scholarly journals Transplacental innate immune training via maternal microbial exposure: the XBP1-ERN1 axis in programming dendritic cell precursors

2019 ◽  
Author(s):  
Kyle T. Mincham ◽  
Anya C. Jones ◽  
Marie Bodinier ◽  
Naomi M. Scott ◽  
Jean-Francois Lauzon-Joset ◽  
...  
Keyword(s):  
Large Scale ◽  
Postnatal Period ◽  
Innate Immune ◽  
Treatment Target ◽  
Tissue Microenvironment ◽  
Enhanced Resistance ◽  
Pathogen Challenge ◽  
Immunological Homeostasis ◽  
Progenitor Compartment ◽  
Airways Inflammation

AbstractWe recently reported that the offspring of mice treated during pregnancy with the microbial-derived immunomodulator OM-85 manifest striking resistance postnatally to allergic airways inflammation, and localised the potential treatment target to the fetal cDC progenitor compartment which expands to increase the pool of precursors available at birth, enabling accelerated postnatal seeding of the lung mucosal cDC network required for establishment of immunological homeostasis in the airways. Here, we profile maternal OM-85 treatment-associated transcriptomic signatures in fetal bone marrow, and identify a series of immunometabolic pathways which provide essential metabolites for accelerated myelopoiesis, that are hallmarks of classical “immune training”. In addition, the cDC progenitor compartment displayed treatment-associated activation of the XBP1-ERN1 signalling axis which has previously been shown to be essential for tissue survival of cDC, particularly within the lung microenvironment. Our forerunner studies indicate uniquely rapid turnover of airway mucosal cDCs at baseline, with further large-scale upregulation of population dynamics during aeroallergen and/or pathogen challenge. XBP1-ERN1 signalling plays a key role in mitigation of ER stress-associated toxicity which frequently accompanies DC hyper-activation during intense immunoinflammatory responses, and we suggest that enhanced capacity for XBP1-ERN1-dependent cDC survival within the airway mucosal tissue microenvironment may be a crucial element of the OM-85-mediated transplacental “innate immune training” process which results in enhanced resistance to airway inflammatory disease during the high-risk early postnatal period.

scholarly journals Transplacental Innate Immune Training via Maternal Microbial Exposure: Role of XBP1-ERN1 Axis in Dendritic Cell Precursor Programming

2020 ◽  
Vol 11 ◽  
Author(s):  
Kyle T. Mincham ◽  
Anya C. Jones ◽  
Marie Bodinier ◽  
Naomi M. Scott ◽  
Jean-Francois Lauzon-Joset ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Large Scale ◽  
Innate Immune ◽  
Mucosal Tissue ◽  
Treatment Target ◽  
Tissue Microenvironment ◽  
Pathogen Challenge ◽  
Progenitor Compartment ◽  
Airways Inflammation

We recently reported that offspring of mice treated during pregnancy with the microbial-derived immunomodulator OM-85 manifest striking resistance to allergic airways inflammation, and localized the potential treatment target to fetal conventional dendritic cell (cDC) progenitors. Here, we profile maternal OM-85 treatment-associated transcriptomic signatures in fetal bone marrow, and identify a series of immunometabolic pathways which provide essential metabolites for accelerated myelopoiesis. Additionally, the cDC progenitor compartment displayed treatment-associated activation of the XBP1-ERN1 signalling axis which has been shown to be crucial for tissue survival of cDC, particularly within the lungs. Our forerunner studies indicate uniquely rapid turnover of airway mucosal cDCs at baseline, with further large-scale upregulation of population dynamics during aeroallergen and/or pathogen challenge. We suggest that enhanced capacity for XBP1-ERN1-dependent cDC survival within the airway mucosal tissue microenvironment may be a crucial element of OM-85-mediated transplacental innate immune training which results in postnatal resistance to airway inflammatory disease.

scholarly journals System-Based Approaches to Delineate the Antiviral Innate Immune Landscape

Viruses ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 1196
Author(s):  
Karsten Krey ◽  
Aleksandra W. Babnis ◽  
Andreas Pichlmair
Keyword(s):  
Large Scale ◽  
Innate Immune ◽  
Host Interactions ◽  
Interferon Stimulated Genes ◽  
Cellular Processes ◽  
Virus Inhibition ◽  
Cellular Factors ◽  
Functional Factors ◽  
Infected Cells ◽  
Screening Approaches

Viruses pose substantial challenges for society, economy, healthcare systems, and research. Their distinctive pathologies are based on specific interactions with cellular factors. In order to develop new antiviral treatments, it is of central importance to understand how viruses interact with their host and how infected cells react to the virus on a molecular level. Invading viruses are commonly sensed by components of the innate immune system, which is composed of a highly effective yet complex network of proteins that, in most cases, mediate efficient virus inhibition. Central to this process is the activity of interferons and other cytokines that coordinate the antiviral response. So far, numerous methods have been used to identify how viruses interact with cellular processes and revealed that the innate immune response is highly complex and involves interferon-stimulated genes and their binding partners as functional factors. Novel approaches and careful experimental design, combined with large-scale, high-throughput methods and cutting-edge analysis pipelines, have to be utilized to delineate the antiviral innate immune landscape at a global level. In this review, we describe different currently used screening approaches, how they contributed to our knowledge on virus–host interactions, and essential considerations that have to be taken into account when planning such experiments.

scholarly journals Innate Immune Defenses Induced by CpG Do Not Promote Vaccine-Induced Protection against Foot-and-Mouth Disease Virus in Pigs

2009 ◽  
Vol 16 (8) ◽  
pp. 1151-1157 ◽  
Author(s):  
M. P. Alves ◽  
L. Guzylack-Piriou ◽  
V. Juillard ◽  
J.-C. Audonnet ◽  
T. Doel ◽  
...  
Keyword(s):  
Disease Virus ◽  
Large Scale ◽  
Control Strategies ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Innate Immune ◽  
Noticeable Effect ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Natural Hosts

ABSTRACT Emergency vaccination as part of the control strategies against foot-and-mouth disease virus (FMDV) has the potential to limit virus spread and reduce large-scale culling. To reduce the time between vaccination and the onset of immunity, immunostimulatory CpG was tested for its capacity to promote early protection against FMDV challenge in pigs. To this end, CpG 2142, an efficient inducer of alpha interferon, was injected intramuscularly. Increased transcription of Mx1, OAS, and IRF-7 was identified as a sensitive measurement of CpG-induced innate immunity, with increased levels detectable to at least 4 days after injection of CpG formulated with Emulsigen. Despite this, CpG combined with an FMD vaccine did not promote protection. Pigs vaccinated 2 days before challenge had disease development, which was at least as acute as that of unvaccinated controls. All pigs vaccinated 7 days before challenge were protected without a noticeable effect of CpG. In summary, our results demonstrate the caution required when translating findings from mouse models to natural hosts of FMDV.

scholarly journals Chromosome-level de novo assembly of the pig-tailed macaque genome using linked-read sequencing and HiC proximity scaffolding

GigaScience ◽  
2020 ◽  
Vol 9 (7) ◽  
Author(s):  
Morteza Roodgar ◽  
Afshin Babveyh ◽  
Lan H Nguyen ◽  
Wenyu Zhou ◽  
Rahul Sinha ◽  
...  
Keyword(s):  
Large Scale ◽  
De Novo ◽  
Innate Immune ◽  
Human Diseases ◽  
Macaca Nemestrina ◽  
Proximity Ligation Assay ◽  
Immune Gene ◽  
Proteomics Data ◽  
Macaque Species ◽  
Chromosome Level

Abstract Background Macaque species share >93% genome homology with humans and develop many disease phenotypes similar to those of humans, making them valuable animal models for the study of human diseases (e.g., HIV and neurodegenerative diseases). However, the quality of genome assembly and annotation for several macaque species lags behind the human genome effort. Results To close this gap and enhance functional genomics approaches, we used a combination of de novo linked-read assembly and scaffolding using proximity ligation assay (HiC) to assemble the pig-tailed macaque (Macaca nemestrina) genome. This combinatorial method yielded large scaffolds at chromosome level with a scaffold N50 of 127.5 Mb; the 23 largest scaffolds covered 90% of the entire genome. This assembly revealed large-scale rearrangements between pig-tailed macaque chromosomes 7, 12, and 13 and human chromosomes 2, 14, and 15. We subsequently annotated the genome using transcriptome and proteomics data from personalized induced pluripotent stem cells derived from the same animal. Reconstruction of the evolutionary tree using whole-genome annotation and orthologous comparisons among 3 macaque species, human, and mouse genomes revealed extensive homology between human and pig-tailed macaques with regards to both pluripotent stem cell genes and innate immune gene pathways. Our results confirm that rhesus and cynomolgus macaques exhibit a closer evolutionary distance to each other than either species exhibits to humans or pig-tailed macaques. Conclusions These findings demonstrate that pig-tailed macaques can serve as an excellent animal model for the study of many human diseases particularly with regards to pluripotency and innate immune pathways.

scholarly journals Vitamin D-regulated Gene Expression Profiles: Species-specificity and Cell-specific Effects on Metabolism and Immunity

Endocrinology ◽  
2020 ◽  
Vol 162 (2) ◽  
Author(s):  
Vassil Dimitrov ◽  
Camille Barbier ◽  
Aiten Ismailova ◽  
Yifei Wang ◽  
Katy Dmowski ◽  
...  
Keyword(s):  
Vitamin D ◽  
Large Scale ◽  
Expression Profiles ◽  
Mammalian Target Of Rapamycin ◽  
Gene Expression Profiles ◽  
Innate Immune ◽  
Monocytic Cells ◽  
Specific Regulation ◽  
Regulated Gene Expression ◽  
Vitamin D Signaling

Abstract Vitamin D has pleiotropic physiological actions including immune system regulation, in addition to its classical role in calcium homeostasis. Hormonal 1,25-dihydroxyvitamin D (1,25D) signals through the nuclear vitamin D receptor, and large-scale expression profiling has provided numerous insights into its diverse physiological roles. To obtain a comprehensive picture of vitamin D signaling, we analyzed raw data from 94 (80 human, 14 mouse) expression profiles of genes regulated by 1,25D or its analogs. This identified several thousand distinct genes directly or indirectly up- or downregulated in a highly cell-specific manner in human cells using a 1.5-fold cut-off. There was significant overlap of biological processes regulated in human and mouse but minimal intersection between genes regulated in each species. Disease ontology clustering confirmed roles for 1,25D in immune homeostasis in several human cell types, and analysis of canonical pathways revealed novel and cell-specific roles of vitamin D in innate immunity. This included cell-specific regulation of several components of Nucleotide-binding Oligomerization Domain-like (NOD-like) pattern recognition receptor signaling, and metabolic events controlling innate immune responses. Notably, 1,25D selectively enhanced catabolism of branched-chain amino acids (BCAAs) in monocytic cells. BCAA levels regulate the major metabolic kinase mammalian Target of Rapamycin (mTOR), and pretreatment with 1,25D suppressed BCAA-dependent activation of mTOR signaling. Furthermore, ablation of BCAT1 expression in monocytic cells blocked 1,25D-induced increases in autophagy marker LAMP1. In conclusion, the data generated represents a powerful tool to further understand the diverse physiological roles of vitamin D signaling and provides multiple insights into mechanisms of innate immune regulation by 1,25D.

scholarly journals Administration of a Postbiotic Causes Immunomodulatory Responses in Broiler Gut and Reduces Disease Pathogenesis Following Challenge

2019 ◽  
Vol 7 (8) ◽  
pp. 268 ◽  
Author(s):  
Casey N. Johnson ◽  
Michael H. Kogut ◽  
Kenneth Genovese ◽  
Haiqi He ◽  
Steve Kazemi ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune ◽  
Necrotic Enteritis ◽  
Peptide Array ◽  
Performance Measurements ◽  
Disease Pathogenesis ◽  
Promising Alternative ◽  
Positive Effects ◽  
Pathogen Challenge ◽  
Proinflammatory Responses

With the reemergence of poultry diseases such as necrotic enteritis following the restriction of in-feed antibiotics, the search for antibiotic alternatives has become critically important. Postbiotics are non-viable bacterial products or metabolic byproducts from probiotic microorganisms that have positive effects on the host or microbiota. These are a promising alternative to antibiotics. Here, we describe the mechanism of action of a postbiotic in the context of a Clostridium perfringens (C. perfringens) challenge model. By using performance measurements and a peptide array kinome analysis, we describe the kinotypes and signal transduction changes elicited by the postbiotic with and without C. perfringens challenge. The postbiotic improves lesion scores, C. perfringens counts and mortality compared to challenge groups without the postbiotic, and it improves weight gain in the most severely challenged birds. The postbiotic predominantly affects the innate immune response and appears immunomodulatory. In the context of infection, it reduces the proinflammatory responses and generates a homeostatic-like response. This postbiotic is a viable alternative to antibiotics to improve poultry health in the context of C. perfringens pathogen challenge.

scholarly journals Stimulus-selective crosstalk via the NF-κB signaling system reinforces innate immune response to alleviate gut infection

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Balaji Banoth ◽  
Budhaditya Chatterjee ◽  
Bharath Vijayaragavan ◽  
MVR Prasad ◽  
Payel Roy ◽  
...  
Keyword(s):  
Feedback Loop ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Important Determinant ◽  
Innate Immune ◽  
Signal Integration ◽  
Signaling System ◽  
Gene Expressions ◽  
Tissue Microenvironment ◽  
Β Receptor

Tissue microenvironment functions as an important determinant of the inflammatory response elicited by the resident cells. Yet, the underlying molecular mechanisms remain obscure. Our systems-level analyses identified a duration code that instructs stimulus specific crosstalk between TLR4-activated canonical NF-κB pathway and lymphotoxin-β receptor (LTβR) induced non-canonical NF-κB signaling. Indeed, LTβR costimulation synergistically enhanced the late RelA/NF-κB response to TLR4 prolonging NF-κB target gene-expressions. Concomitant LTβR signal targeted TLR4-induced newly synthesized p100, encoded by Nfkb2, for processing into p52 that not only neutralized p100 mediated inhibitions, but potently generated RelA:p52/NF-κB activity in a positive feedback loop. Finally, Nfkb2 connected lymphotoxin signal within the intestinal niche in reinforcing epithelial innate inflammatory RelA/NF-κB response to Citrobacter rodentium infection, while Nfkb2−/− mice succumbed to gut infections owing to stromal defects. In sum, our results suggest that signal integration via the pleiotropic NF-κB system enables tissue microenvironment derived cues in calibrating physiological responses.

scholarly journals Infectious diseases of marine molluscs and host responses as revealed by genomic tools

2016 ◽  
Vol 371 (1689) ◽  
pp. 20150206 ◽  
Author(s):  
Ximing Guo ◽  
Susan E. Ford
Keyword(s):  
Infectious Diseases ◽  
Large Scale ◽  
Environmental Changes ◽  
Gene Families ◽  
Eastern Oyster ◽  
Innate Immune ◽  
Host Responses ◽  
Host Immune System ◽  
Marine Molluscs ◽  
Ostreid Herpesvirus 1

More and more infectious diseases affect marine molluscs. Some diseases have impacted commercial species including MSX and Dermo of the eastern oyster, QPX of hard clams, withering syndrome of abalone and ostreid herpesvirus 1 (OsHV-1) infections of many molluscs. Although the exact transmission mechanisms are not well understood, human activities and associated environmental changes often correlate with increased disease prevalence. For instance, hatcheries and large-scale aquaculture create high host densities, which, along with increasing ocean temperature, might have contributed to OsHV-1 epizootics in scallops and oysters. A key to understanding linkages between the environment and disease is to understand how the environment affects the host immune system. Although we might be tempted to downplay the role of immunity in invertebrates, recent advances in genomics have provided insights into host and parasite genomes and revealed surprisingly sophisticated innate immune systems in molluscs. All major innate immune pathways are found in molluscs with many immune receptors, regulators and effectors expanded. The expanded gene families provide great diversity and complexity in innate immune response, which may be key to mollusc's defence against diverse pathogens in the absence of adaptive immunity. Further advances in host and parasite genomics should improve our understanding of genetic variation in parasite virulence and host disease resistance.

scholarly journals Octopaminergic Signaling Mediates Neural Regulation of Innate Immunity in Caenorhabditis elegans

mBio ◽  
2018 ◽  
Vol 9 (5) ◽  
Author(s):  
Durai Sellegounder ◽  
Chung-Hsiang Yuan ◽  
Phillip Wibisono ◽  
Yiyong Liu ◽  
Jingru Sun
Keyword(s):  
Innate Immunity ◽  
Nervous System ◽  
Caenorhabditis Elegans ◽  
Immune Responses ◽  
Human Health ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Pathogen Infection ◽  
Content Type ◽  
Immunological Homeostasis

ABSTRACT Upon pathogen infection, the nervous system regulates innate immunity to confer coordinated protection to the host. However, the precise mechanisms of such regulation remain unclear. Previous studies have demonstrated that OCTR-1, a putative G protein-coupled receptor for catecholamine, functions in the sensory neurons designated “ASH” to suppress innate immune responses in Caenorhabditis elegans. It is unknown what molecules act as OCTR-1 ligands in the neural immune regulatory circuit. Here we identify neurotransmitter octopamine (OA) as an endogenous ligand for OCTR-1 in immune regulation and show that the OA-producing RIC neurons function in the OCTR-1 neural circuit to suppress innate immunity. RIC neurons are deactivated in the presence of pathogens but transiently activated by nonpathogenic bacteria. Our data support a model whereby an octopaminergic immunoinhibitory pathway is tonically active under normal conditions to maintain immunological homeostasis or suppress unwanted innate immune responses but downregulated upon pathogen infection to allow enhanced innate immunity. As excessive innate immune responses have been linked to a myriad of human health concerns, our study could potentially benefit the development of more-effective treatments for innate immune disorders. IMPORTANCE Insufficient or excessive immune responses to pathogen infection are major causes of disease. Increasing evidence indicates that the nervous system regulates the immune system to help maintain immunological homeostasis. However, the precise mechanisms of this regulation are largely unknown. Here we show the existence of an octopaminergic immunoinhibitory pathway in Caenorhabditis elegans. Our study results indicate that this pathway is tonically active under normal conditions to maintain immunological homeostasis or suppress unwanted innate immune responses but downregulated upon pathogen infection to allow enhanced innate immunity. As excessive innate immune responses have been linked to human health conditions such as Crohn's disease, rheumatoid arthritis, atherosclerosis, diabetes, and Alzheimer's disease, elucidating octopaminergic neural regulation of innate immunity could be helpful in the development of new treatments for innate immune diseases.

scholarly journals Functional Antibodies in COVID-19 Convalescent Plasma

2021 ◽  
Author(s):  
Jonathan D. Herman ◽  
Chuangqi Wang ◽  
Carolin Loos ◽  
Hyunah Yoon ◽  
Johanna Rivera ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Large Scale ◽  
Therapeutic Benefit ◽  
Innate Immune ◽  
Therapeutic Interventions ◽  
Effective Vaccine ◽  
Immunomodulatory Effects ◽  
Specific Igg ◽  
Functional Antibodies ◽  
Prevailing View

AbstractIn the absence of an effective vaccine or monoclonal therapeutic, transfer of convalescent plasma (CCP) was proposed early in the SARS-CoV-2 pandemic as an easily accessible therapy. However, despite the global excitement around this historically valuable therapeutic approach, results from CCP trials have been mixed and highly debated. Unlike other therapeutic interventions, CCP represents a heterogeneous drug. Each CCP unit is unique and collected from an individual recovered COVID-19 patient, making the interpretation of therapeutic benefit more complicated. While the prevailing view in the field would suggest that it is administration of neutralizing antibodies via CCP that centrally provides therapeutic benefit to newly infected COVID-19 patients, many hospitalized COVID-19 patients already possess neutralizing antibodies. Importantly, the therapeutic benefit of antibodies can extend far beyond their simple ability to bind and block infection, especially related to their ability to interact with the innate immune system. In our work we deeply profiled the SARS-CoV-2-specific Fc-response in CCP donors, along with the recipients prior to and after CCP transfer, revealing striking SARS-CoV-2 specific Fc-heterogeneity across CCP units and their recipients. However, CCP units possessed more functional antibodies than acute COVID-19 patients, that shaped the evolution of COVID-19 patient humoral profiles via distinct immunomodulatory effects that varied by pre-existing SARS-CoV-2 Spike (S)-specific IgG titers in the patients. Our analysis identified surprising influence of both S and Nucleocapsid (N) specific antibody functions not only in direct antiviral activity but also in anti-inflammatory effects. These findings offer insights for more comprehensive interpretation of correlates of immunity in ongoing large scale CCP trials and for the design of next generation therapeutic design.

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