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Nature Communications Nov 2023Legionella pneumophila (LP) secretes more than 300 effectors into the host cytosol to facilitate intracellular replication. One of these effectors, SidH, 253 kDa in...
Legionella pneumophila (LP) secretes more than 300 effectors into the host cytosol to facilitate intracellular replication. One of these effectors, SidH, 253 kDa in size with no sequence similarity to proteins of known function is toxic when overexpressed in host cells. SidH is regulated by the LP metaeffector LubX which targets SidH for degradation in a temporal manner during LP infection. The mechanism underlying the toxicity of SidH and its role in LP infection are unknown. Here, we determined the cryo-EM structure of SidH at 2.7 Å revealing a unique alpha helical arrangement with no overall similarity to known protein structures. Surprisingly, purified SidH came bound to a E. coli EF-Tu/t-RNA/GTP ternary complex which could be modeled into the cryo-EM density. Mutation of residues disrupting the SidH-tRNA interface and SidH-EF-Tu interface abolish the toxicity of overexpressed SidH in human cells, a phenotype confirmed in infection of Acanthamoeba castellani. We also present the cryo-EM structure of SidH in complex with a U-box domain containing ubiquitin ligase LubX delineating the mechanism of regulation of SidH. Our data provide the basis for the toxicity of SidH and into its regulation by the metaeffector LubX.
Topics: Humans; Legionella pneumophila; Escherichia coli; Peptide Elongation Factor Tu; Legionnaires' Disease; Ubiquitin-Protein Ligases; Bacterial Proteins
PubMed: 37923743
DOI: 10.1038/s41467-023-42683-8 -
European Journal of Cell Biology Dec 2023The study of virulence of Legionella pneumophila and its interactions with its hosts has been predominantly conducted in cellulo in the past decades. Although easy to... (Review)
Review
The study of virulence of Legionella pneumophila and its interactions with its hosts has been predominantly conducted in cellulo in the past decades. Although easy to implement and allowing the dissection of molecular pathways underlying host-pathogen interactions, these cellular models fail to provide conditions of the complex environments encountered by the bacteria during the infection of multicellular organisms. To improve our understanding of human infection, several animal models have been developed. This review provides an overview of the invertebrate and vertebrate models that have been established to study L. pneumophila infection and that are alternatives to the classical mouse model, which does not recall human infection with L. pneumophila well. Finally we provide insight in the main contributions made by these models along with their pros and cons.
Topics: Animals; Mice; Humans; Legionnaires' Disease; Legionella pneumophila; Invertebrates; Vertebrates; Disease Models, Animal
PubMed: 37926040
DOI: 10.1016/j.ejcb.2023.151369 -
Frontiers in Cellular and Infection... 2023Severe Legionnaires' disease (LD) can lead to multi-organ failure or death in 10%-30% of patients. Although hyper-inflammation and immunoparalysis are well described in...
INTRODUCTION
Severe Legionnaires' disease (LD) can lead to multi-organ failure or death in 10%-30% of patients. Although hyper-inflammation and immunoparalysis are well described in sepsis and are associated with high disease severity, little is known about the immune response in LD. This study aimed to evaluate the immune status of patients with LD and its association with disease severity.
METHODS
A total of 92 hospitalized LD patients were included; 19 plasmatic cytokines and pulmonary DNA load were measured in 84 patients on the day of inclusion (day 0, D0). Immune functional assays (IFAs) were performed from whole blood samples collected at D2 and stimulated with concanavalin A [conA, = 19 patients and = 21 healthy volunteers (HV)] or lipopolysaccharide (LPS, = 14 patients and = 9 HV). A total of 19 cytokines (conA stimulation) and TNF-α (LPS stimulation) were quantified from the supernatants. The Sequential Organ Failure Assessment (SOFA) severity score was recorded at D0 and the mechanical ventilation (MV) status was recorded at D0 and D8.
RESULTS
Among the 84 patients, a higher secretion of plasmatic MCP-1, MIP1-β, IL-6, IL-8, IFN-γ, TNF-α, and IL-17 was observed in the patients with D0 and D8 MV. Multiparametric analysis showed that these seven cytokines were positively associated with the SOFA score. Upon conA stimulation, LD patients had a lower secretion capacity for 16 of the 19 quantified cytokines and a higher release of IL-18 and MCP-1 compared to HV. IL-18 secretion was higher in D0 and D8 MV patients. TNF-α secretion, measured after LPS stimulation, was significantly reduced in LD patients and was associated with D8 MV status.
DISCUSSION
The present findings describe a hyper-inflammatory phase at the initial phase of pneumonia that is more pronounced in patients with severe LD. These patients also present an immunoparalysis for a large number of cytokines, except IL-18 whose secretion is increased. An assessment of the immune response may be relevant to identify patients eligible for future innovative host-directed therapies.
Topics: Humans; Interleukin-18; Tumor Necrosis Factor-alpha; Lipopolysaccharides; Legionnaires' Disease; Cytokines
PubMed: 37965258
DOI: 10.3389/fcimb.2023.1252515 -
Cureus May 2024Legionnaires' disease is an atypical pneumonia caused by species are found in freshwater sources and are transmitted through inhalation of contaminated aerosols....
Legionnaires' disease is an atypical pneumonia caused by species are found in freshwater sources and are transmitted through inhalation of contaminated aerosols. Patients commonly present with fever, chills, and cough. However, in immunosuppressed patients or severe cases, the disease can lead to multiorgan failure. In recent years, the incidence of Legionnaires' disease has drastically increased and unfortunately is commonly underdiagnosed. Gold-standard diagnosis is made through sputum cultures; however, urine antigen remains the most common test used for diagnosis. Goal-directed care includes antibiotics and supportive care. This case highlights a rare and unique presentation of Legionnaires' disease presenting with an elevated 2:1 aspartate aminotransferase to alanine transaminase pattern, typically seen with alcoholic hepatitis.
PubMed: 38910759
DOI: 10.7759/cureus.60856 -
Annali Di Igiene : Medicina Preventiva... 2023Legionnaires' disease is caused by inhalation or aspiration of small water droplets contaminated with Legionella, commonly found in natural and man-made water systems...
BACKGROUND
Legionnaires' disease is caused by inhalation or aspiration of small water droplets contaminated with Legionella, commonly found in natural and man-made water systems and in moist soil. Over the past 5 years, notification rates of this disease have almost doubled in the European Union (EU) / European Environmental Agency (EEA), from 1.4 in 2015 to 2.2 cases per 100,000 population in 2019. Some studies show that the greater presence of the microorganism in the water network and the increase in cases of legionellosis could be related to the variations in some environmental factors, such as air temperature, which may influence the water temperature.
STUDY DESIGN
Climate change is currently a prominent topic worldwide because of its significant impact on the natural environment. It is responsible for the increase in numerous waterborne pathologies. The purpose of this study was to correlate the air temperature recorded in Apulia region from January 2018 to April 2023 with the presence of Legionella in the water networks of public and private facilities and the incidence rates of legionellosis during the same period.
METHODS
During the period from January 2018 to April 2023, water samples were collected from facilities involved in legionellosis cases and analyzed for Legionella. During the same period, all the cases notified to the regional epidemiological observatory (OER-Apulia) were included in this study. Statistical analyses were conducted using the Shapiro-Wilk test to determine whether the Legionella load was distributed normally, the Wilcoxon rank sum test to compare the air temperatures (average and range) of the negative and positive samples for Legionella detection, and the multivariate analysis (Poisson regression) to compare the Legionella load with the water sample temperature, average air temperature, and temperature range on the day of sampling. The Wilcoxon test for paired samples was used to compare legionellosis cases between the warmer and colder months.
RESULTS
Overall, 13,044 water samples were analyzed for Legionella and 460 cases of legionellosis were notified. Legionella was isolated in 20.1% of the samples examined. The difference in the air temperature between negative samples and positive samples was statistically significant (p-value < 0.0001): on days when water samples tested positive for Legionella a higher temperature range was observed than on days when water samples tested negative (p-value = 0.004). Poisson regression showed a direct correlation between Legionella load, water temperature, and average air temperature. The incidence of legionellosis cases in warmer months was higher than in colder months (p-value = 0.03).
CONCLUSIONS
Our study highlights a significant increase in the load of Legionella in the Apulian water network, and an association between warmer temperatures and legionellosis incidence. In our opinion, further investigations are needed in different contexts and territories to characterize the epidemiology of legionellosis, and to explain its extreme variability in different geographical areas and how these data may be influenced by different risk factors.
PubMed: 37724578
DOI: 10.7416/ai.2023.2578 -
BMC Infectious Diseases Sep 2023Severe community-acquired pneumonia (SCAP) is commonly treated with an empiric combination therapy, including a macrolide, or a quinolone and a β-lactam. However, the...
BACKGROUND
Severe community-acquired pneumonia (SCAP) is commonly treated with an empiric combination therapy, including a macrolide, or a quinolone and a β-lactam. However, the risk of Legionella pneumonia may lead to a prolonged combination therapy even after negative urinary antigen tests (UAT).
METHODS
We conducted a retrospective cohort study in a French intensive care unit (ICU) over 6 years and included all the patients admitted with documented SCAP. All patients received an empirical combination therapy with a β-lactam plus a macrolide or quinolone, and a Legionella UAT was performed. Macrolide or quinolone were discontinued when the UAT was confirmed negative. We examined the clinical and epidemiological features of SCAP and analysed the independent factors associated with ICU mortality.
RESULTS
Among the 856 patients with documented SCAP, 26 patients had atypical pneumonia: 18 Legionella pneumophila (LP) serogroup 1, 3 Mycoplasma pneumonia (MP), and 5 Chlamydia psittaci (CP). UAT diagnosed 16 (89%) Legionella pneumonia and PCR confirmed the diagnosis for the other atypical pneumonia. No atypical pneumonia was found by culture only. Type of pathogen was not associated with a higher ICU mortality in the multivariate analysis.
CONCLUSION
Legionella pneumophila UAT proved to be highly effective in detecting the majority of cases, with only a negligible percentage of patients being missed, but is not sufficient to diagnose atypical pneumonia, and culture did not provide any supplementary information. These results suggest that the discontinuation of macrolides or quinolones may be a safe option when Legionella UAT is negative in countries with a low incidence of Legionella pneumonia.
Topics: Humans; Anti-Bacterial Agents; Retrospective Studies; Pneumonia, Mycoplasma; Legionnaires' Disease; Lactams; Quinolones; Antigens, Bacterial; Community-Acquired Infections; Influenza, Human; beta-Lactams
PubMed: 37723456
DOI: 10.1186/s12879-023-08493-5 -
Annals of Agricultural and... Dec 2023Legionella bacteria are commonly found in natural aquatic environments such as rivers, lakes, ponds and hot springs. Legionella infection occurs through the inhalation...
INTRODUCTION AND OBJECTIVE
Legionella bacteria are commonly found in natural aquatic environments such as rivers, lakes, ponds and hot springs. Legionella infection occurs through the inhalation of water-air aerosol generated, for example, by showers or hot tubs. The most common species responsible for infection is Legionella pneumophila, which can cause Pontiac fever, and Legionnaires' disease, as well as a rare extrapulmonary form. The aim of the study's is to assess the susceptibility of Legionella pneumophila bacteria isolated from water systems of public buildings in Poland to antibiotics and chemotherapeutic agents used in the treatment of Legionellosis pneumonia.
MATERIAL AND METHODS
A total of 100 L. pneumophila strains isolated from public buildings, such as hospitals and water recreation facilities, were used for the study. The drug sensitivity of the following antibiotics was determined: erythromycin, azithromycin, ciprofloxacin, levofloxacin, rifampicin, trimethoprim-sulfamethoxazole and tetracycline. Mean MIC50 and MIC90 values were read using accepted standards.
RESULTS
The highest mean MIC value was obtained for tetracycline 6,130+/-0,353 μg/ml (with a range from 1,500 μg/ml to 16,000 μg/ml. In contrast, the lowest MIC was recorded with rifampicin: 0.020+/-0.037 μg/ml (with a range from 0.016 μg/ml to 0.380 μg/ml).
CONCLUSIONS
The lowest biocidal concentration was found for levofloxacin, the highest for tetracycline. The highest MIC50 and MIC90 values were found for tetracycline and the lowest for rifampicin. The highest biocidal values were found for azithromycin and the lowest for tetracycline.
Topics: Humans; Anti-Bacterial Agents; Legionella pneumophila; Rifampin; Levofloxacin; Azithromycin; Poland; Legionnaires' Disease; Tetracycline; Water; Legionella; Microbial Sensitivity Tests
PubMed: 38153060
DOI: 10.26444/aaem/167934 -
New Microbes and New Infections Oct 2023
PubMed: 38024335
DOI: 10.1016/j.nmni.2023.101194 -
International Journal of Molecular... Sep 2023is the primary causative agent of Legionnaires' disease. The mutant-type strain interrupted in the ORF7 gene region responsible for the lipopolysaccharide biosynthesis...
is the primary causative agent of Legionnaires' disease. The mutant-type strain interrupted in the ORF7 gene region responsible for the lipopolysaccharide biosynthesis of the strain Heysham-1, lacking the -acetyl groups attached to the rhamnose of the core part, showed a higher surface polarity compared with the wild-type strain. The measurement of excitation energy transfer between fluorophores located on the surface of bacteria and eukaryotic cells showed that, at an early stage of interaction with host cells, the mutant exhibited weaker interactions with cells and THP-1-derived macrophages. The mutant displayed reduced adherence to macrophages but enhanced adherence to , suggesting that the -acetyl group of the LPS core region plays a crucial role in facilitating interaction with macrophages. The lack of core rhamnose -acetyl groups made it easier for the bacteria to multiply in amoebae and macrophages. The mutant induced TNF-α production more strongly compared with the wild-type strain. The mutant synthesized twice as many ceramides Cer(t34:0) and Cer(t38:0) than the wild-type strain. The study showed that the internal sugars of the LPS core region of sg 1 can interact with eukaryotic cell surface receptors and mediate in contacting and attaching bacteria to host cells as well as modulating the immune response to infection.
Topics: Humans; Legionella pneumophila; Lipopolysaccharides; Rhamnose; Serogroup; Bacterial Proteins; Legionnaires' Disease
PubMed: 37834049
DOI: 10.3390/ijms241914602 -
Journal of Epidemiology Dec 2023Legionella pneumonia, a severe form of pneumonia, is caused by Legionella bacteria. The epidemiology of Legionnaires' disease in Japan, including seasonal trends, risk...
BACKGROUND
Legionella pneumonia, a severe form of pneumonia, is caused by Legionella bacteria. The epidemiology of Legionnaires' disease in Japan, including seasonal trends, risk factors for severe disease, and fatality rates, is unclear. This study examined the epidemiology of Legionella pneumonia in Japan.
METHODS
This retrospective cohort study included data of adult patients hospitalized for Legionella pneumonia (identified using the ICD-10 code, A481) in the Japanese Diagnosis Procedure Combination inpatient database, from April 2011 to March 2021. We performed multivariable logistic regression analysis to explore the prognostic factors of in-hospital mortality.
RESULTS
Of 7370 enrolled hospitalized patients from 1140 hospitals (male, 84.4%; aged >50 years, 87.9%), 469 (6.4%) died during hospitalization. The number of hospitalized patients increased yearly, from 658 in 2016 to 975 in 2020. Multivariable logistic regression analysis revealed that higher in-hospital mortality was associated with older age, male sex, lower body mass index, worsened level of consciousness, comorbidities (congestive heart failure, chronic renal diseases, and metastasis), hospitalization from November to May, and ambulance use. However, lower in-hospital mortality was associated with comorbidity (liver diseases), hospitalization after 2013, and hospitalization in hospitals with higher case volume.
CONCLUSIONS
The characterized epidemiology of Legionella pneumonia in Japan revealed a high mortality rate of 6.4%. To the best of our knowledge, this is the first study to demonstrate a higher mortality rate in winter and in patients with congestive heart failure and metastasis. Further research is needed to understand the complex interplay between the prognostic factors of Legionella pneumonia.
PubMed: 38105002
DOI: 10.2188/jea.JE20230178