Project description:The factors predisposing towards the development of pulmonary non-tuberculous mycobacterial disease (pNTM) and influencing disease progression remain unclear. Impaired immune responses have been reported in individuals with pNTM but data are limited and inconsistent. This study aimed to use gene expression profiling to examine the host response to pNTM. Microarray analysis of whole blood gene expression was performed on 25 subjects with pNTM and 27 uninfected controls with respiratory disease. Gene expression results were compared to phenotypic variables and survival data. Compared with uninfected controls, pNTM was associated with down-regulation of 213 transcripts enriched for terms related to T cell signalling including IFNG. Reduced IFNG expression was associated with more severe CT changes and impaired lung function. Mortality was associated with the expression of transcripts related to the innate immune response and inflammation, whereas transcripts related to T and B cell function were associated with improved survival. These findings suggest that pNTM is associated with an aberrant immune response which may reflect an underlying propensity to infection, or result from NTM infection itself. There were important differences in the immune response associated with survival and mortality in pNTM.
Project description:<p>This project aims at characterizing the human host susceptibility to pulmonary non-tuberculous mycobacterial (PNTM) infections. PNTM infections occur in patients with chronic lung disease, but also in a distinct group of elderly women without lung defects but who share a common body morphology: tall and lean with scoliosis, pectus excavatum, and mitral valve prolapse. We performed whole exome and genome sequencing in extended families of patients with active PNTM. This unique collection of familial cohorts in PNTM represents an important opportunity for a high yield search for genes that regulate mucosal immunity. We also sequenced the genome of mycobacterial isolates from PNTM patients to integrate host PNTM susceptibility with mycobacterial genotypes and gain insights into the key factors involved in this devastating disease.</p>
Project description:We identified 18 patients with the distinct clinical phenotype of disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, primarily histoplasmosis and molds. This syndrome typically had its onset in adulthood and was characterized by profound circulating monocytopenia, B lymphocytopenia, and NK lymphocytopenia. T lymphocytes were variably affected. Despite these peripheral cytopenias, all patients had macrophages and plasma cells at sites of inflammation and normal immunoglobulin levels. This novel clinical syndrome links mycobacterial, viral, and fungal susceptibility with malignancy and is transmitted in an autosomal dominant pattern. In order to elucidate the possible genetic defect that results in this novel clinical syndrome, we performed microarray expression analysis on polymorphonuclear leukocytes (PMNs) isolated from affected patients and healthy controls. Keywords: healthy donor vs affected patient
Project description:To understand nontuberculous mycobacterial (NTM) pathogenesis, we evaluated immune responses to Mycobacterium avium (Mav) in asymptomatic individuals with a previous history of M. avium complex lung disease (MACDZ). We analyzed global gene expression in paired Mav-infected and uninfected peripheral blood monocytes from 17 MACDZ and 17 healthy controls.
Project description:Background: Patients with cystic fibrosis (CF) have an elevated lifetime risk of infection and disease caused by nontuberculous mycobacteria (NTM). Currently, there is no method to predict whether patients with cystic fibrosis will develop disease related to non-tuberculous mycobacteria. In non cystic fibrosis populations, several genetic susceptibility factors have been described. In this study, we examined whether patients with cystic fibrosis demonstrate a similar pattern of genetic susceptibility and explored host immune-related biomarkers predictive of NTM pulmonary disease (NTM-PD). Methods: We evaluated whole blood gene expression using bulk RNA-seq in a cohort of CF patients at the time of first isolation of NTM. Differential gene expression was compared in patients who did (n = 12) vs. did not (n= 30) develop NTM-PD following first NTM growth. Results: No differences in demographics or composition of white blood cell sample populations at the time of sample collection were identified between groups. There were no significant differences in the expression of genes previously reported to confer susceptibility to NTM-PD in non-CF populations. However, CF patients who went on to develop NTM-PD had higher expression of genes involved in the interferon ( and ), tumor necrosis factor, and IL6 STAT3 JAK pathways. Conclusion: Patients with CF who develop NTM-PD have increased expression of genes involved in innate immunity, in contrast to non-CF populations where these responses seem to be suppressed.
Project description:We identified 18 patients with the distinct clinical phenotype of disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and fungal infections, primarily histoplasmosis and molds. This syndrome typically had its onset in adulthood and was characterized by profound circulating monocytopenia, B lymphocytopenia, and NK lymphocytopenia. T lymphocytes were variably affected. Despite these peripheral cytopenias, all patients had macrophages and plasma cells at sites of inflammation and normal immunoglobulin levels. This novel clinical syndrome links mycobacterial, viral, and fungal susceptibility with malignancy and is transmitted in an autosomal dominant pattern. In order to elucidate the possible genetic defect that results in this novel clinical syndrome, we performed microarray expression analysis on polymorphonuclear leukocytes (PMNs) isolated from affected patients and healthy controls. Keywords: healthy donor vs affected patient Gene expression data for polymorphonuclear leukocytes (PMNs) isolated from the blood of affected patients and healthy donors. There are two separate data sets: For the first data set, there are 7 healthy controls and 3 affected patients [Samples GSM400913-GSM400922]. For the second data set, there are 5 healthy controls and 5 affected patients [GSM400923-GSM400932].