scholarly journals The induction of preterm labor in rhesus macaques is determined by the  strength of immune response to intrauterine infection

PLoS Biology ◽  
2021 ◽  
Vol 19 (9) ◽  
pp. e3001385
Author(s):  
Monica Cappelletti ◽  
Pietro Presicce ◽  
Ma Feiyang ◽  
Paranthaman Senthamaraikannan ◽  
Lisa A. Miller ◽  
...  
Keyword(s):  
Immune Response ◽  
Preterm Labor ◽  
Iron Homeostasis ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Intrauterine Infection ◽  
Neutrophil Infiltration ◽  
Type I ◽  
Rna Seq ◽  
Neutrophilic Infiltration

Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor (PTL). However, IUI does not invariably cause PTL. We hypothesized that quantitative and qualitative differences in immune response exist in subjects with or without PTL. To define the triggers for PTL, we developed rhesus macaque models of IUI driven by lipopolysaccharide (LPS) or live Escherichia coli. PTL did not occur in LPS challenged rhesus macaques, while E. coli–infected animals frequently delivered preterm. Although LPS and live E. coli both caused immune cell infiltration, E. coli–infected animals showed higher levels of inflammatory mediators, particularly interleukin 6 (IL-6) and prostaglandins, in the chorioamnion-decidua and amniotic fluid (AF). Neutrophil infiltration in the chorio-decidua was a common feature to both LPS and E. coli. However, neutrophilic infiltration and IL6 and PTGS2 expression in the amnion was specifically induced by live E. coli. RNA sequencing (RNA-seq) analysis of fetal membranes revealed that specific pathways involved in augmentation of inflammation including type I interferon (IFN) response, chemotaxis, sumoylation, and iron homeostasis were up-regulated in the E. coli group compared to the LPS group. Our data suggest that the intensity of the host immune response to IUI may determine susceptibility to PTL.

scholarly journals The intensity of the immune response to LPS and E. coli regulates the induction of preterm labor in Rhesus Macaques

2021 ◽  
Author(s):  
Monica Cappelletti ◽  
Pietro Presicce ◽  
Feyiang Ma ◽  
Paranthaman Senthamaraikannan ◽  
Lisa Miller ◽  
...  
Keyword(s):  
Immune Response ◽  
Rhesus Macaque ◽  
Preterm Labor ◽  
Iron Homeostasis ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Neutrophil Infiltration ◽  
Interferon Response ◽  
Type I ◽  
E Coli

Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor (PTL). However, IUI does not invariably cause PTL. We hypothesized that quantitative and qualitative differences in immune response exist in subjects with or without PTL. To define the triggers for PTL, we developed Rhesus macaque models of IUI driven by lipopolysaccharyde (LPS) or live  E. coli . PTL did not occur in LPS challenged Rhesus macaque while  E. coli  infected animals frequently delivered preterm. Although LPS and live  E. coli  both caused immune cell infiltration,  E. coli  infected animals showed higher levels of inflammatory mediators, particularly IL6 and prostaglandins, in the chorioamnion decidua and amniotic fluid. Neutrophil infiltration in the chorion was a common feature to both LPS and  E. coli . However, neutrophilic infiltration and  IL6 and PTGS2 expression in the amnion was specifically induced by live  E. coli . RNASeq analysis of fetal membranes revealed that specific pathways involved in augmentation of inflammation including type I interferon response, chemotaxis, sumoylation and iron homeostasis were upregulated in the  E. coli group compared to the LPS group. Our data suggest that intensity of the host immune response to IUI may determine susceptibility to PTL.

scholarly journals RNA Sequencing (RNA-Seq) Based Transcriptome Analysis in Immune Response of Holstein Cattle to Killed Vaccine against Bovine Viral Diarrhea Virus Type I

Animals ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 344 ◽  
Author(s):  
Bryan Irvine Lopez ◽  
Kier Gumangan Santiago ◽  
Donghui Lee ◽  
Seungmin Ha ◽  
Kangseok Seo
Keyword(s):  
Immune Response ◽  
Enrichment Analysis ◽  
Receptor Interaction ◽  
Type I ◽  
Rna Seq ◽  
Diarrhea Virus ◽  
Viral Diarrhea ◽  
Kegg Pathways ◽  
Viral Diarrhea Virus

Immune response of 107 vaccinated Holstein cattle was initially obtained prior to the ELISA test. Five cattle with high and low bovine viral diarrhea virus (BVDV) type I antibody were identified as the final experimental animals. Blood samples from these animals were then utilized to determine significant differentially expressed genes (DEGs) using the RNA-seq transcriptome analysis and enrichment analysis. Our analysis identified 261 DEGs in cattle identified as experimental animals. Functional enrichment analysis in gene ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed the DEGs potentially induced by the inactivated BVDV type I vaccine, and might be responsible for the host immune responses. Our findings suggested that inactivated vaccine induced upregulation of genes involved in different GO annotations, including antigen processing and presentation of peptide antigen (via MHC class I), immune response, and positive regulation of interferon-gamma production. The observed downregulation of other genes involved in immune response might be due to inhibition of toll-like receptors (TLRs) by the upregulation of the Bcl-3 gene. Meanwhile, the result of KEGG pathways revealed that the majority of DEGs were upregulated and enriched to different pathways, including cytokine-cytokine receptor interaction, platelet activation, extracellular matrix (ECM) receptor interaction, hematopoietic cell lineage, and ATP-binding cassette (ABC) transporters. These significant pathways supported our initial findings and are known to play a vital role in shaping adaptive immunity against BVDV type 1. In addition, type 1 diabetes mellitus pathways tended to be significantly enriched. Thus, further studies are needed to investigate the prevalence of type 1 diabetes mellitus in cattle vaccinated with inactivated and live BVDV vaccine.

scholarly journals Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques

2019 ◽  
Vol 117 (38) ◽  
pp. 23317-23322 ◽  
Author(s):  
Joaquín Sanz ◽  
Paul L. Maurizio ◽  
Noah Snyder-Mackler ◽  
Noah D. Simons ◽  
Tawni Voyles ◽  
...  
Keyword(s):  
Gene Expression ◽  
Social Status ◽  
Social History ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Expression Patterns ◽  
Social Experience ◽  
Type I ◽  
Gene Expression Response ◽  
Expression Of Genes

Social experience is an important predictor of disease susceptibility and survival in humans and other social mammals. Chronic social stress is thought to generate a proinflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here we manipulated long-term social status in female rhesus macaques to show that social subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-κB–dependent proinflammatory pathways and lower expression of genes involved in the antiviral response and type I IFN signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-κB– and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are linked not only to social status at the time of sampling, but also to social history (i.e., past social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current social status than those who climbed the social hierarchy. Taken together, our results indicate that the effects of social status on immune cell gene expression depend on pathogen exposure, pathogen type, and social history—in support of social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.

scholarly journals Distinct Roles of Interferon Alpha and Beta in Controlling Chikungunya Virus Replication and Modulating Neutrophil-Mediated Inflammation

2019 ◽  
Vol 94 (1) ◽  
Author(s):  
Lindsey E. Cook ◽  
Marissa C. Locke ◽  
Alissa R. Young ◽  
Kristen Monte ◽  
Matthew L. Hedberg ◽  
...  
Keyword(s):  
Immune Response ◽  
Chikungunya Virus ◽  
Biological Activities ◽  
Neutrophil Infiltration ◽  
Type I Interferons ◽  
Type I ◽  
Functional Variation ◽  
Chikv Infection ◽  
Blocking Antibody ◽  
Type I Ifns

ABSTRACT Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-α-blocking antibody). Mice lacking either IFN-α or IFN-β developed severe clinical disease following infection with CHIKV, with a marked increase in foot swelling compared to wild-type mice. Virological analysis revealed that mice lacking IFN-α sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-β-KO mice displayed minimal differences in viral burdens within the ankle or at distal sites and instead had an altered cellular immune response. Mice lacking IFN-β had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-β-KO but not IRF7-KO mice mitigated musculoskeletal disease caused by CHIKV. Our findings suggest disparate roles for the IFN subtypes during CHIKV infection, with IFN-α limiting early viral replication and dissemination and IFN-β modulating neutrophil-mediated inflammation. IMPORTANCE Type I interferons (IFNs) possess a range of biological activity and protect against a number of viruses, including alphaviruses. Despite signaling through a shared receptor, there are established biochemical and functional differences among the IFN subtypes. The significance of our research is in demonstrating that IFN-α and IFN-β both have protective roles during acute chikungunya virus (CHIKV) infection but do so by distinct mechanisms. IFN-α limits CHIKV replication and dissemination, whereas IFN-β protects from CHIKV pathogenesis by limiting inflammation mediated by neutrophils. Our findings support the premise that the IFN subtypes have distinct biological activities in the antiviral response.

scholarly journals Natural Compounds of Marine Origin as Inducers of Immunogenic Cell Death (ICD): Potential Role for Cancer Interception and Therapy

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 231
Author(s):  
Clementina Sansone ◽  
Antonino Bruno ◽  
Concetta Piscitelli ◽  
Denisa Baci ◽  
Angelo Fontana ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Immune System ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Immunogenic Cell Death ◽  
Type I ◽  
Bioactive Natural Products ◽  
Signalling Molecules ◽  
Major Factors

Regulated cell death (RCD) has always been considered a tolerogenic event. Immunogenic cell death (ICD) occurs as a consequence of tumour cell death accompanied by the release of damage-associated molecular patterns (DAMPs), triggering an immune response. ICD plays a major role in stimulating the function of the immune system in cancer during chemotherapy and radiotherapy. ICD can therefore represent one of the routes to boost anticancer immune responses. According to the recommendations of the Nomenclature Committee on Cell Death (2018), apoptosis (type I cell death) and necrosis (type II cell death) represent are not the only types of RCD, which also includes necroptosis, pyroptosis, ferroptosis and others. Specific downstream signalling molecules and death-inducing stimuli can regulate distinct forms of ICD, which develop and promote the immune cell response. Dying cells deliver different potential immunogenic signals, such as DAMPs, which are able to stimulate the immune system. The acute exposure of DAMPs can prime antitumour immunity by inducing activation of antigen-presenting cells (APC), such as dendritic cells (DC), leading to the downstream response by cytotoxic T cells and natural killer cells (NK). As ICD represents an important target to direct and develop new pharmacological interventions, the identification of bioactive natural products, which are endowed with low side effects, higher tolerability and preferentially inducing immunogenic programmed cell death, represents a priority in biomedical research. The ability of ICD to drive the immune response depends on two major factors, neither of which is intrinsic to cell death: ‘Antigenicity and adjuvanticity’. Indeed, the use of natural ICD-triggering molecules, alone or in combination with different (immuno)therapies, can result in higher efficacy and tolerability. Here, we focused on natural (marine) compounds, particularly on marine microalgae derived molecules such as exopolysaccharides, sulphated polysaccharides, glycopeptides, glycolipids, phospholipids, that are endowed with ICD-inducing properties and sulfavants. Here, we discuss novel and repurposed small-molecule ICD triggers, as well as their ability to target important molecular pathways including the IL-6, TNF-α and interferons (IFNs), leading to immune stimulation, which could be used alone or in combinatorial immunotherapeutic strategies in cancer prevention and therapies.

scholarly journals Immune Response in Severe and Non-Severe Coronavirus Disease 2019 (COVID-19) Infection: A Mechanistic Landscape

2021 ◽  
Vol 12 ◽  
Author(s):  
Kavitha Mukund ◽  
Priya Nayak ◽  
Chethan Ashokkumar ◽  
Sohail Rao ◽  
Jose Almeda ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Severe Disease ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Type I ◽  
Γδt Cells ◽  
Mait Cells ◽  
Integrative Analyses ◽  
Severe Infections

The mechanisms underlying the immune remodeling and severity response in coronavirus disease 2019 (COVID-19) are yet to be fully elucidated. Our comprehensive integrative analyses of single-cell RNA sequencing (scRNAseq) data from four published studies, in patients with mild/moderate and severe infections, indicate a robust expansion and mobilization of the innate immune response and highlight mechanisms by which low-density neutrophils and megakaryocytes play a crucial role in the cross talk between lymphoid and myeloid lineages. We also document a marked reduction of several lymphoid cell types, particularly natural killer cells, mucosal-associated invariant T (MAIT) cells, and gamma-delta T (γδT) cells, and a robust expansion and extensive heterogeneity within plasmablasts, especially in severe COVID-19 patients. We confirm the changes in cellular abundances for certain immune cell types within a new patient cohort. While the cellular heterogeneity in COVID-19 extends across cells in both lineages, we consistently observe certain subsets respond more potently to interferon type I (IFN-I) and display increased cellular abundances across the spectrum of severity, as compared with healthy subjects. However, we identify these expanded subsets to have a more muted response to IFN-I within severe disease compared to non-severe disease. Our analyses further highlight an increased aggregation potential of the myeloid subsets, particularly monocytes, in COVID-19. Finally, we provide detailed mechanistic insights into the interaction between lymphoid and myeloid lineages, which contributes to the multisystemic phenotype of COVID-19, distinguishing severe from non-severe responses.

scholarly journals Synergy between Toxoplasma gondii type I ΔGRA17 immunotherapy and PD-L1 checkpoint inhibition triggers the regression of targeted and distal tumors

2021 ◽  
Vol 9 (11) ◽  
pp. e002970
Author(s):  
Yu-Chao Zhu ◽  
Hany M Elsheikha ◽  
Jian-Hua Wang ◽  
Shuai Fang ◽  
Jun-Jun He ◽  
...  
Keyword(s):  
Immune Response ◽  
Toxoplasma Gondii ◽  
Tumor Growth ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Complete Regression ◽  
Type I

BackgroundIn this study, we hypothesize that the ability of the protozoan Toxoplasma gondii to modulate immune response within the tumor might improve the therapeutic effect of immune checkpoint blockade. We examined the synergetic therapeutic activity of attenuated T. gondii RH ΔGRA17 strain and programmed death ligand-1 (PD-L1) treatment on both targeted and distal tumors in mice.MethodsThe effects of administration of T. gondii RH ΔGRA17 strain on the tumor volume and survival rate of mice bearing flank B16-F10, MC38, or LLC tumors were studied. We characterized the effects of ΔGRA17 on tumor biomarkers’ expression, PD-L1 expression, immune cells infiltrating the tumors, and expression of immune-related genes by using immunohistochemistry, immunofluorescence, flow cytometry, NanoString platform, and real-time quantitative PCR, respectively. The role of immune cells in the efficacy of ΔGRA17 plus PD-L1 blockade therapy was determined via depletion of immune cell subtypes.ResultsTreatment with T. gondii ΔGRA17 tachyzoites and anti-PD-L1 therapy significantly extended the survival of mice and suppressed tumor growth in preclinical mouse models of melanoma, Lewis lung carcinoma, and colon adenocarcinoma. Attenuation of the tumor growth was detected in the injected and distant tumors, which was associated with upregulation of innate and adaptive immune pathways. Complete regression of tumors was underpinned by late interferon-gamma-producing CD8+ cytotoxic T cells.ConclusionThe results from these models indicate that intratumoral injection of ΔGRA17 induced a systemic effect, improved mouse immune response, and sensitized immunologically ‘cold’ tumors and rendered them sensitive to immune checkpoint blockade therapy.

scholarly journals Transcriptomic analysis of bovine monocytes in response to non-cytopathic bovine viral diarrhea virus infection

2020 ◽  
Author(s):  
Yanhua HE ◽  
Jinke HE ◽  
Yajun YANG ◽  
Xin HUANG ◽  
Yunfen ZHANG ◽  
...  
Keyword(s):  
Immune Response ◽  
Bovine Viral Diarrhea Virus ◽  
Expression Profiles ◽  
Differentially Expressed Gene ◽  
Bovine Viral Diarrhea ◽  
Type I ◽  
Rna Seq ◽  
Diarrhea Virus ◽  
Viral Diarrhea ◽  
Viral Diarrhea Virus

Abstract Background: Monocytes are significant players in the detection of invading pathogens, particularly in pathogen defense. Bovine Viral Diarrhea Virus (BVDV) can cause a persistent infection and immune suppression if animals are infected with an non-cytopathic (ncp) biotype. However, its exact role in ncp BVDV1-infected bovine monocytes remains poorly understood. Results: RNA sequencing (RNA-seq) was used to investigate the effect of ncp BVDV1 infection on the transcriptional profile of bovine monocytes. Compared with the non-infected cells, 9959 and 7977 differentially expressed gene (DEGs) were identified at 2 and 24 h hpi, respectively. These DEGs were associated with signal transduction, immune response, apoptotic process, cellular process , binding and cellular component. The differential expression profiles of select the type I interferon signaling pathway , interferon (IFN)-stimulated genes (ISGs), and genes involved in the innate immune response, including IRF7, DDX3X, TLR13, DDX58(RIG-I), MVAS, TLR9, TRAF6, IRF1, IFIT1, STAT1, ISG20, TRIM25, MX1,NLRX1, CYLD, SIKE1 and ZAP70 were confirmed by real-time quantitative PCR and consistent with the RNA-seq data. Conclusion: Our transciptome anslysis provides useful initial data towards better understanding of the infection mechanisms used by ncp BVDV1, while highlighting the potential molecular relationships occurring between the virus and the host’s immune response.

scholarly journals An elastic-net logistic regression approach to generate classifiers and gene signatures for types of immune cells and T helper cell subsets

2019 ◽  
Author(s):  
Arezo Torang ◽  
Paraag Gupta ◽  
David J. Klinke
Keyword(s):  
Machine Learning ◽  
Immune Response ◽  
Immune Cell ◽  
Cell Types ◽  
Host Immune Response ◽  
T Helper Cell ◽  
Helper Cell ◽  
Rna Seq ◽  
T Helper ◽  
Gene Signatures

AbstractBackgroundHost immune response is coordinated by a variety of different specialized cell types that vary in time and location. While host immune response can be studied using conventional low-dimensional approaches, advances in transcriptomics analysis may provide a less biased view. Yet, leveraging transcriptomics data to identify immune cell subtypes presents challenges for extracting informative gene signatures hidden within a high dimensional transcriptomics space characterized by low sample numbers with noisy and missing values. To address these challenges, we explore using machine learning methods to select gene subsets and estimate gene coefficients simultaneously.ResultsElastic-net logistic regression, a type of machine learning, was used to construct separate classifiers for ten different types of immune cell and for five T helper cell subsets. The resulting classifiers were then used to develop gene signatures that best discriminate among immune cell types and T helper cell subsets using RNA-seq datasets. We validated the approach using single-cell RNA-seq (scRNA-seq) datasets, which gave consistent results. In addition, we classified cell types that were previously unannotated. Finally, we benchmarked the proposed gene signatures against other existing gene signatures.ConclusionsDeveloped classifiers can be used as priors in predicting the extent and functional orientation of the host immune response in diseases, such as cancer, where transcriptomic profiling of bulk tissue samples and single cells are routinely employed. Information that can provide insight into the mechanistic basis of disease and therapeutic response. The source code and documentation are available through GitHub: https://github.com/KlinkeLab/ImmClass2019.

scholarly journals Meta-analysis reveals consistent immune response patterns in COVID-19 infected patients at single-cell resolution

2021 ◽  
Author(s):  
Manik Garg ◽  
Xu Li ◽  
Pablo Moreno ◽  
Irene Papatheodorou ◽  
Yuelong Shu ◽  
...  
Keyword(s):  
Immune Response ◽  
Single Cell ◽  
Immune Cell ◽  
Meta Analysis ◽  
Specific Cell ◽  
Type I ◽  
Response Patterns ◽  
Healthy Control ◽  
Human Immune Response ◽  
The Individual

AbstractA number of single-cell RNA studies looking at the human immune response to the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recently published. However, the number of samples used in each individual study typically is small, moreover the technologies and protocols used in different studies vary, thus somewhat restricting the range of conclusions that can be made with high confidence. To better capture the cellular gene expression changes upon SARS-CoV-2 infection at different levels and stages of disease severity and to minimise the effect of technical artefacts, we performed meta-analysis of data from 9 previously published studies, together comprising 143 human samples, and a set of 16 healthy control samples (10X). In particular, we used generally accepted immune cell markers to discern specific cell subtypes and to look at the changes of the cell proportion over different disease stages and their consistency across the studies. While half of the observations reported in the individual studies can be confirmed across multiple studies, half of the results seem to be less conclusive. In particular, we show that the differentially expressed genes consistently point to upregulation of type I Interferon signal pathway and downregulation of the mitochondrial genes, alongside several other reproducibly consistent changes. We also confirm the presence of expanded B-cell clones in COVID-19 patients, however, no consistent trend in T-cell clonal expansion was observed.

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