scholarly journals Severe Adaptive Immune Suppression May Be Why Patients With Severe COVID-19 Cannot Be Discharged From the ICU Even After Negative Viral Tests

2021 ◽  
Vol 12 ◽  
Author(s):  
Yue Zhou ◽  
Xuelian Liao ◽  
Xiangrong Song ◽  
Min He ◽  
Fei Xiao ◽  
...  
Keyword(s):  
Immune Suppression ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Severe Disease ◽  
Gene Expression Profiles ◽  
Severe Infection ◽  
Underlying Mechanism ◽  
Adaptive Immune ◽  
Secondary Infections ◽  
Peripheral Immune Cells

During the COVID-19 pandemic, a phenomenon emerged in which some patients with severe disease were critically ill and could not be discharged from the ICU even though they exhibited negative viral tests. To explore the underlying mechanism, we collected blood samples from these patients and analyzed the gene expression profiles of peripheral immune cells. We found that all enrolled patients, regardless of changes in genes related to different symptoms and inflammatory responses, showed universally and severely decreased expression of adaptive immunity-related genes, especially those related to T/B cell arms and HLA molecules, and that these patients exhibited long-term secondary infections. In addition, no significant change was found in the expression of classic immunosuppression molecules including PD-1, PD-L1, and CTLA-4, suggesting that the adaptive immune suppression may not be due to the change of these genes. According to the published literatures and our data, this adaptive immunosuppression is likely to be caused by the “dysregulated host response” to severe infection, similar to the immunosuppression that exists in other severely infected patients with sepsis.

scholarly journals Severe Adaptive Immune Suppression May be Why Patients with Severe COVID-19 Cannot be Discharged From the ICU Even After Negative Viral Tests

2021 ◽  
Author(s):  
Yue Zhou ◽  
Xuelian Liao ◽  
Xiangrong Song ◽  
Min He ◽  
Fei Xiao ◽  
...  
Keyword(s):  
Critically Ill ◽  
Immune Suppression ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Severe Disease ◽  
Antifungal Drugs ◽  
The Body ◽  
Adaptive Immune ◽  
Secondary Infections

Abstract Background: During the COVID-19 pandemic, a phenomenon emerged in which some patients with severe disease were critically ill and could not be discharged from the ICU even though they exhibited negative viral tests. In general, continuous negative viral tests are thought to indicate that the virus has been cleared from the body and that the patients can be considered "recovered". However, because these patients were still critically ill, they obviously had not truly recovered from the disease. We sought to investigate why these patients were still critically ill even though they exhibited negative viral tests by analyzing the gene expression profiles of their peripheral immune cells using transcriptome sequencing.Methods: Fourteen severe COVID-19 patients with at least 3 negative virus tests but were still in critical ill and could not be discharged from the ICU were enrolled. Blood samples from 14 patients and 5 healthy donors were collected. Total RNA was extracted from nucleated cells for RNA-Sequencing. FeatureCounts v1.5.0-p3 was used to count the reads numbers mapped to each gene. Results: All enrolled patients, regardless of changes in genes related to different symptoms and inflammatory responses, showed universally and severely decreased expression of adaptive immunity-related genes, especially those related to T/B cell arms and HLA molecules, and that these patients exhibited long-term secondary infections. This adaptive immune suppression is unlikely due to classic immune checkpoint molecules such as PD-1 or long-term use of glucocorticoids but may be caused by an unknown mechanism that has not yet been discovered.Conclusions: Our findings strongly suggest that an initial recovery of these severe COVID-19 patients, as indicated by negative viral tests, may not indicate actual recovery. They still suffer from secondary infections for a long period of time because of severe adaptive immunosuppression and need to receive a variety of antibiotics, antifungal drugs, or combination therapies. Appropriate methods should be used to detect their adaptive immune function, and appropriate immunotherapy that can activate the adaptive immune response should be developed. Trial registration: Not applicable (this study does not involve intervention on human participants).

scholarly journals Ad26.COV2.S Prevents SARS-CoV-2 Induced Pathways of Inflammation and Thrombosis in Hamsters

2021 ◽  
Author(s):  
Malika Aid ◽  
Samuel Vidal ◽  
Cesar Piedra-Mora ◽  
Sarah Ducat ◽  
Chi Chan ◽  
...  
Keyword(s):  
Immune Responses ◽  
Expression Profiles ◽  
Severe Disease ◽  
Gene Expression Profiles ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Type I ◽  
Adaptive Immune ◽  
Syrian Golden Hamsters ◽  
The Impact

Syrian golden hamsters exhibit features of severe disease after SARS-CoV-2 challenge and are therefore useful models of COVID-19 pathogenesis and prevention with vaccines. Recent studies have shown that SARS-CoV-2 infection stimulates type I interferon, myeloid, and inflammatory signatures similar to human disease, and that weight loss can be prevented with vaccines. However, the impact of vaccination on transcriptional programs associated with COVID-19 pathogenesis and protective adaptive immune responses is unknown. Here we show that SARS-CoV-2 challenge in hamsters stimulates antiviral, myeloid, and inflammatory programs as well as signatures of complement and thrombosis associated with human COVID-19. Notably, single dose immunization with Ad26.COV2.S, an adenovirus serotype 26 vector (Ad26)-based vaccine expressing a stabilized SARS-CoV-2 spike protein, prevents the upregulation of these pathways such that the gene expression profiles of vaccinated hamsters are comparable to uninfected animals. Finally, we show that Ad26.COV2.S vaccination induces T and B cell signatures that correlate with binding and neutralizing antibody responses. These data provide further insights into the mechanisms of Ad26.COV2.S based protection against severe COVID-19 in hamsters.

scholarly journals Postnatal lymph node expansion of stromal progenitors towards reticular and CD34+ stromal cell subsets is determined by distinct transcriptional programs

2021 ◽  
Author(s):  
Joern Pezoldt ◽  
Carolin Wiechrs ◽  
Maria Litovchenko ◽  
Marjan Biočanin ◽  
Mangge Zou ◽  
...  
Keyword(s):  
Immune Responses ◽  
Stromal Cell ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Developmental Trajectory ◽  
Mesenteric Lymph Nodes ◽  
Adaptive Immune Responses ◽  
Tissue Specific ◽  
Adaptive Immune

Abstract Gut-draining mesenteric lymph nodes (mLN) provide the framework and microenvironment to shape intestinal adaptive immune responses. We previously delineated transcriptional signatures in LN stromal cells (SC), pointing to tissue-specific variability in composition and immuno-modulatory function of SCs. Here, we dissect the tissue-specific epigenomic DNA accessibility and CpG methylation landscape of LN non-endothelial SCs and identify a microbiota-independent core epigenomic signature of LN SCs. By combined analysis of transcription factor (TF) binding sites together with the gene expression profiles of non-endothelial SCs, we delineated TFs poising skin-draining peripheral LN (pLN) SCs for pro-inflammatory responses. Furthermore, using scRNA-seq, we dissected the developmental trajectory of mLN SCs derived from postnatal to aged mice, identifying two distinct putative progenitors, namely CD34+SC and fibroblastic reticular stromal cell (FRC) progenitors, which both feed the rapid postnatal LN expansion. Finally, we identified Irf3 as a key differentiation TF inferred from the epigenomic signature of mLN SCs that is dynamically expressed along the differentiation trajectories of FRCs, and validated Irf3 as a regulator of Cxcl9+ FRC differentiation. Together, our data constitute a comprehensive transcriptional and epigenomic map of mLN development and dissect location-specific, microbiota-independent properties of mLN non-endothelial SCs. As such, our findings represent a valuable resource to identify core transcriptional regulators that impinge on the developing mLN early in life, thereby shaping long-lasting intestinal adaptive immune responses.

scholarly journals Postnatal lymph node expansion of stromal progenitors towards reticular and CD34+ stromal cell subsets is determined by distinct transcriptional programs

2021 ◽  
Author(s):  
Joern Pezoldt ◽  
Carolin Wiechers ◽  
Maria Litovchenko ◽  
Marjan Biocanin ◽  
Mangge Zou ◽  
...  
Keyword(s):  
Immune Responses ◽  
Stromal Cell ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Developmental Trajectory ◽  
Mesenteric Lymph Nodes ◽  
Adaptive Immune Responses ◽  
Tissue Specific ◽  
Adaptive Immune

Gut-draining mesenteric lymph nodes (mLN) provide the framework and microenvironment to shape intestinal adaptive immune responses. We previously delineated transcriptional signatures in LN stromal cells (SC), pointing to tissue-specific variability in composition and immuno-modulatory function of SCs. Here, we dissect the tissue-specific epigenomic DNA accessibility and CpG methylation landscape of LN non-endothelial SCs and identify a microbiota-independent core epigenomic signature of LN SCs. By combined analysis of transcription factor (TF) binding sites together with the gene expression profiles of non-endothelial SCs, we delineated TFs poising skin-draining peripheral LN (pLN) SCs for pro-inflammatory responses. Furthermore, using scRNA-seq, we dissected the developmental trajectory of mLN SCs derived from postnatal to aged mice, identifying two distinct putative progenitors, namely CD34+ SC and fibroblastic reticular stromal cell (FRC) progenitors, which both feed the rapid postnatal LN expansion. Finally, we identified Irf3 as a key differentiation TF inferred from the epigenomic signature of mLN SCs that is dynamically expressed along the differentiation trajectories of FRCs, and validated Irf3 as a regulator of Cxcl9+ FRC differentiation. Together, our data constitute a comprehensive transcriptional and epigenomic map of mLN development and dissect location-specific, microbiota-independent properties of mLN non-endothelial SCs. As such, our findings represent a valuable resource to identify core transcriptional regulators that impinge on the developing mLN early in life, thereby shaping long-lasting intestinal adaptive immune responses.

Simulated microgravity using the Random Positioning Machine inhibits differentiation and alters gene expression profiles of 2T3 preosteoblasts

2005 ◽  
Vol 288 (6) ◽  
pp. C1211-C1221 ◽  
Author(s):  
Steven J. Pardo ◽  
Mamta J. Patel ◽  
Michelle C. Sykes ◽  
Manu O. Platt ◽  
Nolan L. Boyd ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alkaline Phosphatase ◽  
Bone Loss ◽  
Simulated Microgravity ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Underlying Mechanism ◽  
Bone Biology ◽  
Random Positioning Machine

Exposure to microgravity causes bone loss in humans, and the underlying mechanism is thought to be at least partially due to a decrease in bone formation by osteoblasts. In the present study, we examined the hypothesis that microgravity changes osteoblast gene expression profiles, resulting in bone loss. For this study, we developed an in vitro system that simulates microgravity using the Random Positioning Machine (RPM) to study the effects of microgravity on 2T3 preosteoblast cells grown in gas-permeable culture disks. Exposure of 2T3 cells to simulated microgravity using the RPM for up to 9 days significantly inhibited alkaline phosphatase activity, recapitulating a bone loss response that occurs in real microgravity conditions without altering cell proliferation and shape. Next, we performed DNA microarray analysis to determine the gene expression profile of 2T3 cells exposed to 3 days of simulated microgravity. Among 10,000 genes examined using the microarray, 88 were downregulated and 52 were upregulated significantly more than twofold using simulated microgravity compared with the static 1-g condition. We then verified the microarray data for some of the genes relevant in bone biology using real-time PCR assays and immunoblotting. We confirmed that microgravity downregulated levels of alkaline phosphatase, runt-related transcription factor 2, osteomodulin, and parathyroid hormone receptor 1 mRNA; upregulated cathepsin K mRNA; and did not significantly affect bone morphogenic protein 4 and cystatin C protein levels. The identification of gravisensitive genes provides useful insight that may lead to further hypotheses regarding their roles in not only microgravity-induced bone loss but also the general patient population with similar pathological conditions, such as osteoporosis.

scholarly journals n-3 Fatty acids, inflammation and immunity: new mechanisms to explain old actions

2013 ◽  
Vol 72 (3) ◽  
pp. 326-336 ◽  
Author(s):  
Philip C. Calder
Keyword(s):  
Fatty Acids ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Mechanisms Of Action ◽  
Lipid Mediators ◽  
Functional Responses ◽  
New Family ◽  
Epa And Dha ◽  
Novel Interactions

Numerous effects of n-3 fatty acids EPA and DHA on functional responses of cells involved in inflammation and immunity have been described. Fatty acid-induced modifications in membrane order and in the availability of substrates for eicosanoid synthesis are long-standing mechanisms that are considered important in explaining the effects observed. More recently, effects on signal transduction pathways and on gene expression profiles have been identified. Over the last 10 years or so, significant advances in understanding the mechanisms of action of n-3 fatty acids have been made. These include the identification of new actions of lipid mediators that were already described and of novel interactions among those mediators and the description of an entirely new family of lipid mediators, resolvins and protectins that have anti-inflammatory actions and are critical to the resolution of inflammation. It is also recognised that EPA and DHA can inhibit activation of the prototypical inflammatory transcription factor NF-κB. Recent studies suggest three alternative mechanisms by which n-3 fatty acids might have this effect. Within T-cells, as well as other cells of relevance to immune and inflammatory responses, EPA and DHA act to disrupt very early events involving formation of the structures termed lipid rafts which bring together various proteins to form an effective signalling platform. In summary, recent research has identified a number of new mechanisms of action that help to explain previously identified effects of n-3 fatty acids on inflammation and immunity.

Whole blood genome-wide gene expression profile in males after prolonged wakefulness and sleep recovery

2012 ◽  
Vol 44 (21) ◽  
pp. 1003-1012 ◽  
Author(s):  
R. Pellegrino ◽  
D. Y. Sunaga ◽  
C. Guindalini ◽  
R. C. S. Martins ◽  
D. R. Mazzotti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Whole Blood ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Killer Cell ◽  
Gene Expression Profiles ◽  
Sleep Loss ◽  
The Body ◽  
Dna Damage And Repair ◽  
Peripheral Tissues

Although the specific functions of sleep have not been completely elucidated, the literature has suggested that sleep is essential for proper homeostasis. Sleep loss is associated with changes in behavioral, neurochemical, cellular, and metabolic function as well as impaired immune response. Using high-resolution microarrays we evaluated the gene expression profiles of healthy male volunteers who underwent 60 h of prolonged wakefulness (PW) followed by 12 h of sleep recovery (SR). Peripheral whole blood was collected at 8 am in the morning before the initiation of PW (Baseline), after the second night of PW, and one night after SR. We identified over 500 genes that were differentially expressed. Notably, these genes were related to DNA damage and repair and stress response, as well as diverse immune system responses, such as natural killer pathways including killer cell lectin-like receptors family, as well as granzymes and T-cell receptors, which play important roles in host defense. These results support the idea that sleep loss can lead to alterations in molecular processes that result in perturbation of cellular immunity, induction of inflammatory responses, and homeostatic imbalance. Moreover, expression of multiple genes was downregulated following PW and upregulated after SR compared with PW, suggesting an attempt of the body to re-establish internal homeostasis. In silico validation of alterations in the expression of CETN3, DNAJC, and CEACAM genes confirmed previous findings related to the molecular effects of sleep deprivation. Thus, the present findings confirm that the effects of sleep loss are not restricted to the brain and can occur intensely in peripheral tissues.

Distinct gene expression profiles provoked by polyacrylamide beads (Biogel) during chronic and acute inflammation in mice selected for maximal and minimal inflammatory responses

2016 ◽  
Vol 65 (4) ◽  
pp. 313-323 ◽  
Author(s):  
Jussara Gonçalves Fernandes ◽  
Tatiane Canhamero ◽  
Andrea Borrego ◽  
José Ricardo Jensen ◽  
Wafa Hanna Cabrera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Inflammation ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Distinct Gene

scholarly journals Revisit the Cellular Transmission and Emerging Techniques in Understanding the Mechanisms of Proteinopathies

2021 ◽  
Vol 15 ◽  
Author(s):  
Jinwen Jiang ◽  
Yu Liu ◽  
Qihui Wu
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Single Cell ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Molecular Taxonomy ◽  
Gene Expression Profiles ◽  
Underlying Mechanism ◽  
Signal Pathways ◽  
Parkinson’S Diseases

Alzheimer’s and Parkinson’s diseases (AD and PD) are amongst top of the prevalent neurodegenerative disease. One-third of PD patients are diagnosed with dementia, a pre-symptom of AD, but the underlying mechanism is elusive. Amyloid beta (Aβ) and α-synuclein are two of the most investigated proteins, whose pathological aggregation and spreading are crucial to the pathogenesis of AD and PD, respectively. Transcriptomic studies of the mammalian central nervous system shed light on gene expression profiles at molecular levels, regarding the complexity of neuronal morphologies and electrophysiological inputs/outputs. In the last decade, the booming of the single-cell RNA sequencing technique helped to understand gene expression patterns, alternative splicing, novel transcripts, and signal pathways in the nervous system at single-cell levels, providing insight for molecular taxonomy and mechanistic targets of the degenerative nervous system. Here, we re-visited the cell-cell transmission mechanisms of Aβ and α-synuclein in mediating disease propagation, and summarized recent single-cell transcriptome sequencing from different perspectives and discussed its understanding of neurodegenerative diseases.

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