Lounging in a lysosome: the intracellular lifestyle of Coxiella burnetii.
TL;DR: Current understanding of the cellular events that occur during parasitism of host cells by Coxiella, including deployment of a type IV secretion system to deliver effector proteins to the host cytosol is summarized.
Abstract: Summary
Most intracellular parasites employ sophisticated mechanisms to direct biogenesis of a vacuolar replicative niche that circumvents default maturation through the endolysosomal cascade. However, this is not the case of the Q fever bacterium, Coxiella burnetii. This hardy, obligate intracellular pathogen has evolved to not only survive, but to thrive, in the harshest of intracellular compartments: the phagolysosome. Following internalization, the nascent Coxiella phagosome ultimately develops into a large and spacious parasitophorous vacuole (PV) that acquires lysosomal characteristics such as acidic pH, acid hydrolases and cationic peptides, defences designed to rid the host of intruders. However, transit of Coxiella to this environment is initially stalled, a process that is apparently modulated by interactions with the autophagic pathway. Coxiella actively participates in biogenesis of its PV by synthesizing proteins that mediate phagosome stalling, autophagic interactions, and development and maintenance of the mature vacuole. Among the potential mechanisms mediating these processes is deployment of a type IV secretion system to deliver effector proteins to the host cytosol. Here we summarize our current understanding of the cellular events that occur during parasitism of host cells by Coxiella.
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TL;DR: An overview of the antimicrobial defences of the host cell is presented, with emphasis on macrophages, for which phagocytosis has been studied most extensively and some of the evasive strategies used by bacteria are described.
Abstract: Professional phagocytes have a vast and sophisticated arsenal of microbicidal features. They are capable of ingesting and destroying invading organisms, and can present microbial antigens on their surface, eliciting acquired immune responses. To survive this hostile response, certain bacterial species have developed evasive strategies that often involve the secretion of effectors to co-opt the cellular machinery of the host. In this Review, we present an overview of the antimicrobial defences of the host cell, with emphasis on macrophages, for which phagocytosis has been studied most extensively. In addition, using Mycobacterium tuberculosis, Listeria monocytogenes, Legionella pneumophila and Coxiella burnetii as examples, we describe some of the evasive strategies used by bacteria.
849 citations
TL;DR: All the progress made over the last 20 years on this topic are reviewed, including the breaking of the old dichotomy between “acute” and “chronic” Q fever and the achievement of determining the genome sequences of several strains of this species and comparative genomic analyses.
Abstract: Coxiella burnetii is the agent of Q fever, or ``query fever,'' a zoonosis first described in Australia in 1937. Since this first description, knowledge about this pathogen and its associated infections has increased dramatically. We review here all the progress made over the last 20 years on this topic. C. burnetii is classically a strict intracellular, Gram-negative bacterium. However, a major step in the characterization of this pathogen was achieved by the establishment of its axenic culture. C. burnetii infects a wide range of animals, from arthropods to humans. The genetic determinants of virulence are now better known, thanks to the achievement of determining the genome sequences of several strains of this species and comparative genomic analyses. Q fever can be found worldwide, but the epidemiological features of this disease vary according to the geographic area considered, including situations where it is endemic or hyperendemic, and the occurrence of large epidemic outbreaks. In recent years, a major breakthrough in the understanding of the natural history of human infection with C. burnetii was the breaking of the old dichotomy between ``acute'' and ``chronic'' Q fever. The clinical presentation of C. burnetii infection depends on both the virulence of the infecting C. burnetii strain and specific risks factors in the infected patient. Moreover, no persistent infection can exist without a focus of infection. This paradigm change should allow better diagnosis and management of primary infection and long-term complications in patients with C. burnetii infection.
563 citations
Cites background from "Lounging in a lysosome: the intrace..."
...characteristics, such as an acidic pH, acid hydrolysates, and cationic peptides (8)....
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TL;DR: Human livers contain two pluripotent hepatic progenitors, hepatic stem cells and hepatoblasts, with size, morphology, and gene expression profiles distinct from that of mature hepatocytes.
Abstract: Human livers contain two pluripotent hepatic progenitors, hepatic stem cells and hepatoblasts, with size, morphology, and gene expression profiles distinct from that of mature hepatocytes. Hepatic stem cells, the precursors to hepatoblasts, persist in stable numbers throughout life, and those isolated from the livers of all age donors from fetal to adult are essentially identical in their gene and protein expression profiles. The gene expression profile of hepatic stem cells throughout life consists of high levels of expression of cytokeratin 19 (CK19), neuronal cell adhesion molecule (NCAM), epithelial cell adhesion molecule (EpCAM), and claudin-3 (CLDN-3); low levels of albumin; and a complete absence of expression of α-fetoprotein (AFP) and adult liver-specific proteins. By contrast, hepatoblasts, the dominant cell population in fetal and neonatal livers, decline in numbers with age and are found as <0.1% of normal adult livers. They express high levels of AFP, elevated levels of albumin, low levels of expression of adult liver-specific proteins, low levels of CK19, and a loss of NCAM and CLDN-3. Mature hepatocytes lack expression altogether of EpCAM, NCAM, AFP, CLDN-3, cytokeratin 19, and have acquired the well-known adult-specific profile that includes expression of high levels of albumin, cytochrome P4503A4, connexins, phosphoenolpyruvate carboxykinase, and transferrin. Thus, hepatic stem cells have a unique stem cell phenotype, whereas hepatoblasts have low levels of expression of both stem cell genes and genes expressed in high levels in mature hepatocytes.
343 citations
TL;DR: The endocytic entry processes used by viruses and bacteria are discussed and strategies used by these dissimilar classes of pathogens are compared.
Abstract: Of the many pathogens that infect humans and animals, a large number use cells of the host organism as protected sites for replication. To reach the relevant intracellularcompartments, they take advantage of the endocytosis machinery and exploit the network of endocytic organelles for penetration into the cytosol or as sites of replication. In this review, we discusstheendocyticentryprocessesusedbyvirusesandbacteriaandcomparethestrategies used by these dissimilar classes of pathogens.
286 citations
TL;DR: The data indicate that mAb 84 may be useful in eliminating residual hESC from differentiated cells populations for clinical applications, and the antigen is podocalyxin‐like protein‐1.
Abstract: Future therapeutic applications of differentiated human embryonic stem cells (hESC) carry a risk of teratoma formation by contaminating undifferentiated hESC. We generated 10 monoclonal antibodies (mAbs) against surface antigens of undifferentiated hESC, showing strong reactivity against undifferentiated, but not differentiated hESC. The mAbs did not cross react with mouse fibroblasts and showed weak to no reactivity against human embryonal carcinoma cells. Notably, one antibody (mAb 84) is cytotoxic to undifferentiated hESC and NCCIT cells in a concentration-dependent, complement-independent manner. mAb 84 induced cell death of undifferentiated, but not differentiated hESC within 30 minutes of incubation, and immunoprecipitation of the mAb-antigen complex revealed that the antigen is podocalyxin-like protein-1. Importantly, we observed absence of tumor formation when hESC and NCCIT cells were treated with mAb 84 prior to transplantation into severe combined immunodeficiency mice. Our data indicate that mAb 84 may be useful in eliminating residual hESC from differentiated cells populations for clinical applications. Disclosure of potential conflicts of interest is found at the end of this article.
265 citations
References
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TL;DR: It is demonstrated that autophagic pathways can overcome the trafficking block imposed by M. tuberculosis, which is a hormonally, developmentally, and immunologically regulated process, represents an underapp appreciated innate defense mechanism for control of intracellular pathogens.
2,108 citations
"Lounging in a lysosome: the intrace..." refers background in this paper
...…employed to remove defective organelles and cytoplasmic material via trafficking of this material to autophagolysosomes (Kirkegaard et al., 2004), and pathogen interactions with autophagosomes can have either beneficial or detrimental effects (PizarroCerda et al., 1998; Gutierrez et al., 2004)....
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..., 2004), and pathogen interactions with autophagosomes can have either beneficial or detrimental effects (PizarroCerda et al., 1998; Gutierrez et al., 2004)....
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TL;DR: In this paper, a large number of mutants called dot that were unable to replicate intracellularly because of an inability of the bacteria to alter the endocytic pathway of macrophages were isolated.
Abstract: Legionella pneumophila, the causative agent of Legionnaires' pneumonia, replicates within alveolar macrophages by preventing phagosome-lysosome fusion. Here, a large number of mutants called dot (defective for organelle trafficking) that were unable to replicate intracellularly because of an inability of the bacteria to alter the endocytic pathway of macrophages were isolated. The dot virulence genes encoded a large putative membrane complex that functioned as a secretion system that was able to transfer plasmid DNA from one cell to another.
703 citations
TL;DR: Findings suggest that M. tuberculosis retards the maturation of its phagosome along the endosomal-lysosomal pathway and resides in a compartment with endosome, as opposed to lysosomal, characteristics; and the intraphagosomal pathway, i.e., the pathway followed by several intracellular parasites that inhibit phagosomes-lysOSome fusion, is heterogeneous.
Abstract: We have used the cryosection immunogold technique to study the composition of the Mycobacterium tuberculosis phagosome. We have used quantitative immunogold staining to determine the distribution of several known markers of the endosomal-lysosomal pathway in human monocytes after ingestion of either M. tuberculosis, Legionella pneumophila, or polystyrene beads. Compared with the other phagocytic particles studied, the M. tuberculosis phagosome exhibits delayed clearance of major histocompatibility complex (MHC) class I molecules, relatively intense staining for MHC class II molecules and the endosomal marker transferrin receptor, and relatively weak staining for the lysosomal membrane glycoproteins, CD63, LAMP-1, and LAMP-2 and the lysosomal acid protease, cathepsin D. In contrast to M. tuberculosis, the L. pneumophila phagosome rapidly clears MHC class I molecules and excludes all endosomal-lysosomal markers studied. In contrast to both live M. tuberculosis and L. pneumophila phagosomes, phagosomes containing either polystyrene beads or heat-killed M. tuberculosis stain intensely for lysosomal membrane glycoproteins and cathepsin D. These findings suggest that (a) M. tuberculosis retards the maturation of its phagosome along the endosomal-lysosomal pathway and resides in a compartment with endosomal, as opposed to lysosomal, characteristics; and (b) the intraphagosomal pathway, i.e., the pathway followed by several intracellular parasites that inhibit phagosome-lysosome fusion, is heterogeneous.
702 citations
"Lounging in a lysosome: the intrace..." refers background in this paper
...More striking is the trafficking of M. avium and M. tuberculosis to the Coxiella PV as maturation of their respective vacuoles normally stalls at an early endosomal stage (Clemens and Horwitz, 1995; Sturgill-Koszycki et al., 1996)....
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...tuberculosis to the Coxiella PV as maturation of their respective vacuoles normally stalls at an early endosomal stage (Clemens and Horwitz, 1995; Sturgill-Koszycki et al., 1996)....
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TL;DR: The determinants and consequences of the fusion and fission reactions that underlie phagosomal maturation are the topic of this review.
Abstract: Foreign particles and apoptotic bodies are eliminated from the body by phagocytic leucocytes. The initial stage of the elimination process is the internalization of the particles into a plasma membrane-derived vacuole known as the phagosome. Such nascent phagosomes, however, lack the ability to kill pathogens or to degrade the ingested targets. These properties are acquired during the course of phagosomal maturation, a complex sequence of reactions that result in drastic remodelling of the phagosomal membrane and contents. The determinants and consequences of the fusion and fission reactions that underlie phagosomal maturation are the topic of this review.
685 citations
"Lounging in a lysosome: the intrace..." refers background in this paper
...Coxiella impedance of signals that promote stalling of the mycobacterial phagosome might be mediated by a type IV effector(s) that alters Rab GTPase(s) or vesicle/target SNARE(s) function (Vieira et al., 2002)....
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TL;DR: It is shown that L. pneumophilaproduce a protein called RalF that functions as an exchange factor for the ADP ribosylation factor (ARF) family of guanosine triphosphatases (GTPases) and is a substrate of the Dot/Icm secretion apparatus.
Abstract: The intracellular pathogen Legionella pneumophila subverts vesicle traffic in eukaryotic host cells to create a vacuole that supports replication. The dot/icm genes encode a protein secretion apparatus that L. pneumophila require for biogenesis of this vacuole. Here we show that L. pneumophila produce a protein called RalF that functions as an exchange factor for the ADP ribosylation factor (ARF) family of guanosine triphosphatases (GTPases). The RalF protein is required for the localization of ARF on phagosomes containing L. pneumophila. Translocation of RalF protein through the phagosomal membrane is a dot/icm-dependent process. Thus, RalF is a substrate of the Dot/Icm secretion apparatus.
534 citations
"Lounging in a lysosome: the intrace..." refers background in this paper
...Moreover, Coxiella does not contain homologues of Legionella type IV substrates including RalF (Nagai et al., 2002) and SidM/DrrA (Machner and Isberg, 2006) (guanine exchange factors), VipD, VpdA and VpdB (phospholipases) (VanRheenen et al....
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...Moreover, Coxiella does not contain homologues of Legionella type IV substrates including RalF (Nagai et al., 2002) and SidM/DrrA (Machner and Isberg, 2006) (guanine exchange factors), VipD, VpdA and VpdB (phospholipases) (VanRheenen et al., 2006), and the paralogue Sde (SdeA–...
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