scholarly journals Blood transcriptomics reveal the evolution and resolution of the immune response in tuberculosis

2021 ◽  
Vol 218 (10) ◽  
Author(s):  
Olivier Tabone ◽  
Raman Verma ◽  
Akul Singhania ◽  
Probir Chakravarty ◽  
William J. Branchett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Treatment Response ◽  
Clinical Management ◽  
Household Contacts ◽  
Tb Treatment ◽  
Time Changes ◽  
Blood Transcriptomics

Blood transcriptomics have revealed major characteristics of the immune response in active TB, but the signature early after infection is unknown. In a unique clinically and temporally well-defined cohort of household contacts of active TB patients that progressed to TB, we define minimal changes in gene expression in incipient TB increasing in subclinical and clinical TB. While increasing with time, changes in gene expression were highest at 30 d before diagnosis, with heterogeneity in the response in household TB contacts and in a published cohort of TB progressors as they progressed to TB, at a bulk cohort level and in individual progressors. Blood signatures from patients before and during anti-TB treatment robustly monitored the treatment response distinguishing early and late responders. Blood transcriptomics thus reveal the evolution and resolution of the immune response in TB, which may help in clinical management of the disease.

scholarly journals High-Density Blood Transcriptomics Reveals Precision Immune Signatures of SARS-CoV-2 Infection in Hospitalized Individuals

2021 ◽  
Vol 12 ◽  
Author(s):  
Jeremy W. Prokop ◽  
Nicholas L. Hartog ◽  
Dave Chesla ◽  
William Faber ◽  
Chanise P. Love ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Viral Infections ◽  
Secretory Granules ◽  
Mitotic Cell ◽  
Hospitalized Patients ◽  
High Density ◽  
Type I ◽  
Secondary Infections ◽  
Blood Transcriptomics

The immune response to COVID-19 infection is variable. How COVID-19 influences clinical outcomes in hospitalized patients needs to be understood through readily obtainable biological materials, such as blood. We hypothesized that a high-density analysis of host (and pathogen) blood RNA in hospitalized patients with SARS-CoV-2 would provide mechanistic insights into the heterogeneity of response amongst COVID-19 patients when combined with advanced multidimensional bioinformatics for RNA. We enrolled 36 hospitalized COVID-19 patients (11 died) and 15 controls, collecting 74 blood PAXgene RNA tubes at multiple timepoints, one early and in 23 patients after treatment with various therapies. Total RNAseq was performed at high-density, with >160 million paired-end, 150 base pair reads per sample, representing the most sequenced bases per sample for any publicly deposited blood PAXgene tube study. There are 770 genes significantly altered in the blood of COVID-19 patients associated with antiviral defense, mitotic cell cycle, type I interferon signaling, and severe viral infections. Immune genes activated include those associated with neutrophil mechanisms, secretory granules, and neutrophil extracellular traps (NETs), along with decreased gene expression in lymphocytes and clonal expansion of the acquired immune response. Therapies such as convalescent serum and dexamethasone reduced many of the blood expression signatures of COVID-19. Severely ill or deceased patients are marked by various secondary infections, unique gene patterns, dysregulated innate response, and peripheral organ damage not otherwise found in the cohort. High-density transcriptomic data offers shared gene expression signatures, providing unique insights into the immune system and individualized signatures of patients that could be used to understand the patient’s clinical condition. Whole blood transcriptomics provides patient-level insights for immune activation, immune repertoire, and secondary infections that can further guide precision treatment.

scholarly journals Exploring a combined biomarker for tuberculosis treatment response: protocol for a prospective observational cohort study

BMJ Open ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. e052885
Author(s):  
Frank Kloprogge ◽  
Ibrahim Abubakar ◽  
Hanif Esmail ◽  
Vanessa Hack ◽  
Heinke Kunst ◽  
...  
Keyword(s):  
Immune Response ◽  
Cohort Study ◽  
Treatment Response ◽  
Host Immune Response ◽  
Observational Cohort Study ◽  
Series Data ◽  
Antibiotic Exposure ◽  
Tb Treatment ◽  
Observational Cohort ◽  
Host Blood

IntroductionAn improved understanding of factors explaining tuberculosis (TB) treatment response is urgently needed to help clinicians optimise and personalise treatment and assist scientists undertaking novel treatment regimen trials. Promising outcome proxy measures, including sputum bacillary load and host immune response, are widely reported with variable results. However, they have not been studied together in combination with antibiotic exposure. The aim of this observational cohort study is to investigate which antibiotic exposures correlate with sputum bacillary load and which with the host immune response. Subsequently, we will explore if these correlations can be used to inform a candidate combined biomarker predicting cure.Methods and analysisAll patients aged ≥ 18, diagnosed with drug-sensitive pulmonary TB (culture or molecular test), eligible for standard anti-TB treatment, at selected London, UK TB Services, will be invited to participate in this observational cohort study (target sample size=210). Patients will be asked to give blood for host transcriptomics and antibiotic plasma exposure, in addition to standard of care sputum samples for bacillary load. Antibiotic plasma concentrations will be quantified using a validated liquid chromatograph triple quadrupole mass spectrometer (LC-MS/MS) assay and sputum bacillary load by mycobacterial growth incubator tube time to positivity. Expression from a total of 35 prespecified host blood genes will be quantified using NanoString®. Antibiotic exposure, sputum bacillary load and host blood transcriptomic time series data will be analysed using nonlinear mixed-effects models. Correlations between combinations of longitudinal biomarkers and microbiological cure at the end of treatment and remaining relapse free for 1 year thereafter will be analysed using logistic regression and Cox proportional hazard models.Ethics and disseminationThe observational cohort study has been approved by the UK’s HRA REC (20/SW/0007). Written informed consent will be obtained. Results will be disseminated via publication, presentation and through engagement with institutes/companies developing novel anti-TB treatment combinations.

scholarly journals Modulation of the Immune Response by Deferasirox in Myelodysplastic Syndrome Patients

2021 ◽  
Vol 14 (1) ◽  
pp. 41
Author(s):  
Hana Votavova ◽  
Zuzana Urbanova ◽  
David Kundrat ◽  
Michaela Dostalova Merkerova ◽  
Martin Vostry ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Blood Cell ◽  
Myelodysplastic Syndrome ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Adaptive Immune Response ◽  
Gene Expression Profiles ◽  
Iron Chelator ◽  
Multiple Cancer

Deferasirox (DFX) is an oral iron chelator used to reduce iron overload (IO) caused by frequent blood cell transfusions in anemic myelodysplastic syndrome (MDS) patients. To study the molecular mechanisms by which DFX improves outcome in MDS, we analyzed the global gene expression in untreated MDS patients and those who were given DFX treatment. The gene expression profiles of bone marrow CD34+ cells were assessed by whole-genome microarrays. Initially, differentially expressed genes (DEGs) were determined between patients with normal ferritin levels and those with IO to address the effect of excessive iron on cellular pathways. These DEGs were annotated to Gene Ontology terms associated with cell cycle, apoptosis, adaptive immune response and protein folding and were enriched in cancer-related pathways. The deregulation of multiple cancer pathways in iron-overloaded patients suggests that IO is a cofactor favoring the progression of MDS. The DEGs between patients with IO and those treated with DFX were involved predominantly in biological processes related to the immune response and inflammation. These data indicate DFX modulates the immune response mainly via neutrophil-related genes. Suppression of negative regulators of blood cell differentiation essential for cell maturation and upregulation of heme metabolism observed in DFX-treated patients may contribute to the hematopoietic improvement.

scholarly journals Protein citrullination as a source of cancer neoantigens

2021 ◽  
Vol 9 (6) ◽  
pp. e002549
Author(s):  
Hiroyuki Katayama ◽  
Makoto Kobayashi ◽  
Ehsan Irajizad ◽  
Alejandro Sevillarno ◽  
Nikul Patel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Immune Response ◽  
Protein Expression ◽  
Cell Lines ◽  
Cancer Cell ◽  
Family Members ◽  
Immunohistochemical Analysis ◽  
Cancer Cell Lines ◽  
Mhc Ii

BackgroundCitrulline post-translational modification of proteins is mediated by protein arginine deiminase (PADI) family members and has been associated with autoimmune diseases. The role of PADI-citrullinome in immune response in cancer has not been evaluated. We hypothesized that PADI-mediated citrullinome is a source of neoantigens in cancer that induces immune response.MethodsProtein expression of PADI family members was evaluated in 196 cancer cell lines by means of indepth proteomic profiling. Gene expression was assessed using messenger RNA data sets from The Cancer Genome Atlas. Immunohistochemical analysis of PADI2 and peptidyl-citrulline was performed using breast cancer tissue sections. Citrullinated 12–34-mer peptides in the putative Major Histocompatibility Complex-II (MHC-II) binding range were profiled in breast cancer cell lines to investigate the relationship between protein citrullination and antigen presentation. We further evaluated immunoglobulin-bound citrullinome by mass spectrometry using 156 patients with breast cancer and 113 cancer-free controls.ResultsProteomic and gene expression analyses revealed PADI2 to be highly expressed in several cancer types including breast cancer. Immunohistochemical analysis of 422 breast tumor tissues revealed increased expression of PADI2 in ER− tumors (p<0.0001); PADI2 protein expression was positively correlated (p<0.0001) with peptidyl-citrulline staining. PADI2 expression exhibited strong positive correlations with a B cell immune signature and with MHC-II-bound citrullinated peptides. Increased circulating citrullinated antigen–antibody complexes occurred among newly diagnosed breast cancer cases relative to controls (p=0.0012).ConclusionsAn immune response associated with citrullinome is a rich source of neoantigens in breast cancer with a potential for diagnostic and therapeutic applications.

scholarly journals H-Ras gene takes part to the host immune response to COVID-19

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Salvatore Sciacchitano ◽  
Andrea Sacconi ◽  
Claudia De Vitis ◽  
Giovanni Blandino ◽  
Giulia Piaggio ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Severe Disease ◽  
Host Immune Response ◽  
Severe Form ◽  
Ras Gene ◽  
Peripheral Blood Mononuclear ◽  
Ras Genes

AbstractRas gene family members play a relevant role in cancer, especially when they are mutated. However, they may play additional roles in other conditions beside cancer. We performed gene expression analysis using the NanoString PanCancer IO 360 panel in the peripheral blood mononuclear cell (PBMC) of six COVID-19 patients and we found that H-Ras gene was significantly upregulated, while both K-Ras and N-Ras genes were downregulated. In particular, H-Ras gene upregulation was more evident in COVID-19 patients with a more severe disease. We compared our results with those obtained by analyzing two different and independent datasets, including a total of 53 COVID-19 patients, in which the gene expression analysis was performed using the Immunology_V2 panel. Comparative analysis of the H-Ras gene expression in these patients confirmed our preliminary results. In both of them, in fact, we were able to confirm the upregulation of the expression of the H-Ras gene. The exact role of this specific upregulation of the H-Ras gene in response to SARS-CoV-2 infection and its possible role in cancer still remains to be elucidated. In conclusion, H-Ras gene participates to the host immune response to SARS-CoV-2 virus infection, especially in patients affected by the most severe form of the COVID-19.

scholarly journals Transversal gene expression panel to evaluate intestinal health in broiler chickens in different challenging conditions

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
L. Criado-Mesas ◽  
N. Abdelli ◽  
A. Noce ◽  
M. Farré ◽  
J. F. Pérez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Barrier Function ◽  
Nutrient Transport ◽  
Gene Expression Pattern ◽  
Vaccine Dose ◽  
Special Focus ◽  
Intestinal Health ◽  
Barrier Failure ◽  
Expression Of Genes

AbstractThere is a high interest on gut health in poultry with special focus on consequences of the intestinal diseases, such as coccidiosis and C. perfringens-induced necrotic enteritis (NE). We developed a custom gene expression panel, which could provide a snapshot of gene expression variation under challenging conditions. Ileum gene expression studies were performed through high throughput reverse transcription quantitative real-time polymerase chain reaction. A deep review on the bibliography was done and genes related to intestinal health were selected for barrier function, immune response, oxidation, digestive hormones, nutrient transport, and metabolism. The panel was firstly tested by using a nutritional/Clostridium perfringens model of intestinal barrier failure (induced using commercial reused litter and wheat-based diets without exogenous supplementation of enzymes) and the consistency of results was evaluated by another experiment under a coccidiosis challenge (orally gavaged with a commercial coccidiosis vaccine, 90× vaccine dose). Growth traits and intestinal morphological analysis were performed to check the gut barrier failure occurrence. Results of ileum gene expression showed a higher expression in genes involved in barrier function and nutrient transport in chickens raised in healthy conditions, while genes involved in immune response presented higher expression in C.perfringens-challenged birds. On the other hand, the Eimeria challenge also altered the expression of genes related to barrier function and metabolism, and increased the expression of genes related to immune response and oxidative stress. The panel developed in the current study gives us an overview of genes and pathways involved in broiler response to pathogen challenge. It also allows us to deep into the study of differences in gene expression pattern and magnitude of responses under either a coccidial vaccine or a NE.

scholarly journals A novel gene signature based on five immune checkpoint genes predicts the survival of glioma

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Wei Zhang ◽  
You Zhai ◽  
Guanzhang Li ◽  
Tao Jiang
Keyword(s):  
Gene Expression ◽  
Central Nervous System ◽  
Immune Response ◽  
Nervous System ◽  
Cox Regression ◽  
Gene Signature ◽  
Immune Checkpoints ◽  
The Novel ◽  
The Central Nervous System ◽  
Checkpoint Genes

Abstract Background Glioma is the most common and fatal type of nerve neoplasm in the central nervous system. Several biomarkers have been considered for prognosis prediction, which is not accurate enough. We aimed to carry out a gene signature related to the expression of immune checkpoints which was enough for its performance in prediction. Methods Gene expression of immune checkpoints in TGGA database was filtrated. The 5 selected genes underwent verification by COX and Lasso-COX regression. Next, the selected genes were included to build a novel signature for further analysis. Results Patients were sub-grouped into high and low risk according to the novel signature. Immune response, clinicopathologic characters, and survival showed significant differences between those 2 groups. Terms including “naive,” “effector,” and “IL-4” were screened out by GSEA. The results showed strong relevance between the signature and immune response. Conclusions We constructed a gene signature with 5 immune checkpoints. The signature predicted survival effectively. The novel signature performed more functional than previous biomarkers.

scholarly journals The Sex Differences in Uveal Melanoma: Potential Roles of EIF1AX, Immune Response and Redox Regulation

2021 ◽  
Vol 28 (4) ◽  
pp. 2801-2811
Author(s):  
Feng Liu-Smith ◽  
Chi-Yang Chiu ◽  
Daniel L. Johnson ◽  
Phillip Winston Miller ◽  
Evan S. Glazer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Sex Difference ◽  
Uveal Melanoma ◽  
Disulfide Bond ◽  
Bond Formation ◽  
Disulfide Bond Formation ◽  
Men And Women ◽  
Copy Numbers ◽  
Differential Gene

Background: Uveal melanoma (UVM) is a rare cancer that shows sex difference in incidence and survival, with little previous report for the underlying mechanism. Methods: This study used the SEER data (1974–2016) for an age-dependent analysis on sex difference in UVM, and further used the TCGA-UVM genomics dataset for analyzing the differential gene expression profiles in tumors from men and women. Results: Our results demonstrate a sex difference in older age (≥40 years) but not in younger patients, with men exhibiting a higher incidence rate than women. However, younger women have shown a continuous increasing trend since 1974. Examining the 11 major oncogenes and tumor suppressors in UVM revealed that EIF1AX showed a significant sex difference in mRNA accumulation and copy number variation, with female tumors expressing higher levels of EIF1AX and exhibiting more variations in copy numbers. EIF1AX mRNA levels were significantly inversely correlated with EIF1AX copy numbers in female tumors only, but not in male tumors. Differential gene expression analysis at the whole genomic level identified a set of 92 protein-coding and 16 RNA-coding genes which exhibited differential expression in men and women (fold of change cutoff at 1.7, adjusted p value < 0.05, FDR < 0.05). Network analysis showed significant difference in immune response and in disulfide bond formation, with EGR1/EGR2 and PDIA2 genes as regulators for immune response and disulfide bond formation, respectively. The melanocortin pathway which is linked to both melanin synthesis and obesity seems to be altered with unclear significance, as the sex difference in POMC, DCT/TYRP2, and MRAP2 was observed but with no clear direction. Conclusion: This study reveals possible mechanisms for the sex difference in tumorigenesis of UVM which has potentials for better understanding and prevention of UVM.

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