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Nature Communications Apr 2023Legionella pneumophila replicates intracellularly by secreting effectors via a type IV secretion system. One of these effectors is a eukaryotic methyltransferase (RomA)...
Legionella pneumophila replicates intracellularly by secreting effectors via a type IV secretion system. One of these effectors is a eukaryotic methyltransferase (RomA) that methylates K14 of histone H3 (H3K14me3) to counteract host immune responses. However, it is not known how L. pneumophila infection catalyses H3K14 methylation as this residue is usually acetylated. Here we show that L. pneumophila secretes a eukaryotic-like histone deacetylase (LphD) that specifically targets H3K14ac and works in synergy with RomA. Both effectors target host chromatin and bind the HBO1 histone acetyltransferase complex that acetylates H3K14. Full activity of RomA is dependent on the presence of LphD as H3K14 methylation levels are significantly decreased in a ∆lphD mutant. The dependency of these two chromatin-modifying effectors on each other is further substantiated by mutational and virulence assays revealing that the presence of only one of these two effectors impairs intracellular replication, while a double knockout (∆lphD∆romA) can restore intracellular replication. Uniquely, we present evidence for "para-effectors", an effector pair, that actively and coordinately modify host histones to hijack the host response. The identification of epigenetic marks modulated by pathogens has the potential to lead to the development of innovative therapeutic strategies to counteract bacterial infection and strengthening host defences.
Topics: Humans; Legionella; Chromatin; Bacterial Proteins; Legionella pneumophila; Legionnaires' Disease; Histones
PubMed: 37059817
DOI: 10.1038/s41467-023-37885-z -
Epidemiology and Infection Nov 2014We investigated a mixed outbreak of Legionnaires' disease (LD) and Pontiac fever (PF) at a military base to identify the outbreak's environmental source as well as known...
We investigated a mixed outbreak of Legionnaires' disease (LD) and Pontiac fever (PF) at a military base to identify the outbreak's environmental source as well as known legionellosis risk factors. Base workers with possible legionellosis were interviewed and, if consenting, underwent testing for legionellosis. A retrospective cohort study collected information on occupants of the buildings closest to the outbreak source. We identified 29 confirmed and probable LD and 38 PF cases. All cases were exposed to airborne pathogens from a cooling tower. Occupants of the building closest to the cooling tower were 6·9 [95% confidence interval (CI) 2·2-22·0] and 5·5 (95% CI 2·1-14·5) times more likely to develop LD and PF, respectively, than occupants of the next closest building. Thorough preventive measures and aggressive responses to outbreaks, including searching for PF cases in mixed legionellosis outbreaks, are essential for legionellosis control.
Topics: Acute Disease; Adult; Age Distribution; Cohort Studies; Confidence Intervals; Disease Outbreaks; Environmental Exposure; Female; Fever; Humans; Incidence; Legionella pneumophila; Legionellosis; Legionnaires' Disease; Male; Middle Aged; Military Facilities; Military Personnel; Respiratory Tract Infections; Retrospective Studies; Risk Factors; Severity of Illness Index; Sex Distribution; United States; Young Adult
PubMed: 25267405
DOI: 10.1017/S0950268813003440 -
Emerging Infectious Diseases Oct 2020Healthcare-associated Legionnaires' disease (HCA LD) can cause nosocomial outbreaks with high death rates. We compared community-acquired LD cases with HCA LD cases in...
Healthcare-associated Legionnaires' disease (HCA LD) can cause nosocomial outbreaks with high death rates. We compared community-acquired LD cases with HCA LD cases in Europe during 2008-2017 using data from The European Surveillance System. A total of 29 countries reported 40,411 community-acquired and 4,315 HCA LD cases. Of the HCA LD cases, 2,937 (68.1%) were hospital-acquired and 1,378 (31.9%) were linked to other healthcare facilities. The odds of having HCA LD were higher for women, children and persons <20 years of age, and persons >60 years of age. Out of the cases caused by Legionella pneumophila with a known serotype, community-acquired LD was more likely to be caused by L. pneumophila serogroup 1 (92.3%) than was HCA LD (85.1%). HCA LD patients were more likely to die. HCA LD is associated with specific patient demographics, causative strains, and outcomes. Healthcare facilities should consider these characteristics when designing HCA LD prevention strategies.
Topics: Child; Delivery of Health Care; Disease Outbreaks; Europe; Female; Humans; Legionella pneumophila; Legionnaires' Disease
PubMed: 32946366
DOI: 10.3201/eid2610.181889 -
Virulence Dec 2021Bacteria of the genus are natural pathogens of amoebae that can cause a severe pneumonia in humans called Legionnaires' Disease. Human disease results from inhalation... (Review)
Review
Bacteria of the genus are natural pathogens of amoebae that can cause a severe pneumonia in humans called Legionnaires' Disease. Human disease results from inhalation of -contaminated aerosols and subsequent bacterial replication within alveolar macrophages. pathogenicity in humans has resulted from extensive co-evolution with diverse genera of amoebae. To replicate intracellularly, generates a replication-permissive compartment called the -containing vacuole (LCV) through the concerted action of hundreds of Dot/Icm-translocated effector proteins. In this review, we present a collective overview of pathogenicity including infection mechanisms, secretion systems, and translocated effector function. We also discuss innate and adaptive immune responses to , the implications of genome diversity and future avenues for the field.
Topics: Humans; Immunity; Legionella; Legionnaires' Disease; Vacuoles; Virulence
PubMed: 33843434
DOI: 10.1080/21505594.2021.1903199 -
American Journal of Respiratory Cell... May 2021TOLLIP (Toll-interacting protein) is an intracellular adaptor protein with diverse actions throughout the body. In a context- and cell type-specific manner, TOLLIP can... (Review)
Review
TOLLIP (Toll-interacting protein) is an intracellular adaptor protein with diverse actions throughout the body. In a context- and cell type-specific manner, TOLLIP can function as an inhibitor of inflammation and endoplasmic-reticulum stress, an activator of autophagy, or a critical regulator of intracellular vacuole trafficking. The distinct functions of this protein have been linked to innate immune responses and lung epithelial-cell apoptosis. genetic variants have been associated with a variety of chronic lung diseases, including idiopathic pulmonary fibrosis, asthma, and primary graft dysfunction after lung transplantation, and with infections, such as tuberculosis, pneumonia, and respiratory viruses. TOLLIP exists in a delicate homeostatic balance, with both positive and negative effects on the trajectory of pulmonary diseases. This translational review summarizes the genetic and molecular associations that link TOLLIP to the development and progression of noninfectious and infectious pulmonary diseases. We highlight current limitations of and models in assessing the role of TOLLIP in these conditions, and we describe future approaches that will enable a more nuanced exploration of the role of TOLLIP in pulmonary conditions. There has been a surge in recent research evaluating the role of this protein in human diseases, but critical mechanistic pathways require further exploration. By understanding its biologic functions in disease-specific contexts, we will be able to determine whether TOLLIP can be therapeutically modulated to treat pulmonary diseases.
Topics: Animals; Asthma; Cytokines; Disease Models, Animal; Gene Expression Regulation; Graft Rejection; Humans; Idiopathic Pulmonary Fibrosis; Immunity, Innate; Intracellular Signaling Peptides and Proteins; Legionnaires' Disease; Lung Transplantation; Mice; MicroRNAs; Respirovirus Infections; Signal Transduction; Tuberculosis, Pulmonary
PubMed: 33233920
DOI: 10.1165/rcmb.2020-0470TR -
Acta Bio-medica : Atenei Parmensis Aug 2023Legionnaires' disease is a severe form of pneumonia caused by the inhalation or aspiration of water droplets contaminated with Legionella pneumophila and other...
BACKGROUND AND AIM
Legionnaires' disease is a severe form of pneumonia caused by the inhalation or aspiration of water droplets contaminated with Legionella pneumophila and other Legionella species. These bacteria are commonly found in natural habitats and man-made water systems. Legionnaires' disease is a significant public health problem, especially in healthcare settings where patients may be exposed to contaminated environmental sources. Nosocomial outbreaks have been reported worldwide, leading to high morbidity and mortality rates, and increased healthcare costs. This study aimed to compare, the clonal relationship of clinical L. pneumophila strains from two different hospitals with L. pneumophila strains isolated from the water supply.
METHODS
In the period from 2019 to 2021, clinical and environmental strains involved in three cases of legionellosis were compared by means of pulsed field gel electrophoresis and sequence based typing techniques.
RESULTS
Our findings highlight the persistence of clonally distinct strains within each hospital examined. Furthermore, the L. pneumophila strains detected from hospital environmental sources were related to the clinical strains isolated, demonstrating the nosocomial origin of these cases.
CONCLUSIONS
Therefore, it is important to implement more accurate surveillance systems both for epidemiological studies and to check the effectiveness of remediation procedures. (www.actabiomedica.it).
Topics: Humans; Legionnaires' Disease; Cross Infection; Legionella pneumophila; Water Supply; Water
PubMed: 37773490
DOI: 10.23750/abm.v94iS3.15048 -
Indian Journal of Medical Microbiology 2018Legionella pneumophila was first recognised as a fatal cause of pneumonia more than four decades ago, during the 1976-American Legion convention in Philadelphia, USA.... (Review)
Review
Legionella pneumophila was first recognised as a fatal cause of pneumonia more than four decades ago, during the 1976-American Legion convention in Philadelphia, USA. Legionella spp. continue to cause disease outbreaks of public health significance, and at present, Legionnaires' disease (LD) has emerged as an important cause of community and hospital-acquired pneumonia. Parallel to this, the understanding of LD has also increased exponentially. However, the disease is likely to be underreported in many countries because of the dearth of common definitions, diagnostic tests and active surveillance systems. In this review, we outline the basic concepts of Legionella including clinical presentations, epidemiology, laboratory diagnosis and the status of LD in India. This article also summarises the progress of research related to Legionella in this country, identifying the research gaps and discussing priorities to explore this unexplored pathogen in India.
Topics: Biomedical Research; Clinical Laboratory Techniques; Community-Acquired Infections; Cross Infection; Humans; India; Legionella pneumophila; Legionnaires' Disease
PubMed: 30429383
DOI: 10.4103/ijmm.IJMM_18_298 -
Journal of Molecular Biology Oct 2019Legionella pneumophila is the causative agent of the severe pneumonia Legionnaires' disease. L. pneumophila is ubiquitously found in freshwater environments, where it... (Review)
Review
Legionella pneumophila is the causative agent of the severe pneumonia Legionnaires' disease. L. pneumophila is ubiquitously found in freshwater environments, where it replicates within free-living protozoa. Aerosolization of contaminated water supplies allows the bacteria to be inhaled into the human lung, where L. pneumophila can be phagocytosed by alveolar macrophages and replicate intracellularly. The Dot/Icm type IV secretion system (T4SS) is one of the key virulence factors required for intracellular bacterial replication and subsequent disease. The Dot/Icm apparatus translocates more than 300 effector proteins into the host cell cytosol. These effectors interfere with a variety of cellular processes, thus enabling the bacterium to evade phagosome-lysosome fusion and establish an endoplasmic reticulum-derived Legionella-containing vacuole, which facilitates bacterial replication. In turn, the immune system has evolved numerous strategies to recognize intracellular bacteria such as L. pneumophila, leading to potent inflammatory responses that aid in eliminating infection. This review aims to provide an overview of L. pneumophila pathogenesis in the context of the host immune response.
Topics: Animals; Cytokines; Endoplasmic Reticulum; Humans; Legionella pneumophila; Legionnaires' Disease; Macrophages, Alveolar
PubMed: 31351897
DOI: 10.1016/j.jmb.2019.07.028 -
ELife May 2023The amoeba-resistant bacterium causes Legionnaires' disease and employs a type IV secretion system (T4SS) to replicate in the unique, ER-associated -containing vacuole...
The amoeba-resistant bacterium causes Legionnaires' disease and employs a type IV secretion system (T4SS) to replicate in the unique, ER-associated -containing vacuole (LCV). The large fusion GTPase Sey1/atlastin is implicated in ER dynamics, ER-derived lipid droplet (LD) formation, and LCV maturation. Here, we employ cryo-electron tomography, confocal microscopy, proteomics, and isotopologue profiling to analyze LCV-LD interactions in the genetically tractable amoeba . Dually fluorescence-labeled producing LCV and LD markers revealed that Sey1 as well as the T4SS and the Ran GTPase activator LegG1 promote LCV-LD interactions. In vitro reconstitution using purified LCVs and LDs from parental or Δ mutant indicated that Sey1 and GTP promote this process. Sey1 and the fatty acid transporter FadL were implicated in palmitate catabolism and palmitate-dependent intracellular growth. Taken together, our results reveal that Sey1 and LegG1 mediate LD- and FadL-dependent fatty acid metabolism of intracellular .
Topics: Humans; Legionella pneumophila; GTP Phosphohydrolases; Macrophages; Dictyostelium; Lipid Droplets; Vacuoles; Legionella; Legionnaires' Disease; Bacterial Proteins
PubMed: 37158597
DOI: 10.7554/eLife.85142 -
Frontiers in Cellular and Infection... 2023The pathogenicity of , the causative agent of Legionnaires' disease, depends on an arsenal of interacting proteins. Here we describe how surface-associated and secreted... (Review)
Review
The pathogenicity of , the causative agent of Legionnaires' disease, depends on an arsenal of interacting proteins. Here we describe how surface-associated and secreted virulence factors of this pathogen interact with each other or target extra- and intracellular host proteins resulting in host cell manipulation and tissue colonization. Since progress of computational methods like AlphaFold, molecular dynamics simulation, and docking allows to predict, analyze and evaluate experimental proteomic and interactomic data, we describe how the combination of these approaches generated new insights into the multifaceted "protein sociology" of the zinc metalloprotease ProA and the peptidyl-prolyl isomerase Mip (macrophage infectivity potentiator). Both virulence factors of interact with numerous proteins including bacterial flagellin (FlaA) and host collagen, and play important roles in virulence regulation, host tissue degradation and immune evasion. The recent progress in protein-ligand analyses of virulence factors suggests that machine learning will also have a beneficial impact in early stages of drug discovery.
Topics: Humans; Legionella pneumophila; Bacterial Proteins; Virulence Factors; Proteomics; Peptidylprolyl Isomerase; Legionnaires' Disease
PubMed: 36936764
DOI: 10.3389/fcimb.2023.1140688