Cathelicidin insufficiency in patients with fatal leptospirosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE72946 | GEO | 2016/09/23
SECONDARY ACCESSION(S): PRJNA295399
REPOSITORIES: GEO
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Project description:Leptospirosis causes significant morbidity and mortality worldwide; however, the role of the host immune response in disease progression and high case fatality (>10-50%) is poorly understood. We conducted a multi-parameter investigation of patients with acute leptospirosis to identify mechanisms associated with case fatality. Whole blood transcriptional profiling of 16 hospitalized Brazilian patients with acute leptospirosis (13 survivors, 3 deceased) revealed fatal cases had lower expression of the antimicrobial peptide, cathelicidin, and chemokines, but more abundant pro-inflammatory cytokine receptors. In contrast, survivors generated strong adaptive immune signatures, including transcripts relevant to antigen presentation and immunoglobulin production. In an independent cohort (23 survivors, 22 deceased), fatal cases had higher bacterial loads (P = 0.0004) and lower anti-Leptospira antibody titers (P = 0.02) at the time of hospitalization, independent of the duration of illness. Low serum cathelicidin and RANTES levels during acute illness were independent risk factors for higher bacterial loads (P = 0.005) and death (P = 0.04), respectively. To investigate the mechanism of cathelicidin in patients surviving acute disease, we administered LL-37, the active peptide of cathelicidin, in a hamster model of lethal leptospirosis and found it significantly decreased bacterial loads and increased survival. Our findings indicate that the host immune response plays a central role in severe leptospirosis disease progression. While drawn from a limited study size, significant conclusions include that poor clinical outcomes are associated with high systemic bacterial loads, and a decreased antibody response. Furthermore, our data identified a key role for the antimicrobial peptide, cathelicidin, in mounting an effective bactericidal response against the pathogen, which represents a valuable new therapeutic approach for leptospirosis.
| S-EPMC5094754 | biostudies-literature
Project description:Background: Leptospirosis is a global zoonotic infectious disease with various clinical manifestations ranging from mild self-limiting illness to life-threatening infection with multi-organ damage. This study was aimed at investigating transcription profiles from whole blood samples of patients with leptospirosis and identifying genes as novel biomarkers for predicting severe leptospirosis. Methods: In a discovery cohort, 12 serum samples of patients with severe and non-severe leptospirosis at initial clinical presentation were selected for gene expression profiling using the NanoString nCounter PanCancer IO 360 gene expression panel. In a validated cohort of 99 samples, top candidate genes were selected and further tested by qRT-PCR in whole blood samples of 30 and 69 individuals with severe and non-severe leptospirosis, respectively. Results: The discovery set identified 20 differentially expressed genes (DEGs) among the two groups. The top three down-regulated candidate genes including programmed cell death 1 (PDCD1), interleukin 4 (IL4), and nitric oxide synthase 2 (NOS2) were selected and further validated. In the validated cohort, PDCD1 levels were significantly lower in the severe group compared with the non-severe group(Stats?). Based on the ROC analysis, PDCD1 levels could discriminate between the severe and non-severe groups. Additionally , PDCD1 levels displayed good predictive power of subsequent pulmonary hemorrhage with an AUROC of 0.86 (95% CI;0.76-0.96, p = 0.007). PDCD1 also emerged as an independent prognostic factor of severe leptospirosis in the multivariate regression analysis.. Conclusion: Our data indicated that whole blood gene expression profiles were significantly different between the severe and non-severe leptospirosis groups. PDCD1 expression levels at presentation could potentially serve as a biomarker for predicting severe leptospirosis.
2025-04-01 | GSE200188 | GEO
Project description:Background: Leptospirosis, a global zoonotic infectious disease, has various clinical manifestations ranging from mild self-limiting illness to life-threatening with multi-organ damage, including liver involvement. This study was aimed at identifying circulating microRNAs (miRNAs) as novel biomarkers for predicting severe liver involvement in patients with leptospirosis. Methods: In a discovery set, 12 serum samples of patients with anicteric and icteric leptospirosis at initial clinical presentation were used for miRNA profiling by a NanoString nCounter miRNA assay. In a validated cohort, top candidate miRNAs were selected and further tested by qRT-PCR in serum samples of 81 and 16 individuals with anicteric and icteric leptospirosis, respectively. Results: The discovery set identified 38 significantly differential expression miRNAs between the two groups. Among these, miR-601 and miR-630 were selected as the top two candidates significantly up-regulated expressed in the icteric group. The enriched KEGG pathway showed that these miRNAs were mainly involved in immune responses and inflammation. In the validated cohort, miR-601 and miR-630 levels were significantly higher in the icteric group compared with the anicteric group. Additionally, these two miRNAs displayed good predictors of subsequent acute liver failure with a high sensitivity of 100%. On regression analysis, elevated miR-601 and miR-630 expression were also predictive of multi-organ failures and poor overall survival. Conclusion: Our data indicated that miRNA expression profiles were significantly differentiated between the icteric and anicteric groups. Serum miR-601 and miR-630 at presentation could potentially serve as promising biomarkers for predicting subsequent acute liver failure and overall survival in patients with leptospirosis.
2021-07-07 | GSE179426 | GEO
Project description:Leptospirosis is zoonotic disease of global importance, with over a million cases andnearly 60,000 deaths annually. Symptomatic disease presentation ranges from a mildfebrile disease with non-specific symptoms to severe forms, characterized by multi-organ failure, lung hemorrhage, and death. Factors governing severe outcomes remainunclear, but the host immune response likely plays an important role. In the presentstudy, we applied high throughput techniques to identify the antibody profiles ofpatients with severe and mild leptospirosis. We discovered a limited number ofimmunodominant antigens, specific to patients. Surprisingly, we found the antibodyrepertoire varies in patients with different clinical outcomes and hypothesized thatpatients with mild symptoms were protected from severe disease due to pre-existingantibodies, while the profile of patients with severe outcomes was representative of afirst exposure. These findings represent a substantial step forward in the knowledge ofthe humoral immune response to Leptospira infection, and we have identified newtargets for vaccine and diagnostic test development.
2016-09-10 | GSE86630 | GEO
Project description:Gene expression profiling of whole blood in patients with severe leptospirosis
| PRJNA823595 | ENA
Project description:Background The mysterious chronic kidney disease is multifactorial causes. One of the risk factors is leptospirosis, a re-emerging infectious disease caused by Leptospira spp., for endemic leptospirosis tend to coincide with high-incidence regions of chronic kidney disease of unknown etiology. This study aims to investigate the role of leptospirosis as an emerging culprit in which chronic subclinical kidney injury, may predispose to progressive kidney disease when superimposed on secondary nephrotoxic injury. Methods Adenine-induced renal injury in chronic leptospira-infected C57/BL6 mice were studied for evaluating the renal function, histology and gene expression changes. We employed RNA sequencing-based renal transcriptome to investigate pathogenic pathways associated with secondary nephrotoxic injury in chronic kidney injury due to leptospirosis. Results The severity of kidney lesions was increased and the expression of immune/inflammation/fibrosis genes were significantly up-regulated in either low-dose (0.1%) and high-dose (0.2%) adenine-induced renal injury superimposed on infected mice. Whole renal transcriptome analysis reveals that the substantial amplification of the tremendous amount of expressed genes and fibrosis-related pathways was found in adenine-induced kidney injury add-on to leptospira-infected mice which correlated with kidney dysfunction and fibrosis compared to infection or adenine itself. A total of 41 differentially expressed genes associated with fibrosis were identified in infected mice fed with adenine, suggesting that these potential genes contributed to aggravated renal progression occurred in adenine-fed chronic leptospira-infected mice. Conclusions In summary, this study indicates that chronic subclinical kidney infection when exposed to different degree of secondary nephrotoxic injury may predispose to exacerbated and progressive chronic kidney disease.
2021-04-05 | GSE150641 | GEO
Project description:LEPTOSPIROSIS AMONG PATIENTS WITH PRESUMPTIVE DIAGNOSIS OF DENGUE-LIKE ILLNESS IN SELANGOR, MALAYSIA
| PRJEB37767 | ENA
Project description:Leptospirosis is a neglected zoonotic disease. In 2015, leptospirosis was diagnosed in 2 prison inmates in South Africa. Using real-time PCR and DNA sequencing, we identified Leptospira interrogans serogroup Icterohaemorrhagiae in rodents and water samples within the prison. Leptospirosis might be frequently underdiagnosed in South Africa.
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Project description:Avian influenza A (H7N9) viruses have emerged in China in 2013 and caused zoonotic disease associated with a case-fatality ratio of over 30%. Transcriptional profile from peripheral blood has been shown to reflect host responses against a specific respiratory pathogen and can be used to understand the disease. Methods: We correlated the clinical data and blood transcriptomic profile of patients with avian influenza A (H7N9) disease and determined the biological significance of the infection from the analysis.
2018-05-31 | GSE114466 | GEO
Project description:Coronavirus disease 2019 (COVID-19) is an unprecedented global threat caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The COVID-19 pandemic is a global health crisis. Recent reports have exposed an astonishing case fatality rate of 61.5% for critical cases, increasing sharply with age and for patients with underlying comorbidities. Mass spectrometry (MS)-based proteomics has the potential to become an ideal technology to be applied in this urgent situations, because it can quickly deliver substantial amounts of clinical and biological information from blood plasma or serum in an untargeted fashion. Furthermore, these MS-based proteomic workflows for biomarker discovery and profiling are well established. However, only two studies have presently applied proteomics to serum of COVID-19 patients with moderate proteome depth. Therefore, it is necessary to gain a more detailed understanding with in-depth proteome of plasma or serum to develop prognostic or predictive protein markers. In this study, we performed in-depth proteome profiling of undepleted plasma samples using BoxCar acquisition method from an exploratory cohort comprising ten COVID-19 patients to identify candidate biomarkers for disease severity evaluation.
2021-05-15 | PXD020354 | Pride