disease. These and future envelope studies are important to advance our collective understanding of F. tularensis virulence mechanisms and offer targets for future vaccine development efforts.
    Full-text · Article · Dec 2015 · Frontiers in Cellular and Infection Microbiology
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    • "Increased TGF-β levels have been found in the lungs and spleen of SCHU S4-infected mice compared with uninfected controls, 24 h post-infection (Bosio et al., 2007). Because F. tularensis prevents immune recognition and the production of pro-inflammatory cytokines for up to 72 h post-infection (Jones et al., 2012), the subsequent response is hypercytokinetic and often fatal (Cowley and Elkins, 2011). Damage-associated molecular patterns (DAMP), such as the high-mobility group protein B1 (HMGB1), are detected at above normal levels in blood serum only after 72 h post-infection "
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    ABSTRACT: Computational models can provide valuable insights into the mechanisms of infection and be used as investigative tools to support development of medical treatments. We develop a stochastic, within-host, computational model of the infection process in the BALB/c mouse, following inhalational exposure to Francisella tularensis SCHU S4. The model is mechanistic and governed by a small number of experimentally verifiable parameters. Given an initial dose, the model generates bacterial load profiles corresponding to those produced experimentally, with a doubling time of approximately 5 h during the first 48 h of infection. Analytical approximations for the mean number of bacteria in phagosomes and cytosols for the first 24 h post-infection are derived and used to verify the stochastic model. In our description of the dynamics of macrophage infection, the number of bacteria released per rupturing macrophage is a geometrically-distributed random variable. When combined with doubling time, this provides a distribution for the time taken for infected macrophages to rupture and release their intracellular bacteria. The mean and variance of these distributions are determined by model parameters with a precise biological interpretation, providing new mechanistic insights into the determinants of immune and bacterial kinetics. Insights into the dynamics of macrophage suppression and activation gained by the model can be used to explore the potential benefits of interventions that stimulate macrophage activation.
    Full-text · Article · Dec 2014 · Frontiers in Cellular and Infection Microbiology
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    • "Fish & Shellfish Immunology vaccination with killed bacteria induces an antibody response with only limited protection [16]. Production of membrane vesicles by cells is a conserved mechanism occurring throughout all domains of life [17]. "
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    ABSTRACT: Infection of fish with the facultative intracellular bacterium Francisella noatunensis remains an unresolved problem for aquaculture industry worldwide as it is difficult to vaccinate against without using live attenuated vaccines. Outer membrane vesicles (OMVs) are biological structures shed by Gramnegative bacteria in response to various environmental stimuli. OMVs have successfully been used to vaccinate against both intracellular and extracellular pathogens, due to an ability to stimulate innate, cell-mediated and humoral immune responses. We show by using atomic force and electron microscopy that the fish pathogenic bacterium E noatunensis subspecies noatunensis (F.n.n.) shed OMVs both in vitro into culture medium and in vivo in a zebrafish infection model. The main protein constituents of the OMV are IgIC, PdpD and PdpA, all known Francisella virulence factors, in addition to the outer membrane protein FopA and the chaperonin GroEL, as analyzed by mass spectrometry. The vesicles, when used as a vaccine, reduced proliferation of the bacterium and protected zebrafish when subsequently challenged with a high dose of F.n.n. without causing adverse effects for the host. Also granulomatous responses were reduced in F.n.n.-challenged zebrafish after OMV vaccination. Taken together, the data support the possible use of OMVs as vaccines against francisellosis in fish. (C) 2014 The Authors. Published by Elsevier Ltd.
    Full-text · Article · Oct 2014 · Fish & Shellfish Immunology
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