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Frontiers in Cellular and Infection... 2014The Gram-negative bacterium Legionella pneumophila is ubiquitous in freshwater environments as a free-swimming organism, resident of biofilms, or parasite of protozoa.... (Review)
Review
The Gram-negative bacterium Legionella pneumophila is ubiquitous in freshwater environments as a free-swimming organism, resident of biofilms, or parasite of protozoa. If the bacterium is aerosolized and inhaled by a susceptible human host, it can infect alveolar macrophages and cause a severe pneumonia known as Legionnaires' disease. A sophisticated cell differentiation program equips L. pneumophila to persist in both extracellular and intracellular niches. During its life cycle, L. pneumophila alternates between at least two distinct forms: a transmissive form equipped to infect host cells and evade lysosomal degradation, and a replicative form that multiplies within a phagosomal compartment that it has retooled to its advantage. The efficient changeover between transmissive and replicative states is fundamental to L. pneumophila's fitness as an intracellular pathogen. The transmission and replication programs of L. pneumophila are governed by a number of metabolic cues that signal whether conditions are favorable for replication or instead trigger escape from a spent host. Several lines of experimental evidence gathered over the past decade establish strong links between metabolism, cellular differentiation, and virulence of L. pneumophila. Herein, we focus on current knowledge of the metabolic components employed by intracellular L. pneumophila for cell differentiation, nutrient salvaging and utilization of host factors. Specifically, we highlight the metabolic cues that are coupled to bacterial differentiation, nutrient acquisition systems, and the strategies utilized by L. pneumophila to exploit host metabolites for intracellular replication.
Topics: Environmental Microbiology; Food; Humans; Legionella pneumophila; Legionnaires' Disease; Phagosomes
PubMed: 24575391
DOI: 10.3389/fcimb.2014.00012 -
Journal of Cell Science Oct 2018Autophagy is one of the most elaborative membrane remodeling systems in eukaryotic cells. Its major function is to recycle cytoplasmic material by delivering it to... (Review)
Review
Autophagy is one of the most elaborative membrane remodeling systems in eukaryotic cells. Its major function is to recycle cytoplasmic material by delivering it to lysosomes for degradation. To achieve this, a membrane cisterna is formed that gradually captures cargo such as organelles or protein aggregates. The diversity of cargo requires autophagy to be highly versatile to adapt the shape of the phagophore to its substrate. Upon closure of the phagophore, a double-membrane-surrounded autophagosome is formed that eventually fuses with lysosomes. In response to environmental cues such as cytotoxicity or starvation, bulk cytoplasm can be captured and delivered to lysosomes. Autophagy thus supports cellular survival under adverse conditions. During the past decades, groundbreaking genetic and cell biological studies have identified the core machinery involved in the process. In this Review, we are focusing on reconstitution approaches to decipher the details and spatiotemporal control of autophagy, and how such studies contributed to our current understanding of the pathways in yeast and mammals. We highlight studies that revealed the function of the autophagy machinery at a molecular level with respect to its capacity to remodel membranes.
Topics: Animals; Autophagosomes; Autophagy; Humans; Lysosomes; Membranes; Phagosomes; Proteins
PubMed: 30381358
DOI: 10.1242/jcs.223792 -
Traffic (Copenhagen, Denmark) Oct 2013Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved intracellular catabolic transport route that generally allows the lysosomal... (Review)
Review
Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved intracellular catabolic transport route that generally allows the lysosomal degradation of cytoplasmic components, including bulk cytosol, protein aggregates, damaged or superfluous organelles and invading microbes. Target structures are sequestered by double-membrane vesicles called autophagosomes, which are formed through the concerted action of the autophagy (ATG)-related proteins. Until recently it was assumed that ATG proteins were exclusively involved in autophagy. A growing number of studies, however, have attributed functions to some of them that are distinct from their classical role in autophagosome biogenesis. Autophagy-independent roles of the ATG proteins include the maintenance of cellular homeostasis and resistance to pathogens. For example, they assist and enhance the turnover of dead cells and microbes upon their phagocytic engulfment, and inhibit murine norovirus replication. Moreover, bone resorption by osteoclasts, innate immune regulation triggered by cytoplasmic DNA and the ER-associated degradation regulation all have in common the requirement of a subset of ATG proteins. Microorganisms such as coronaviruses, Chlamydia trachomatis or Brucella abortus have even evolved ways to manipulate autophagy-independent functions of ATG proteins in order to ensure the completion of their intracellular life cycle. Taken together these novel mechanisms add to the repertoire of functions and extend the number of cellular processes involving the ATG proteins.
Topics: Animals; Autophagy; Homeostasis; Humans; Phagosomes; Proteins
PubMed: 23837619
DOI: 10.1111/tra.12091 -
Clinical Microbiology Reviews Apr 2014CD4(+) T cells are key cells of the adaptive immune system that use T cell antigen receptors to recognize peptides that are generated in endosomes or phagosomes and... (Review)
Review
CD4(+) T cells are key cells of the adaptive immune system that use T cell antigen receptors to recognize peptides that are generated in endosomes or phagosomes and displayed on the host cell surface bound to major histocompatibility complex molecules. These T cells participate in immune responses that protect hosts from microbes such as Mycobacterium tuberculosis, Cryptococcus neoformans, Leishmania major, and Salmonella enterica, which have evolved to live in the phagosomes of macrophages and dendritic cells. Here, we review studies indicating that CD4(+) T cells control phagosomal infections asymptomatically in most individuals by secreting cytokines that activate the microbicidal activities of infected phagocytes but in a way that inhibits the pathogen but does not eliminate it. Indeed, we make the case that localized, controlled, persistent infection is necessary to maintain large numbers of CD4(+) effector T cells in a state of activation needed to eradicate systemic and more pathogenic forms of the infection. Finally, we posit that current vaccines for phagosomal infections fail because they do not produce this "periodic reminder" form of CD4(+) T cell-mediated immune control.
Topics: CD4-Positive T-Lymphocytes; Cryptococcus neoformans; Humans; Leishmania major; Macrophages; Mycobacterium tuberculosis; Phagosomes; Salmonella enterica; Vaccines
PubMed: 24696433
DOI: 10.1128/CMR.00097-13 -
FEMS Microbiology Reviews Nov 2005Phagosome biogenesis, the process by which macrophages neutralize ingested pathogens and initiate antigen presentation, has entered the field of cellular... (Review)
Review
Phagosome biogenesis, the process by which macrophages neutralize ingested pathogens and initiate antigen presentation, has entered the field of cellular mycobacteriology research largely owing to the discovery 30 years ago that phagosomes harboring mycobacteria are refractory to fusion with lysosomes. In the past decade, the use of molecular genetics and biology in different model systems to study phagosome biogenesis have made significant advances in understanding subtle mechanisms by which mycobacteria inhibit the maturation of its phagosome. Thus, we are beginning to appreciate the extent to which these pathogens are able to interfere with innate immune responses and manipulate defense mechanisms to enhance their survival within the human host cell. Here, we summarize current knowledge about phagosome maturation arrest in infected macrophages and the subsequent attenuation of the macrophage-initiated adaptive anti-mycobacterial immune defenses.
Topics: Humans; Macrophages; Mycobacterium bovis; Mycobacterium tuberculosis; Phagosomes; Tuberculosis
PubMed: 16040149
DOI: 10.1016/j.femsre.2005.04.013 -
Autophagosomes, phagosomes, autolysosomes, phagolysosomes, autophagolysosomes... wait, I'm confused.Autophagy Apr 2014When an autophagosome or an amphisome fuse with a lysosome, the resulting compartment is referred to as an autolysosome. Some people writing papers on the topic of...
When an autophagosome or an amphisome fuse with a lysosome, the resulting compartment is referred to as an autolysosome. Some people writing papers on the topic of autophagy use the terms "autolysosome" and "autophagolysosome" interchangeably. We contend that these words should be used to denote 2 different compartments, and that it is worthwhile maintaining this distinction-the autophagolysosome has a particular origin in the process of xenophagy that makes it distinct from an autolysosome.
Topics: Animals; Autophagy; Humans; Lysosomes; Phagosomes; Terminology as Topic
PubMed: 24657946
DOI: 10.4161/auto.28448 -
Frontiers in Cellular and Infection... 2012Hundred-thousands of fungal species are present in our environment, including normal colonizers that constitute part of the human microbiota. The homeostasis of... (Review)
Review
Hundred-thousands of fungal species are present in our environment, including normal colonizers that constitute part of the human microbiota. The homeostasis of host-fungus interactions encompasses efficient fungal sensing, tolerance at mucosal surfaces, as well as antifungal defenses. Decrease in host immune fitness or increase in fungal burden may favor pathologies, ranging from superficial mucocutaneous diseases to invasive life-threatening fungal infections. Toll-like receptors (TLRs) are essential players in this balance, due to their ability to control both inflammatory and anti-inflammatory processes upon recognition of fungal-specific pathogen-associated molecular patterns (PAMPs). Certain members of the TLR family participate to the initial recognition of fungal PAMPs on the cell surface, as well as inside phagosomes of innate immune cells. Active signaling cascades in phagocytes ultimately enable fungus clearance and the release of cytokines that shape and instruct other innate immune cells and the adaptive immune system. Some TLRs cooperate with other pattern recognition receptors (PRRs) (e.g., C-type lectins and Galectins), thus allowing for a tailored immune response. The spatio-temporal and physiological contributions of individual TLRs in fungal infections remains ill-defined, although in humans, TLR gene polymorphisms have been linked to increased susceptibility to fungal infections. This review focuses entirely on the role of TLRs that control the host susceptibility to environmental fungi (e.g., Aspergillus, Cryptoccocus, and Coccidoides), as well as to the most frequent human fungal pathogens represented by the commensal Candida species. The emerging roles of TLRs in modulating host tolerance to fungi, and the strategies that evolved in some of these fungi to evade or use TLR recognition to their advantage will also be discussed, as well as their potential suitability as targets in vaccine therapies.
Topics: Epithelial Cells; Fungi; Humans; Mycoses; Phagocytes; Phagosomes; Signal Transduction; Toll-Like Receptors
PubMed: 23189270
DOI: 10.3389/fcimb.2012.00142 -
The Journal of Cell Biology Jun 2023Degradative organelles contain enzymes that function optimally at the acidic pH generated by the V-ATPase. The resulting transmembrane H+ gradient also energizes the...
Degradative organelles contain enzymes that function optimally at the acidic pH generated by the V-ATPase. The resulting transmembrane H+ gradient also energizes the secondary transport of several solutes, including Cl-. We report that Cl- influx, driven by the 2Cl-/H+ exchanger ClC-7, is necessary for the resolution of phagolysosomes formed by macrophages. Cl- transported via ClC-7 had been proposed to provide the counterions required for electrogenic H+ pumping. However, we found that deletion of ClC-7 had a negligible effect on phagosomal acidification. Instead, luminal Cl- was found to be required for activation of a wide range of phagosomal hydrolases including proteases, nucleases, and glycosidases. These findings argue that the primary role of ClC-7 is the accumulation of (phago)lysosomal Cl- and that the V-ATPases not only optimize the activity of degradative hydrolases by lowering the pH but, importantly, also play an indirect role in their activation by providing the driving force for accumulation of luminal Cl- that stimulates hydrolase activity allosterically.
Topics: Chloride Channels; Chlorides; Hydrogen-Ion Concentration; Hydrolases; Lysosomes; Phagosomes; Vacuolar Proton-Translocating ATPases
PubMed: 37010469
DOI: 10.1083/jcb.202208155 -
Autophagy Jul 2013Age-related macular degeneration (AMD) is a complex, degenerative and progressive eye disease that usually does not lead to complete blindness, but can result in severe... (Review)
Review
Age-related macular degeneration (AMD) is a complex, degenerative and progressive eye disease that usually does not lead to complete blindness, but can result in severe loss of central vision. Risk factors for AMD include age, genetics, diet, smoking, oxidative stress and many cardiovascular-associated risk factors. Autophagy is a cellular housekeeping process that removes damaged organelles and protein aggregates, whereas heterophagy, in the case of the retinal pigment epithelium (RPE), is the phagocytosis of exogenous photoreceptor outer segments. Numerous studies have demonstrated that both autophagy and heterophagy are highly active in the RPE. To date, there is increasing evidence that constant oxidative stress impairs autophagy and heterophagy, as well as increases protein aggregation and causes inflammasome activation leading to the pathological phenotype of AMD. This review ties together these crucial pathological topics and reflects upon autophagy as a potential therapeutic target in AMD.
Topics: Autophagy; Humans; Lysosomes; Macular Degeneration; Phagosomes; Proteasome Endopeptidase Complex; Retinal Pigment Epithelium
PubMed: 23590900
DOI: 10.4161/auto.24546 -
Comptes Rendus Biologies Jun 2012Large numbers of publications investigating the molecular details, the regulation and the physiological roles of autophagic processes have appeared over the last few... (Review)
Review
Large numbers of publications investigating the molecular details, the regulation and the physiological roles of autophagic processes have appeared over the last few years, dealing with animals, plants and unicellular eukaryotic organisms. This strong interest is caused by the fact that autophagic processes are ubiquitous in eukaryotic organisms. They are involved in the adaptation of organisms to their environment and to stressful conditions, thereby contributing to cell and organism survival and longevity. This review article aims to describe the discovery of autophagy, the molecular details of this complex process, its regulation, and its specific functions in plants.
Topics: Adaptation, Physiological; Arabidopsis Proteins; Autophagy; Botany; Chloroplasts; Energy Metabolism; Genes, Plant; Intracellular Membranes; Models, Biological; Phagosomes; Plant Cells; Plant Physiological Phenomena; Plants; Vacuoles
PubMed: 22721559
DOI: 10.1016/j.crvi.2012.04.004