Cathelicidin insufficiency in patients with fatal leptospirosis
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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.
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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.
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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 the most widespread zoonotic disease in the world. The lack of an adequate laboratory test is a major barrier for the diagnosis, especially during the early stages of illness, when antibiotic therapy is most effective. Therefore, there is a critical need for an efficient diagnostic test for this life threatening disease. In order to identify new targets that could be used as diagnostic makers for leptopirosis, we constructed a protein microarray chip comprising 61% of Leptospira interrogans proteome and investigated the IgG response against leptospiral antigens from 274 individuals, including 80 acute-, 80 convalescent-phase patients and 114 healthy control subjects from regions with endemic, high endemic and no endemic transmission of leptospirosis. A nitrocellulose line blot assay was performed to validate the accuracy of the protein microarray results. We found 16 antigens that can discriminate between acute cases and healthy individuals from a region with high endemic transmission of leptospirosis, and 18 antigens that distinguish convalescent cases. Some of the antigens identified in this study, such as LipL32, the non-identical domains of the Lig proteins, GroEL and Loa22 are already known to be recognized by sera from human patients, thus serving as a proof-of-concept for the serodiagnostic antigen discovery approach. Several novel antigens were identified, including the hypothetical protein LIC10215 which showed good sensitivity and specificity rates for both acute- and convalescent-phase patients. Our study is the first large-scale evaluation of immunodominant antigens associated with naturally acquired leptospiral infection and novel as well as known serodiagnostic leptospiral antigens that are recognized by antibodies in the sera of leptospirosis cases were identified. The novel antigens identified here may have potential use in both the development of new tests and the improvement of currently available assays for diagnosing this neglected tropical disease. Further research is needed to assess the accuracy of these antigens in more appropriate diagnostic platforms. Antibody profiling was peformed on sera from infected and non-infected subjects to investigate the IgG response against leptospiral antigens. These samples comprised 80 acute-, 80 convalescent-phase patients and 114 healthy control subjects, including 29 subjects from United States (non-endemic area), 35 blood donors from Salvador/Brazil (endemic area) and 50 healthy individuals from region with high endemicity of leptospirosis.
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Project description:Leptospirosis is a re-emerging tropical infectious disease caused by the pathogenic Leptospira spp. The different host innate immune responses were partially related to the different severity of leptospirosis. In this study, we employed transcriptomics and cytokine array to comparatively calculate the responses of murine peritoneal macrophages (MPM) and human peripheral blood monocytes (HBM) to leptospiral infection, and uncover a series of different expression regulations of these two immune cells. The regulation percentages in several biological processes of MPM, such as the antigen process and presentation, the regulation of membrane potential, and the innate immune response, etc., were much greater than those of HBM (>2 folds). In HBM and MPM, the CASP8 and FADD-like apoptosis regulator genes were significantly up-regulated, which supported previous results that the caspase-8/3 pathway plays an important role in macrophage apoptosis during leptospiral infection. The key component of complement pathway, C3, was only up-regulated in MPM. Several cytokines (e.g. IL-10, TNF-alpha) were differently expressed at both mRNA and protein level in MPM and HBM. The differences in the transcriptomics and the cytokine expression revealed in this study were partially consistent with the different outcomes of the chronic and acute leptospirosis; thus, these findings facilitated further molecular study on the innate immune response to leptospiral infection. Murine peritoneal macrophages (MPM) and human peripheral blood monocytes (HBM) were infected by pathogenic Leptospira. The host cells were collected at 1h, 2h, and 4h after infection. The uninfected macrophage sample was designed as a negative control. Three biological replicates were designed for each sample type. There were totally 24 hybridizations (12 for MPM, and 12 for HBM) included in this submission.
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