Legionella pneumophila

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Legionella pneumophila
Legionella pneumophila 01.jpg
TEM image of L. pneumophila
Scientific classification
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L. pneumophila
Binomial name
Legionella pneumophila
Brenner DJ, Steigerwalt AG, McDade JE 1979

Legionella pneumophila is a thin, aerobic, pleomorphic, flagellated, non-spore-forming, Gram-negative bacterium of the genus Legionella . [1] [2] L. pneumophila is the primary human pathogenic bacterium in this group and is the causative agent of Legionnaires' disease, also known as legionellosis.

Flagellum part of a cell of some organisms

A flagellum is a lash-like appendage that protrudes from the cell body of certain bacteria and eukaryotic cells termed as flagellates. A flagellate can have one or several flagella. The primary function of a flagellum is that of locomotion, but it also often functions as a sensory organelle, being sensitive to chemicals and temperatures outside the cell. The similar structure in the archaea functions in the same way but is structurally different and has been termed the archaellum.

<i>Legionella</i> genus of bacteria

The genus Legionella is a pathogenic group of Gram-negative bacteria that includes the species L. pneumophila, causing legionellosis including a pneumonia-type illness called Legionnaires' disease and a mild flu-like illness called Pontiac fever.

Legionnaires disease legionellosis that is characterized by severe form of infection producing pneumonia. Symptoms include fever, chills, and cough.

Legionnaires' disease, also known as legionellosis, is a form of atypical pneumonia caused by any type of Legionella bacteria. Signs and symptoms include cough, shortness of breath, high fever, muscle pains, and headaches. Nausea, vomiting, and diarrhea may also occur. This often begins 2–10 days after exposure.

Contents

In nature, L. pneumophila infects freshwater and soil amoebae of the genera Acanthamoeba and Naegleria . [3] The mechanism of infection is similar in amoeba and human cells.

Amoeba polyphyletic group including different eucariot taxons

An amoeba, often called amoeboid, is a type of cell or unicellular organism which has the ability to alter its shape, primarily by extending and retracting pseudopods. Amoebas do not form a single taxonomic group; instead, they are found in every major lineage of eukaryotic organisms. Amoeboid cells occur not only among the protozoa, but also in fungi, algae, and animals.

<i>Acanthamoeba</i> genus of protozoans

Acanthamoeba is a genus of amoebae, single-celled eukaryoteis commonly recovered from soil, fresh water, and other habitats, and is classified into the eukaryote supergroup Amoebozoa. Acanthamoeba has two evolutive forms, the metabolically active trophozoite and a dormant, stress resistant cyst. Trophozoites are small, usually 15 to 25 μm in length and amoeboid in shape. In nature, Acanthamoeba species are free-living bacterivores, but in certain situations, they can cause infections (acanthamebiasis) in humans and other animals.

<i>Naegleria</i> genus of Heterolobosea

Naegleria is a free living amoebae protist genus consisting of 47 described species often found in warm aquatic environments as well as soil habitats worldwide. It has three life cycle forms: the amoeboid stage, the cyst stage, and the flagellated stage, and has been routinely studied for its ease in change from amoeboid to flagellated stages. The Naegleria genera became famous when Naegleria fowleri, a human pathogenic strain and the causative agent of primary amoebic meningoencephalitis (PAM), was discovered in 1965. Most species in the genus, however, are non pathogenic.

Characterization

L. pneumophila is a Gram-negative, nonencapsulated, aerobic bacillus with a single, polar flagellum often characterized as being a coccobacillus. It is aerobic and unable to hydrolyse gelatin or produce urease. It is also nonfermentative. L. pneumophila is neither pigmented nor does it autofluoresce. It is oxidase- and catalase-positive, and produces beta-lactamase. L. pneumophila colony morphology is gray-white with a textured, cut-glass appearance; it also requires cysteine and iron to thrive. It grows on yeast extract in "opal-like" colonies.

Coccobacillus

A coccobacillus is a type of bacterium with a shape intermediate between cocci and bacilli. Coccobacilli, then, are very short rods which may be mistaken for cocci.

Aerobic organism

An aerobic organism or aerobe is an organism that can survive and grow in an oxygenated environment. In contrast, an anaerobic organism (anaerobe) is any organism that does not require oxygen for growth. Some anaerobes react negatively or even die if oxygen is present.

Hydrolysis is a term used for both an electro-chemical process and a biological one. The hydrolysis of water is the separation of water molecules into hydrogen and oxygen atoms using electricity (electrolysis).

Cell membrane structure

While L. pneumophila is categorized as a Gram-negative organism, it stains poorly due to its unique lipopolysaccharide content in the outer leaflet of the outer cell membrane. [4] The bases for the somatic antigen specificity of this organism are located on the side chains of its cell wall. The chemical composition of these side chains both with respect to components and arrangement of the different sugars, determines the nature of the somatic or O-antigen determinants, which are important means of serologically classifying many Gram-negative bacteria. At least 35 different serovars of L. pneumophila have been described, as well as several other species being subdivided into a number of serovars.

Lipopolysaccharide chemical compound

Lipopolysaccharides (LPS), also known as lipoglycans and endotoxins, are large molecules consisting of a lipid and a polysaccharide composed of O-antigen, outer core and inner core joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria.

Antigen molecule capable of inducing an immune response (to produce an antibody) in the host organism

In immunology, antigens (Ag) are structures specifically bound by antibodies (Ab) or a cell surface version of Ab ~ B cell antigen receptor (BCR). The terms antigen originally described a structural molecule that binds specifically to an antibody only in the form of native antigen. It was expanded later to refer to any molecule or a linear molecular fragment after processing the native antigen that can be recognized by T-cell receptor (TCR). BCR and TCR are both highly variable antigen receptors diversified by somatic V(D)J recombination. Both T cells and B cells are cellular components of adaptive immunity. The Ag abbreviation stands for an antibody generator.

Detection

Sera have been used both for slide agglutination studies and for direct detection of bacteria in tissues using fluorescent-labelled antibody. Specific antibody in patients can be determined by the indirect fluorescent antibody test. ELISA and microagglutination tests have also been successfully applied.

Serum (blood) cell free fraction of blood

In blood, the serum is the component that is neither a blood cell, nor a clotting factor; it is the blood plasma not including the fibrinogens. Serum includes all proteins not used in blood clotting and all the electrolytes, antibodies, antigens, hormones, and any exogenous substances.

Fluorescence emission of light by a substance that has absorbed light or other electromagnetic radiation

Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation. It is a form of luminescence. In most cases, the emitted light has a longer wavelength, and therefore lower energy, than the absorbed radiation. The most striking example of fluorescence occurs when the absorbed radiation is in the ultraviolet region of the spectrum, and thus invisible to the human eye, while the emitted light is in the visible region, which gives the fluorescent substance a distinct color that can be seen only when exposed to UV light. Fluorescent materials cease to glow nearly immediately when the radiation source stops, unlike phosphorescent materials, which continue to emit light for some time after.

Antibody large Y-shaped protein produced by B-cells, used by the immune system; large, Y-shaped protein produced mainly by plasma cells that is used by the immune system to neutralize pathogens such as pathogenic bacteria and viruses

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein produced mainly by plasma cells that is used by the immune system to neutralize pathogens such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen, via the fragment antigen-binding (Fab) variable region. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize its target directly. Depending on the antigen, the binding may impede the biological process causing the disease or may activate macrophages to destroy the foreign substance. The ability of an antibody to communicate with the other components of the immune system is mediated via its Fc region, which contains a conserved glycosylation site involved in these interactions. The production of antibodies is the main function of the humoral immune system.

Legionella stains poorly with Gram stain, stains positive with silver, and is cultured on charcoal yeast extract with iron and cysteine.

Ecology and reservoirs

L. pneumophila (red chains) multiplying inside Tetrahymena pyriformis T. pyriformis hosting L. pneumophila.png
L. pneumophila (red chains) multiplying inside Tetrahymena pyriformis

L. pneumophila is a facultative intracellular parasite that can invade and replicate inside amoebae in the environment, especially species of the genera Acanthamoeba and Naegleria , which can thus serve as a reservoir for L. pneumophila. These hosts also provide protection from environmental stresses, such as chlorination. [5]

Water chlorination is the process of adding chlorine or chlorine compounds such as sodium hypochlorite to water. This method is used to kill certain bacteria and other microbes in tap water as chlorine is highly toxic. In particular, chlorination is used to prevent the spread of waterborne diseases such as cholera, dysentery, and typhoid.

Frequency of occurrence

In the United States, about 2 infections with L. pneumophila appear per 100,000 residents per year [6] [ not in citation given ]. The infections peak in the summer. Within endemic regions, about 4% to 5% of pneumonia cases are caused by L. pneumophila. [7] .

Pathogenesis

In humans, L. pneumophila invades and replicates inside macrophages. The internalization of the bacteria can be enhanced by the presence of antibody and complement, but is not absolutely required. Internalization of the bacteria appears to occur through phagocytosis. However, L. pneumophila is also capable of infecting nonphagocytic cells through an unknown mechanism. A rare form of phagocytosis known as coiling phagocytosis has been described for L. pneumophila, but this is not dependent on the Dot/Icm secretion system and has been observed for other pathogens. [8] Once internalized, the bacteria surround themselves in a membrane-bound vacuole that does not fuse with lysosomes that would otherwise degrade the bacteria. In this protected compartment, the bacteria multiply.

Dot/Icm type IV secretion system and effector proteins

The bacteria use a type IVB secretion system known as Dot/Icm to inject effector proteins into the host. These effectors are involved in increasing the bacteria's ability to survive inside the host cell. L. pneumophila encodes for over 330 "effector" proteins, [9] which are secreted by the Dot/Icm translocation system to interfere with host cell processes to aid bacterial survival. It has been predicted that the genus Legionella encodes more than 10,000 and possibly up to ~18,000 effectors that have a high probability to be secreted into their host cells. [10] [11]

One key way in which L. pneumophila uses its effector proteins is to interfere with fusion of the Legionella-containing vacuole with the host's endosomes, and thus protect against lysis. [12] Knock-out studies of Dot/Icm translocated effectors indicate that they are vital for the intracellular survival of the bacterium, but many individual effector proteins are thought to function redundantly, in that single-effector knock-outs rarely impede intracellular survival. This high number of translocated effector proteins and their redundancy is likely a result of the bacterium having evolved in many different protozoan hosts. [13]

Legionella-containing vacuole

TEM image of L. pneumophila within a phagocytic cell TEM image of Legionella pneumophila within a phagocytic cell.tif
TEM image of L. pneumophila within a phagocytic cell

For Legionella to survive within macrophages and protozoa, it must create a specialized compartment known as the Legionella-containing vacuole (LCV). Through the action of the Dot/Icm secretion system, the bacteria are able to prevent degradation by the normal endosomal trafficking pathway and instead replicate. Shortly after internalization, the bacteria specifically recruit endoplasmic reticulum-derived vesicles and mitochondria to the LCV while preventing the recruitment of endosomal markers such as Rab5 and Rab7. Formation and maintenance of the vacuoles are crucial for pathogenesis; bacteria lacking the Dot/Icm secretion system are not pathogenic and cannot replicate within cells, while deletion of the Dot/Icm effector SdhA results in destabilization of the vacuolar membrane and no bacterial replication. [14] [15]

Nutrient acquisition

Once inside the host cell, Legionella needs nutrients to grow and reproduce. Inside the vacuole, nutrient availability is low; the high demand of amino acids is not covered by the transport of free amino acids found in the host cytoplasm. To improve the availability of amino acids, the parasite promotes the host mechanisms of proteasomal degradation. This generates an excess of free amino acids in the cytoplasm of L. pneumophila-infected cells that can be used for intravacuolar proliferation of the parasite.

To obtain amino acids, L. pneumophila uses the AnkB bona fide F-Box effector, which is farnesylated by the activity of three host enzymes localized in the membrane of the LCV: farnesyltransferase, Ras-converting enzyme-1 protease, and isoprenyl cysteine carboxyl methyl transferase. Farnesylation allows AnkB to get anchored into the cytoplasmic side of the vacuole.

Once AnkB is anchored into the LCV membrane, it interacts with the SCF1 ubiquitin ligase complex and functions as a platform for the docking of K48-linked polyubiquitinated proteins to the LCV.

The K48-linked polyubiquitination is a marker for proteasomal degradation that releases two- to 24-amino-acid-long peptides, which are quickly degraded to amino acids by various oligopeptidases and aminopeptidases present in the cytoplasm. Amino acids are imported into the LCV through various amino acid transporters such as the SLC1A5 (neutral amino acid transporter). The amino acids are the primary carbon and energy source of L. pneumophila, that have almost 12 classes of ABC transporters, amino-acid permeases, and many proteases, to exploit it. The imported amino acids are used by L. pneumophila to generate energy through the TCA cycle (Krebs cycle) and as sources of carbon and nitrogen.

However, promotion of proteasomal degradation for the obtention of amino acids may not be the only virulence strategy to obtain carbon and energy sources from the host. Type II–secreted degradative enzymes may provide an additional strategy to generate carbon and energy sources.

Genomics

The determination and publication of the complete genome sequences of three clinical L. pneumophila isolates in 2004 paved the way for the understanding of the molecular biology of L. pneumophila in particular and Legionella in general. In-depth comparative genome analysis using DNA arrays to study the gene content of 180 Legionella strains revealed high genome plasticity and frequent horizontal gene transfer. Further insight in the L. pneumophila lifecycle was gained by investigating the gene expression profile of L. pneumophila in Acanthamoeba castellanii, its natural host. L. pneumophila exhibits a biphasic lifecycle and defines transmissive and replicative traits according to gene expression profiles. [2]

Genetic transformation

Transformation is a bacterial adaptation involving the transfer of DNA from one bacterium to another through the surrounding liquid medium. Transformation is a bacterial form of sex. [16] In order for a bacterium to bind, take up, and recombine exogenous DNA into its chromosome, it must enter a special physiological state referred to as "competence".

To determine which molecules may induce competence in Legionella pneumophila, 64 toxic molecules were tested. [17] Only six of these molecules, all DNA damaging agents, caused strong induction of competence. These were mitomycin C (which introduces DNA inter-strand crosslinks), norfloxacin, ofloxacin, and nalidixic acid (inhibitors of DNA gyrase that cause double-strand breaks), bicyclomycin (causes double-strand breaks) and hydroxyurea (causes oxidation of DNA bases). These results suggest that competence for transformation in Legionella pneumophilia evolved as a response to DNA damage. [17] Perhaps induction of competence provides a survival advantage in a natural host, as occurs with other pathogenic bacteria. [16]

Drug Targets

Several enzymes in the bacteria have been proposed as tentative drug targets. For example, enzymes in the iron uptake pathway have been suggested as important drug targets. [18] Further, a cN-II class of IMP/GMP specific 5´nucleotidase which has been extensively characterized kinetically. The tetrameric enzyme shows aspects of positive homotropic cooperativity, substrate activation and presents a unique allosteric site that can be targeted to design effective drugs against the enzyme and thus, the organism. Moreover, the enzyme is distinct than its human counterpart making it an attractive target for drug development. [19]

Treatment

Macrolides (azithromycin or clarithromycin) or fluoroquinolones (levofloxacin or moxifloxacin) are the standard treatment for Legionella pneumonia in humans, with levofloxacin being considered first line with increasing resistance to azithromycin. Two studies support superiority of levofloxacin over macrolides, although not FDA approved. [20]

Related Research Articles

Gram-negative bacteria group of bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation

Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the gram-staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall sandwiched between an inner cytoplasmic cell membrane and a bacterial outer membrane.

Hershey–Chase experiment experiment

The Hershey–Chase experiments were a series of experiments conducted in 1952 by Alfred Hershey and Martha Chase that helped to confirm that DNA is genetic material. While DNA had been known to biologists since 1869, many scientists still assumed at the time that proteins carried the information for inheritance because DNA appeared to be an inert molecule, and, since it is located in the nucleus, its role was considered to be phosphorus storage. In their experiments, Hershey and Chase showed that when bacteriophages, which are composed of DNA and protein, infect bacteria, their DNA enters the host bacterial cell, but most of their protein does not. Although the results were not conclusive, and Hershey and Chase were cautious in their interpretation, previous, contemporaneous, and subsequent discoveries all served to prove that DNA is the hereditary material.

Lysis refers to the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a lysate. In molecular biology, biochemistry, and cell biology laboratories, cell cultures may be subjected to lysis in the process of purifying their components, as in protein purification, DNA extraction, RNA extraction, or in purifying organelles.

Virulence is a pathogen's or microbe's ability to infect or damage a host.

Secretion is the movement of material from one point to another, e.g. secreted chemical substance from a cell or gland. In contrast, excretion, is the removal of certain substances or waste products from a cell or organism. The classical mechanism of cell secretion is via secretory portals at the cell plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structure at the cell plasma membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.

Transformation (genetics) genetic alteration of a cell

In molecular biology, transformation is the genetic alteration of a cell resulting from the direct uptake and incorporation of exogenous genetic material from its surroundings through the cell membrane(s). For transformation to take place, the recipient bacteria must be in a state of competence, which might occur in nature as a time-limited response to environmental conditions such as starvation and cell density, and may also be induced in a laboratory.

<i>Coxiella burnetii</i> species of bacterium

Coxiella burnetii is an obligate intracellular bacterial pathogen, and is the causative agent of Q fever. The genus Coxiella is morphologically similar to Rickettsia, but with a variety of genetic and physiological differences. C. burnetii is a small Gram-negative, coccobacillary bacterium that is highly resistant to environmental stresses such as high temperature, osmotic pressure, and ultraviolet light. These characteristics are attributed to a small cell variant form of the organism that is part of a biphasic developmental cycle, including a more metabolically and replicatively active large cell variant form. It can survive standard disinfectants, and is resistant to many other environmental changes like those presented in the phagolysosome.

Phagosome

In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs). A phagosome is formed by the fusion of the cell membrane around a microorganism, a senescent cell or an apoptotic cell. Phagosomes have membrane-bound proteins to recruit and fuse with lysosomes to form mature phagolysosomes. The lysosomes contain hydrolytic enzymes and reactive oxygen species (ROS) which kill and digest the pathogens. Phagosomes can also form in non-professional phagocytes, but they can only engulf a smaller range of particles, and do not contain ROS. The useful materials from the digested particles are moved into the cytosol, and waste is removed by exocytosis. Phagosome formation is crucial for tissue homeostasis and both innate and adaptive host defense against pathogens.

Intracellular parasites are microparasites that are capable of growing and reproducing inside the cells of a host. Some parasites can cause disease.

Mitomycins group of antibiotics

The mitomycins are a family of aziridine-containing natural products isolated from Streptomyces caespitosus or Streptomyces lavendulae. They include mitomycin A, mitomycin B, and mitomycin C. When the name mitomycin occurs alone, it usually refers to mitomycin C, its international nonproprietary name. Mitomycin C is used as a medicine for treating various disorders associated with the growth and spread of cells.

Natural competence ability of a cell to alter its genetics by taking up extracellular DNA from its environment

In microbiology, genetics, cell biology, and molecular biology, competence is the ability of a cell to alter its genetics by taking up extracellular ("naked") DNA from its environment in the process called transformation. Competence may be differentiated between natural competence, a genetically specified ability of bacteria which is thought to occur under natural conditions as well as in the laboratory, and induced or artificial competence, which arises when cells in laboratory cultures are treated to make them transiently permeable to DNA. Competence allows for rapid adaptation and DNA repair of the cell. This article primarily deals with natural competence in bacteria, although information about artificial competence is also provided.

EEA1 protein-coding gene in the species Homo sapiens

The gene EEA1 encodes for the 1400 amino acid protein, Early Endosome Antigen 1.

Bacterial DNA binding protein

In molecular biology, bacterial DNA binding proteins are a family of small, usually basic proteins of about 90 residues that bind DNA and are known as histone-like proteins. Since bacterial binding proteins have a diversity of functions, it has been difficult to develop a common function for all of them. They are commonly referred to as histone-like and have many similar traits with the eukaryotic histone proteins. Eukaryotic histones package DNA to help it to fit in the nucleus, and they are known to be the most conserved proteins in nature. Examples include the HU protein in Escherichia coli, a dimer of closely related alpha and beta chains and in other bacteria can be a dimer of identical chains. HU-type proteins have been found in a variety of eubacteria and archaebacteria, and are also encoded in the chloroplast genome of some algae. The integration host factor (IHF), a dimer of closely related chains which is suggested to function in genetic recombination as well as in translational and transcriptional control is found in Enterobacteria and viral proteins including the African swine fever virus protein A104R.

Megavirus

Megavirus is a viral genus containing a single identified species named Megavirus chilensis, phylogenetically related to Acanthamoeba polyphaga Mimivirus (APMV). In colloquial speech, Megavirus chilensis is more commonly referred to as just “Megavirus”. Until the discovery of pandoraviruses in 2013, it had the largest capsid diameter of all known viruses, as well as the largest and most complex genome among all known viruses.

AnkB F-Box is a protein excreted by Legionella pneumophila which contains a domain F-box.

Aureolysin

Aureolysin is an extracellular metalloprotease expressed by Staphylococcus aureus. This protease is a major contributor to the bacterium's virulence, or ability to cause disease, by cleaving host factors of the innate immune system as well as regulating S. aureus secreted toxins and cell wall proteins. To catalyze its enzymatic activities, aureolysin requires zinc and calcium which it obtains from the extracellular environment within the host.

Bacterial effector protein

Bacterial effectors are proteins secreted by pathogenic bacteria into the cells of their host, usually using a type 3 secretion system (TTSS/T3SS), a type 4 secretion system (TFSS/T4SS) or a Type VI secretion system (T6SS). Some bacteria inject only a few effectors into their host’s cells while others may inject dozens or even hundreds. Effector proteins may have many different activities, but usually help the pathogen to invade host tissue, suppress its immune system, or otherwise help the pathogen to survive. Effector proteins are usually critical for virulence. For instance, in the causative agent of plague, the loss of the T3SS is sufficient to render the bacteria completely avirulent, even when they are directly introduced into the bloodstream. Gram negative microbes are also suspected to deploy bacterial outer membrane vesicles to translocate effector proteins and virulence factors via a novel membrane vesicle trafficking secretory pathway, in order to modify their environment or attack/invade target cells, for example, at the host-pathogen interface.

Legionella jordanis is a Gram-negative bacterium from the genus Legionella which was isolated from the Jordan River in Bloomington, Indiana and from the sewage in DeKalb County, Georgia. L. jordanis is a rare human pathogen and can cause respiratory tract infections.

Legionella clemsonensis was isolated in 2006, but was discovered in 2016 by Clemson University researchers. It is a Gram-negative bacterium.

Bacterial secretion system

Bacterial secretion systems are protein complexes present on the cell membranes of bacteria for secretion of substances. Specifically, they are the cellular devices used by pathogenic bacteria to secrete their virulence factors to invade the host cells. They can be classified into different types based on their specific structure, composition and activity. These major differences can be distinguished between Gram-negative and Gram-positive bacteria. But the classification is by no means clear and complete. There are at least eight types specific to Gram-negative bacteria, four to Gram-positive bacteria, while two are common to both. Generally, proteins can be secreted through two different processes. One process is a one-step mechanism in which proteins from the cytoplasm of bacteria are transported and delivered directly through the cell membrane into the host cell. Another involves a two-step activity in which the proteins are first transported out of the inner cell membrane, then deposited in the periplasm, and finally through the outer cell membrane into the host cell.

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