Among these, three were confirmed by knockdown of their corresponding mammalian homologues to impact the intracellular survival ofF. processes, ultimately ensuring their survival and proliferation within the host. The Gram-negative bacteriumFrancisella tularensisis the causative agent of tularemia, a vector-borne zoonosis LY317615 (Enzastaurin) of the Northern Hemisphere that can affect humans and cause severe morbidity and mortality if untreated or misdiagnosed. Human tularemia is usually a fulminant disease that can be contracted by exposure to as few as 10 bacteria, the pneumonic form of which is the most severe (Oyston et al.,2004). Three subspecies ofF. tularensis,F. tularensissubsp.tularensis(Type A),F. tularensissubsp.holarctica(Type B), andF. tularensissubsp.mediasiaticaare recognized, among which strains from subspeciestularensisandholarcticacan cause tularemia in humans (Oyston et al.,2004). Additionally,F. novicida, an avirulentFrancisellaspecies in humans that retains high virulence in rodents, has been used extensively as a surrogate model forF. tularensisdue to lower biocontainment requirements (Baron and Nano,1998; Lauriano et al.,2004; Santic et al.,2005a,b,2007,2008; Brotcke et al.,2006; de Bruin et al.,2007; Mohapatra et al.,2007a,b,2008,2010; Weiss et al.,2007; Brotcke and Monack,2008; Barker et al.,2009a,b; Schmerk et al.,2009a,b; Al-Khodor and Abu Kwaik,2010; Asare and Abu Kwaik,2010; Asare et al.,2010). Essential to the development of tularemia is the bacterium’s ability to infect and proliferate within mononuclear phagocytes, such as macrophages and dendritic cells, although this bacterium can also infect polymorphonuclear neutrophils, hepatocytes, epithelial, and endothelial cells (Oyston et al.,2004). Because of the importance of its intracellular lifestyle, the interactions ofF. tularensiswith host cells have been studied thoroughly, with a particular emphasis on those with macrophages. Using a variety ofFrancisellastrains, such asF. novicida, the attenuatedholarcticavaccine strain LVS, or virulent strains such as SchuS4 or clinicaltularensisisolates, and host cell models, including murine or human primary macrophages and macrophage-like cell lines, several laboratories have defined the intracellular cycle ofFrancisella(Figures1and2). Following phagocytic uptake,Francisellainitially resides within a phagosome called theFrancisella-containing phagosome (FCP) that interacts with early LY317615 (Enzastaurin) and late compartments of the endocytic pathway (Clemens et al.,2004; Santic et al.,2005a; Checroun et al.,2006; Chong et al.,2008), prior to phagosomal membrane disruption that allows bacterial release in the macrophage cytosol (Golovliov et al.,2003; Clemens et al.,2004; Santic et al.,2005a; Checroun et al.,2006; Chong et al.,2008; Wehrly et al.,2009). Once cytosolic, bacteria undergo extensive replication that culminates in the apoptotic and pyroptotic deaths of the infected cells (Lai et al.,2001; Lai and Sjostedt,2003; Mariathasan et al.,2005; Santic et al.,2010) and/or reentry into the endocytic compartments inFrancisella-containing vacuoles (FCV) in murine primary macrophages via an autophagy-mediated process (Checroun et al.,2006; Wehrly Rabbit polyclonal to RAB18 et al.,2009). Our current knowledge of theFrancisellaintracellular cycle indicates that this bacterium can be considered a cytosolic pathogen, yet cycles through a variety of intracellular compartments with distinct environments to ensure survival, proliferation, and eventual release. For this purpose, it has likely evolved a battery of mechanisms to subvert various host cell processes. In this LY317615 (Enzastaurin) review, we will focus onFrancisellamacrophage interactions and discuss recent findings about both bacterial and host factors that contribute to the intracellular pathogenesis of this bacterium. == Physique 1. == Contamination cycle ofF. tularensisSchu S4 within C57BL/6J murine bone marrow-derived macrophages (BMMs). BMMs were infected with Schu S4 and processed at various times post LY317615 (Enzastaurin) contamination (pi) for immunofluorescence or transmission electron microscopy. Representative confocal and LY317615 (Enzastaurin) electron (TEM) micrographs of intracellular SchuS4 at 30 min, 1, 4, 8, 12, and 24 h pi, showing the early phagosomal stage, phagosomal disruption, bacterial release in the cytosol, cytosolic replication, and FCV formation. Bacteria appear in green and endosomal, LAMP-1-positive membranes appear in red. White arrowheads indicate either regions of interest in whole images or bacteria enclosed.