Dataset Information

Defective Granuloma Formation in Elderly Infected Patients.

ABSTRACT: Granulomas are compact structures formed in tissues by the immune system in response to aggressions. The in vitro formation of granulomas using circulating mononuclear cells is an innovative method to easily assess the immune response of patients. Monitoring the efficiency of mononuclear cells from patients to form granulomas in vitro would help improve their therapeutic management. Circulating mononuclear cells from 23 elderly patients with sepsis and 24 elderly controls patients were incubated with Sepharose beads coated with either BCG or Coxiella burnetii extracts. The formation of granulomas was measured over 9 days. Most healthy elderly patients (92%) were able to form granulomas in response to BCG and Coxiella burnetii extracts compared to only 48% of infected elderly patients. Undernutrition was significantly associated with impaired granuloma formation in healthy and infected patients. Granulomas typically comprise epithelioid cells and multinucleated giant cells, however, these cells were not detected in samples obtained from patients unable to form granulomas. We also found that the impairment of granuloma formation was associated with reduced production of tumor necrosis factor without overproduction of interleukin-10. Finally, all genes specifically modulated in granulomatous cells were down-modulated in patients with defective granuloma formation. TNFSF10 was the only M1 gene markedly upregulated in patients who did not form granulomas. Our study suggest that defective granuloma formation may be a measurement of altered activation of immune cells which can predispose to nosocomial infections in elderly patients.

SUBMITTER: Daumas A

PROVIDER: S-EPMC7201002 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Defective Granuloma Formation in Elderly Infected Patients.

Daumas Aurélie A Coiffard Benjamin B Chartier Céline C Ben Amara Amira A Alingrin Julie J Villani Patrick P Mege Jean-Louis JL

Frontiers in cellular and infection microbiology 20200429

Granulomas are compact structures formed in tissues by the immune system in response to aggressions. The <i>in vitro</i> formation of granulomas using circulating mononuclear cells is an innovative method to easily assess the immune response of patients. Monitoring the efficiency of mononuclear cells from patients to form granulomas <i>in vitro</i> would help improve their therapeutic management. Circulating mononuclear cells from 23 elderly patients with sepsis and 24 elderly controls patients ...[more]

PMID: 32411623

Similar Datasets

Project description:Bovine tuberculosis is a chronic inflammatory disease that causes granuloma formation. Characterization of granulomatous lesions of Mycobacterium bovis (M. bovis) experimentally infected cattle has helped to better understand the pathogenesis of this disease. However, few studies have described granulomas found in M. bovis naturally infected cattle. The aim of this work was to examine granulomas from Holstein-Friesian cattle naturally infected with M. bovis from a dairy basin located in the central region of Mexico. Tissue samples from thirty-two cattle with lesions suggestive of tuberculosis were collected post-mortem. Fifteen of the 32 sampled animals (46.8%) were 4 months of age or younger (calves), whereas the rest (53.2%, 17/32) were over one year old (adults). Macroscopic lesions suggestive of tuberculosis were found in the mediastinal lymph node chain of all animals (32/32). From the 1,143 granulomatous lesions that were microscopically analyzed, 34.6% (396/1143) were collected from adult animals and subsequently classified according to the nomenclature suggested by Wangoo et al., 2005. Surprisingly, lesions from calf tissues showed an atypical pattern which could not be fitted into the established developmental stages of this classification. Granulomatous lesions found in calves covered most of the affected organ, histologically showed large necrotic areas with central calcification, absence of a connective tissue capsule, and few giant cells. Also, there was a higher percentage of lesions with acid-fast bacilli (AFB) when compared to studied granulomas in adults. Growth of Mycobacterium spp was detected in 11 bacteriological tissue cultures. Genotypic identification of M. bovis was performed by DNA extraction from bacterial isolates, formalin-fixed and paraffin-embedded (FFPE) tissues and samples without bacterial isolation. M. bovis was detected by PCR in 84.3% (27/32) of the studied cases; whereas other AFB were observed in tissues of the remaining sampled animals (5/32). Our results describe atypical granuloma formation in calves 4 months of age or younger, naturally infected with M. bovis. These findings contribute to better understanding the physiopathology of M. bovis infection in cattle.

Project description:Patients with chronic granulomatous disease (CGD) lack generation of reactive oxygen species (ROS) through the phagocyte NADPH oxidase NOX2. CGD is an immune deficiency that leads to frequent infections with certain pathogens; this is well documented for S. aureus and A. fumigatus, but less clear for mycobacteria. We therefore performed an extensive literature search which yielded 297 cases of CGD patients with mycobacterial infections; M. bovis BCG was most commonly described (74%). The relationship between NOX2 deficiency and BCG infection however has never been studied in a mouse model. We therefore investigated BCG infection in three different mouse models of CGD: Ncf1 mutants in two different genetic backgrounds and Cybb knock-out mice. In addition, we investigated a macrophage-specific rescue (transgenic expression of Ncf1 under the control of the CD68 promoter). Wild-type mice did not develop severe disease upon BCG injection. In contrast, all three types of CGD mice were highly susceptible to BCG, as witnessed by a severe weight loss, development of hemorrhagic pneumonia, and a high mortality (? 50%). Rescue of NOX2 activity in macrophages restored BCG resistance, similar as seen in wild-type mice. Granulomas from mycobacteria-infected wild-type mice generated ROS, while granulomas from CGD mice did not. Bacterial load in CGD mice was only moderately increased, suggesting that it was not crucial for the observed phenotype. CGD mice responded with massively enhanced cytokine release (TNF-?, IFN-?, IL-17 and IL-12) early after BCG infection, which might account for severity of the disease. Finally, in wild-type mice, macrophages formed clusters and restricted mycobacteria to granulomas, while macrophages and mycobacteria were diffusely distributed in lung tissue from CGD mice. Our results demonstrate that lack of the NADPH oxidase leads to a markedly increased severity of BCG infection through mechanisms including increased cytokine production and impaired granuloma formation.

Project description:Within the first 2-3 months of a Mycobacterium tuberculosis (Mtb) infection, 2-4 mm spherical structures called granulomas develop in the lungs of the infected hosts. These are the hallmark of tuberculosis (TB) infection in humans and non-human primates. A cascade of immunological events occurs in the first 3 months of granuloma formation that likely shapes the outcome of the infection. Understanding the main mechanisms driving granuloma development and function is key to generating treatments and vaccines. In vitro, in vivo, and in silico studies have been performed in the past decades to address the complexity of granuloma dynamics. This study builds on our previous 2D spatio-temporal hybrid computational model of granuloma formation in TB (GranSim) and presents for the first time a more realistic 3D implementation. We use uncertainty and sensitivity analysis techniques to calibrate the new 3D resolution to non-human primate (NHP) experimental data on bacterial levels per granuloma during the first 100 days post infection. Due to the large computational cost associated with running a 3D agent-based model, our major goal is to assess to what extent 2D and 3D simulations differ in predictions for TB granulomas and what can be learned in the context of 3D that is missed in 2D. Our findings suggest that in terms of major mechanisms driving bacterial burden, 2D and 3D models return very similar results. For example, Mtb growth rates and molecular regulation mechanisms are very important both in 2D and 3D, as are cellular movement and modulation of cell recruitment. The main difference we found was that the 3D model is less affected by crowding when cellular recruitment and movement of cells are increased. Overall, we conclude that the use of a 2D resolution in GranSim is warranted when large scale pilot runs are to be performed and if the goal is to determine major mechanisms driving infection outcome (e.g., bacterial load). To comprehensively compare the roles of model dimensionality, further tests and experimental data will be needed to expand our conclusions to molecular scale dynamics and multi-scale resolutions.

Dataset Information

Defective Granuloma Formation in Elderly Infected Patients.

Publications

Defective Granuloma Formation in Elderly Infected Patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets