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Legionella pneumophila

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Legionella pneumophila
Colorized scanning electron micrograph image of L. pneumophila
Scientific classification Edit this classification
Domain: Bacteria
Phylum: Pseudomonadota
Class: Gammaproteobacteria
Order: Legionellales
Family: Legionellaceae
Genus: Legionella
Species:
L. pneumophila
Binomial name
Legionella pneumophila
Brenner DJ, Steigerwalt AG, McDade JE 1979

Legionella pneumophila is an aerobic, pleomorphic, flagellated, non-spore-forming, Gram-negative bacterium.[1][2] L. pneumophila is a intracellular parasite that preferentially infects soil amoebae and freshwater amoeboflagellates for replication.[3][4] This pathogen is thus found commonly in freshwater environments and invades the unicellular life, using them to carry out metabolic functions.[5][6] Due to L. pneumophila’s ability to thrive in water, it can grow in water filtration systems, leading to faucets, showers, and other fixtures. Aerosolized water droplets containing L. pneumophila originating from these fixtures may be inhaled by humans.[5] Upon entry to the human respiratory tract, L. pneumophila is able to infect and reproduce within human alveolar macrophages.[4] This causes the onset of Legionnaires' disease, also known as legionellosis.[4] Infected humans may display symptoms such as fever, delirium, diarrhea, and decreased liver and kidney function.[7] L. pneumophila infections can be diagnosed by a urine antigen test.[8][9] The infections caused by the bacteria can be treated with fluoroquinolones and azithromycin antibiotics.[8]

Characterization

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L. pneumophila is a coccobacillus.[10] It is a Gram-negative, aerobic bacterium unable to hydrolyse gelatin or produce urease. It is also non-fermentative. L. pneumophila is neither pigmented nor does it autofluoresce. It is oxidase- and catalase-positive, and produces beta-lactamase.[11] L. pneumophila colony morphology is gray-white with a textured, cut-glass appearance; it also requires cysteine and iron to thrive.[12] It grows on buffered charcoal yeast extract agar as well as in moist environments, such as tap water, in "opal-like" colonies.[12]

L. pneumophila is a facultatively intracellular bacterium. In its diseased state, it infects the alveolar macrophages in human lungs. However, a special characteristic allows for the microbe to thrive in extracellular environments, such as various freshwater environments. This is achieved through its two forms: transmissive and replicative. The transition between the two is activated by changes in the availability of metabolic/nutritional resources in its current environment. The transmissive form is assumed when the bacteria is infecting its host, while the replicative form follows to carry out proliferation.[13]

Cell membrane structure

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L. pneumophila is a Gram-negative bacterium based on the cell membrane structure, which is composed of two membranes separated by periplasmic space. Its unique outer membrane composed of lipoproteins, phospholipids, and other proteins is the distinguishing feature of Legionella spp. Like most gram-negative bacteria, L. pneumophila have a three part lipopolysaccharide. Legionella spp. possess unique lipopolysaccharides (LPS) extending from the outer membrane leaflet of the outer cell membrane that play a role in pathogenicity and adhesion to a host cell. Lipopolysaccharides are the leading surface antigen of all Legionella species including L. pneumophila. [14]

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 LPS side chains both with respect to components and arrangement of the different sugars, determines the nature of the somatic or O-antigenic determinants, which are important means of serologically classifying many Gram-negative bacteria. L. pneumophila exhibits distinct chemical characteristics in its LPS structure that distinguish it from other Gram-negative bacteria. [15] The unique attributes are key factors in its serological identity and biological function. [15]

Ecology

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L. pneumophila (red chains) multiplying inside Tetrahymena pyriformis

L. pneumophila is able to live in a diverse range of environmental conditions, tolerating temperatures from 0°C-63 °C, a pH range of 5.0-8.5, and in dissolved oxygen concentrations of 0.2-15.0 mg/liter. However, it multiples within a narrower temperature range of 25 °C to 42 °C [6].

L. pneumophila is notably resistant to chlorine derivatives that are commonly used to control water borne pathogens. This resistance allows infiltration and persistence in water systems even when standard disinfectant processes are employed [5]. Water supply networks are the main source of L. pneumophila contamination which allows it to grow and proliferate in places such as cooling towers, water systems of hospitals, hotels, and cruise ships [16] This bacterium can form and reside in biofilms within water system pipes, allowing it be aerosolized through fixtures such as faucets, showers, and sprinklers. Exposure to these aerosols can lead to infection in susceptible individuals [17].

As an intracellular parasite, L. pneumophila can invade and replicate inside protozoa in the environment, especially within the species of the genera Acanthamoeba and Naegleria, which can thus serve as a reservoir for L. pneumophila. These hosts will provide protection against unfavorable physical and chemical conditions, such as chlorination. [5]

Biofilms

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Biofilms are specialized, surface attachment communities that can consist of one or multiple microbes, ranging from bacteria, algae, and protozoa.[6] These protective matrixes enable the microbe to live for extended periods of time in low-nutrient environments and in the presence of biocides.[11] Multispecies biofilm on plumbing systems and in water distribution systems facilitate L. pneumophila growth due to the presence of freshwater protozoa.[6] [18]

Environmental protozoa

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L. pneumophila is capable of infecting and multiplying within various species of free-living protists and amoebas. Intracellular replication of the bacterium has been seen in approximately 20 different protozoa species. This bacterium can infect and survive within protozoa genera such as Acanthamoeba, Vermamoeba, and Naegleria. [19] It is through their growth in environmental protozoa and amoeba that L. pneumophila may persist in man-made water systems. Cyst-forming protozoans allow L. pneumophila to survive harsh environmental conditions such as chlorine, UV, ozonisation, and thermal treatments.[20]

Prevalence

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L. pneumophila is the primary causative organism for Legionnaires disease, responsible for over 90% of cases within the United States.[21] The Roughly 2 out of 100,000 people are infected each year in the European Union (EU), with an infection rate of approximately 5 per 100,000 in Italy.[22] The highest reported amount of cases in the US, EU, and Italy have been among men over the age of 50. [22][21] L. pneumophila often infects individuals through poor quality water sources. Approximately 20% of reported Legionnaires disease cases come from healthcare, senior living, or travel facilities that have been exposed to water contaminated with L. pneumophila. [21] There may also be an increased risk of contracting L. pneumophila from private wells, as they are often unregulated and not as rigorously disinfected as municipal water systems.[23] Several large outbreaks of Legionnaire's Disease have come from public hot tubs due to the temperature range of the water being ideal for the bacteria's growth.[24][25]

Legionnaires disease gained globally recognition after an outbreak in 1976 at a hotel in Philadelphia, Pennsylvania. The causative agent of the outbreak was L. pneumophila, which had contaminated the hotel's air conditioning water supply, allowing the microbe to be dispersed within the hotel's environment. A prominent mode of transmission for the disease is the inhalation of contaminated water aerosols.[21] The outbreak resulted in a total of 182 reported cases and 29 deaths.[22] This incident piloted research on the disease causing bacteria, as well as, preventative approaches to contamination.[21]

Pathogenesis

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The life cycle of L. pneumophila within a amoeba.
Image of alveoli filled with leukocytes and fibrin due to pneumonia caused by Legionella bacteria.[26]

L. pneumophila is able to invade and replicate within human alveolar macrophages.[27] Internalization of the bacteria appears to occur through phagocytosis or coiling phagocytosis and is reliant on Dot/Icm type 4B secretion system (T4BSS).[27] Once internalized, the Dot/Icm system begins secreting bacterial effector proteins that recruit host factors to the Legionella containing vacuole (LCV). This process prevents the LCV from fusing with the lysosomes that would otherwise degrade the bacteria. Vesicles of the host cell's rough endoplasmic reticulum are attracted to the LCV, and these vacuoles supple the LCV with necessary lipids and proteins.[27] LCV membrane integrity requires a steady supply of host lipids, such as cellular cholesterol and the cis-monounsaturated fatty acid, palmitoleic acid.[28][29] L. pneumophila replication occurs within the LCV. Once nutrients are depleted, the bacteria gain flagella and cytoxicity. To exit the host cell, L. pneumophila lyses the LCV and resides in the cytoplasm. In the cytoplasm, L. pneumophila inhibit organelle and plasma membrane function and structure which ultimately leads to osmotic lysis of the host cell.[30]

Virulence factors

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L. pneumophila exhibits a unique lipopolysaccharide (LPS) structure that is highly hydrophobic due to its being densely packed with branched fatty acids, and elevated levels of O-acetyl and N-acetyl groups.[31] This structure helps prevent interaction with a common LPS immune system co-receptor, CD14.[31] There is also a correlation between an LPS with a high molecular-weight and the inhibition of phagosome-lysosome fusion.[31] L. pneumophila produces pili of varying lengths. The two pili proteins: PilE and Prepilin peptidase (PilD) are responsible for the production of type IV pili and subsequently, intracellular proliferation.[32] L. pneumophila possesses a singular, polar flagellum that is used for cell motility, adhesion, host invasion, and biofilm formation.[31] The same regulators that control flagellation also control lysosome avoidance and cytotoxicity.[31] The macrophage infectivity potentiator is another key component of host cell invasion and intracellular replication. MIP displays peptidyl–prolyl cis/trans isomerase (PPIase) activity which is crucial for survival within the macrophage, along with transmigration across the lung epithelial barrier.[31][32]

Another key virulence factor of L. pneumophila is iron acquisition, the microbe utilizes two methods of iron uptake. Ferrous iron is collected through the use of a transport system involving an inner-membrane protein known as protein FeoB. Optimal intracellular infection is achieved in amoebae and macrophages via this transport system. The second form of uptake, involving ferric iron, is achieved through an iron chelator known as legiobactin. This is secreted by L. pneumophila when the microbes are being grown in a low iron chemically designed media.[33]

Dot/Icm type IV secretion system

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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,[34] 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.[35][36]

One main 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.[37] 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.[38]

Legionella-containing vacuole

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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).[39] 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 Rab5a and Rab7a. 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.[40][41]

Detection and treatment

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Main article: Legionaires disease

Antisera have been used both for slide agglutination studies and for direct detection of bacteria in tissues using immunofluorescence via fluorescent-labelled antibodies. Specific antibodies in patients can be determined by the indirect fluorescent antibody test. ELISA and microagglutination tests have also been successfully applied.[9] A consistent method that has been used to detect the disease is the urine antigen test.[8]

Effective antibiotic treatment for Legionella pneumonia includes fluoroquinolones (levofloxacin or moxifloxacin) or, alternately, azithromycin.[8] There has been no significant difference found between using a fluoroquinolone or azithromycin to treat Legionella pneumonia.[8] Combination treatments with rifampicin are being tested as a response to antibiotic resistance during mono-treatments, though its effectiveness remains uncertain.[8]

These antibiotics work best because L. pneumophila is an intracellular pathogen.[42] Levofloxacin and azithromycin have great intracellular activity and are able to penetrate into Legionella-infected cells. The Infectious Diseases Society of America recommends 5–10 days of treatment with levofloxacin or 3–5 days of treatment with azithromycin; however, patients that are immunocompromised or have a severe disease may require an extended course of treatment.[42]

Metabolism

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L. pneumophila uses glycolysis, the Entner-Doudoroff (ED) pathway, the pentose phosphate pathway (PP), and the citric acid cycle (TCA).[43] Although L. pneumophila can also perform gluconeogenesis, it does not have the genes to encode for 1,6-biphosphatases. Therefore, other enzymes are used to complete gluconeogenesis. One enzyme used instead is fructose 6-phosphate aldolase.[43] This trend is also present when it comes to the PP pathway which can occur without substrates such as 6-phosphogluconate dehydrogenase.[43] The ED and PP pathways are the main pathways for glucose metabolism in this organism. Along with these pathways, serine was found to be a major nutrient due to its ability to be turned into pyruvate, which is an important intermediate in metabolic pathways in L. pneumophila.[43]

Although glucose metabolism is used, it is not one of the main synthesis pathways within the organism. While using media containing glucose, growth of L. pneumophila did not increase and carbohydrates were not considered an important carbon source within L. pneumophila. Glucose can act as a co-substrate only under certain conditions, as this microbe uses amino acids more frequently and efficiently.[43]

Nutrient acquisition

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Legionella is auxotrophic for seven amino acids: cysteine, leucine, methionine, valine, threonine, isoleucine, and arginine. 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 process in L. pneumophila includes the SCF1 ubiquitin ligase and the AnkB 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 ICMT. Farnesylation allows AnkB to get anchored into the cytoplasmic side of the vacuole. SCF1 and AnkB interact with each other to degrade Lys-linked polyubiquitinated proteins.[44] 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.

The K48-linked polyubiquitination is a marker for proteasomal degradation that releases 2 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 neutral amino acid transporter B(0).[44]

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. Because the amino acid degradation acts as the main carbon source for L. pneumophila, this microbe does not rely as heavily on glucose. Despite this, L. pneumophila does contain multiple amylases, such as LamB, which hydrolyzes polysaccharides into glucose monomers for metabolism. The loss of LamB can result in severe growth issues for L. pneumophila.[45]

However, promotion of proteasomal degradation for the obtention of amino acids and the hydrolyzation of polysaccharides may not be the only virulence strategies 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.[46] L. pneumophila is the only known intracellular pathogen to have a Type II Secretion System (secretome). In Type II Secretion, proteins are first translocated across the inner membrane into the periplasmic space. This process is mediated by either the Sec or Tat pathway. Soon after, the same proteins are then transported through a specific pore in the outer membrane to the exterior of the cell. This secretome is believed to have as many as 60 proteins incorporated into the system.[46]

Genomics

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Genomic information
NCBI genome ID416
Ploidyhaploid
Genome size3.44 Mb
Number of chromosomes1
Year of completion2004

There are 14 known serogroups of L. pneumophila, but serogroup 1 is most commonly the causative agent of Legionnaires’ disease.[47] Three strains, L. pneumophila Philadelphia, L. pneumophila Paris, and L. pneumophila Lens, were isolated in 2004 which paved the way for understanding the molecular biology of the bacteria.[48] Subspecies, which are commonly defined by geographical location, share about 80% of their genome with variation between strains that account for the difference in virulence between subspecies.[48] The genome is relatively large of about 3.5 mega base pairs (mbp) which reflects a higher number of genes, corresponding with the ability of Legionella to adapt to different hosts and environments.[48] There is a relatively high abundance genes encoding eukaryotic-like proteins (ELPs). ELPs are beneficial for mimicking the bacteria' eukaryotic hosts for pathogenicity.[48] Other genes of L. pneumophila encode for Legionella-specific vacuoles, efflux transporters, ankyrin-repeat proteins, and many other virulence related characteristics.[48] The bffA gene is associated with biofilm formation, and it is seen that strains without this gene form biofilms both quicker and thicker which aids in resistance to environmental stressors.[49] In-depth comparative genome analysis using DNA arrays to study the gene content of 180 Legionella strains revealed high genomic plasticity and frequent horizontal gene transfer events.[48] Horizontal gene transfer allows L. pneumophila to evolve at a rapid pace and commonly is associated with drug resistance.[50]

Drug targets

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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.[33] 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 from its human counterpart making it an attractive target for drug development.

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