scholarly journals Reverse Genetics System for Shuni Virus, an Emerging Orthobunyavirus with Zoonotic Potential

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 455
Author(s):  
Judith Oymans ◽  
Paul J. Wichgers Schreur ◽  
Sophie van Oort ◽  
Rianka Vloet ◽  
Marietjie Venter ◽  
...  
Keyword(s):  
Immune Responses ◽  
Neurological Disease ◽  
Western Europe ◽  
Reverse Genetics ◽  
Molecular Mechanisms ◽  
Severe Disease ◽  
Innate Immune ◽  
Zoonotic Potential ◽  
Innate Immune Responses ◽  
North Western

The genus Orthobunyavirus (family Peribunyaviridae, order Bunyavirales) comprises over 170 named mosquito- and midge-borne viruses, several of which cause severe disease in animals or humans. Their three-segmented genomes enable reassortment with related viruses, which may result in novel viruses with altered host or tissue tropism and virulence. One such reassortant, Schmallenberg virus (SBV), emerged in north-western Europe in 2011. Shuni virus (SHUV) is an orthobunyavirus related to SBV that is associated with neurological disease in horses in southern Africa and recently caused an outbreak manifesting with neurological disease and birth defects among ruminants in Israel. The zoonotic potential of SHUV was recently underscored by its association with neurological disease in humans. We here report a reverse genetics system for SHUV and provide first evidence that the non-structural (NSs) protein of SHUV functions as an antagonist of host innate immune responses. We furthermore report the rescue of a reassortant containing the L and S segments of SBV and the M segment of SHUV. This novel reverse genetics system can now be used to study SHUV virulence and tropism, and to elucidate the molecular mechanisms that drive reassortment events.

scholarly journals MicroRNAs from Snellenius manilae bracovirus regulate innate and cellular immune responses of its host Spodoptera litura

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Cheng-Kang Tang ◽  
Chih-Hsuan Tsai ◽  
Carol-P. Wu ◽  
Yu-Hsien Lin ◽  
Sung-Chan Wei ◽  
...  
Keyword(s):  
Immune Responses ◽  
Spodoptera Litura ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Sequencing Analysis ◽  
Innate Immune Responses ◽  
Cellular Immune Responses ◽  
Next Generation Sequencing Analysis ◽  
Cellular Immune ◽  
Generation Sequencing

AbstractTo avoid inducing immune and physiological responses in insect hosts, parasitoid wasps have developed several mechanisms to inhibit them during parasitism, including the production of venom, specialized wasp cells, and symbioses with polydnaviruses (PDVs). These mechanisms alter the host physiology to give the wasp offspring a greater chance of survival. However, the molecular mechanisms for most of these alterations remain unclear. In the present study, we applied next-generation sequencing analysis and identified several miRNAs that were encoded in the genome of Snellenius manilae bracovirus (SmBV), and expressed in the host larvae, Spodoptera litura, during parasitism. Among these miRNAs, SmBV-miR-199b-5p and SmBV-miR-2989 were found to target domeless and toll-7 in the host, which are involved in the host innate immune responses. Microinjecting the inhibitors of these two miRNAs into parasitized S. litura larvae not only severely decreased the pupation rate of Snellenius manilae, but also restored the phagocytosis and encapsulation activity of the hemocytes. The results demonstrate that these two SmBV-encoded miRNAs play an important role in suppressing the immune responses of parasitized hosts. Overall, our study uncovers the functions of two SmBV-encoded miRNAs in regulating the host innate immune responses upon wasp parasitism.

scholarly journals N-dihydrogalactochitosan reduces mortality in a lethal mouse model of SARS-CoV-2

2021 ◽  
Author(s):  
Christopher M Weiss ◽  
Hongwei Liu ◽  
Erin E Ball ◽  
Samuel Lam ◽  
Tomas Hode ◽  
...  
Keyword(s):  
Immune Responses ◽  
Infectious Virus ◽  
Severe Disease ◽  
Upper Airway ◽  
Innate Immune ◽  
Morbidity And Mortality ◽  
Vaccine Hesitancy ◽  
Innate Immune Responses ◽  
Before And After ◽  
Rapid Emergence

The rapid emergence and global dissemination of SARS-CoV-2 that causes COVID-19 continues to cause an unprecedented global health burden resulting in more than 4 million deaths in the 20 months since the virus was discovered. While multiple vaccine countermeasures have been approved for emergency use, additional treatments are still needed due to sluggish vaccine rollout and vaccine hesitancy. Immunoadjuvant compounds delivered intranasally can guide non-specific innate immune responses during the critical early stages of viral replication, reducing morbidity and mortality. N-dihydrogalactochitosan (GC) is a novel mucoadhesive immunostimulatory polymer of β-0-4-linked N-acetylglucosamine that is solubilized by the conjugation of galactose glycans. We tested GC as a potential countermeasure for COVID-19. GC administered intranasally before and after SARS-CoV-2 exposure diminished morbidity and mortality in humanized ACE2 receptor expressing mice by up to 75% and reduced infectious virus levels in the upper airway and lungs. Our findings demonstrate a new application for soluble immunoadjuvants like GC for preventing severe disease associated with SARS-CoV-2.

scholarly journals Integrative Transcriptomics Reveals Activation of Innate Immune Responses and Inhibition of Inflammation During Oral Immunotherapy for Egg Allergy in Children

2021 ◽  
Vol 12 ◽  
Author(s):  
Piia Karisola ◽  
Kati Palosuo ◽  
Victoria Hinkkanen ◽  
Lukas Wisgrill ◽  
Terhi Savinko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Outcome ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Oral Immunotherapy ◽  
Innate Immune ◽  
Egg Allergy ◽  
Innate Immune Responses ◽  
Open Label

We previously reported the results of a randomized, open-label trial of egg oral immunotherapy (OIT) in 50 children where 44% were desensitized and 46% were partially desensitized after 8 months of treatment. Here we focus on cell-mediated molecular mechanisms driving desensitization during egg OIT. We sought to determine whether changes in genome-wide gene expression in blood cells during egg OIT correlate with humoral responses and the clinical outcome. The blood cell transcriptome of 50 children receiving egg OIT was profiled using peripheral blood mononuclear cell (PBMC) samples obtained at baseline and after 3 and 8 months of OIT. We identified 467 differentially expressed genes (DEGs) after 3 or 8 months of egg OIT. At 8 months, 86% of the DEGs were downregulated and played a role in the signaling of TREM1, IL-6, and IL-17. In correlation analyses, Gal d 1–4-specific IgG4 antibodies associated positively with DEGs playing a role in pathogen recognition and antigen presentation and negatively with DEGs playing a role in the signaling of IL-10, IL-6, and IL-17. Desensitized and partially desensitized patients had differences in their antibody responses, and although most of the transcriptomic changes were shared, both groups had also specific patterns, which suggest slower changes in partially desensitized and activation of NK cells in the desensitized group. OIT for egg allergy in children inhibits inflammation and activates innate immune responses regardless of the clinical outcome at 8 months. Changes in gene expression patterns first appear as posttranslational protein modifications, followed by more sustained epigenetic gene regulatory functions related to successful desensitization.

scholarly journals Mycobacterium tuberculosisinhibits human innate immune responses via the production of TLR2 antagonist glycolipids

2017 ◽  
Vol 114 (42) ◽  
pp. 11205-11210 ◽  
Author(s):  
Landry Blanc ◽  
Martine Gilleron ◽  
Jacques Prandi ◽  
Ok-ryul Song ◽  
Mi-Seon Jang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Cell Envelope ◽  
Costimulatory Molecule ◽  
Immune Defense ◽  
Innate Immune ◽  
Host Cells ◽  
Innate Immune Responses ◽  
Reporter System

Mycobacterium tuberculosisis a major human pathogen that is able to survive inside host cells and resist immune clearance. Most particularly, it inhibits several arms of the innate immune response, including phagosome maturation or cytokine production. To better understand the molecular mechanisms by whichM. tuberculosiscircumvents host immune defenses, we used a transposon mutant library generated in a virulent clinical isolate ofM. tuberculosisof the W/Beijing family to infect human macrophages, utilizing a cell line derivative of THP-1 cells expressing a reporter system for activation of the transcription factor NF-κB, a key regulator of innate immunity. We identified severalM. tuberculosismutants inducing a NF-κB activation stronger than that of the wild-type strain. One of these mutants was found to be deficient for the synthesis of cell envelope glycolipids, namely sulfoglycolipids, suggesting that the latter can interfere with innate immune responses. Using natural and synthetic molecular variants, we determined that sulfoglycolipids inhibit NF-κB activation and subsequent cytokine production or costimulatory molecule expression by acting as competitive antagonists of Toll-like receptor 2, thereby inhibiting the recognition ofM. tuberculosisby this receptor. Our study reveals that producing glycolipid antagonists of pattern recognition receptors is a strategy used byM. tuberculosisto undermine innate immune defense. Sulfoglycolipids are major and specific lipids ofM. tuberculosis, considered for decades as virulence factors of the bacilli. Our study uncovers a mechanism by which they may contribute toM. tuberculosisvirulence.

scholarly journals Differential Modulation of Innate Immune Responses in Human Primary Cells by Influenza A Viruses Carrying Human or Avian Nonstructural Protein 1

2019 ◽  
Vol 94 (1) ◽  
Author(s):  
Paula L. Monteagudo ◽  
Raquel Muñoz-Moreno ◽  
Miguel Fribourg ◽  
Uma Potla ◽  
Ignacio Mena ◽  
...  
Keyword(s):  
Immune Responses ◽  
Influenza A ◽  
Nonstructural Protein ◽  
Severe Disease ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Influenza A Viruses ◽  
Recombinant Viruses ◽  
Nonstructural Protein 1 ◽  
Human Primary Cells

ABSTRACT The influenza A virus (IAV) nonstructural protein 1 (NS1) contributes to disease pathogenesis through the inhibition of host innate immune responses. Dendritic cells (DCs) release interferons (IFNs) and proinflammatory cytokines and promote adaptive immunity upon viral infection. In order to characterize the strain-specific effects of IAV NS1 on human DC activation, we infected human DCs with a panel of recombinant viruses with the same backbone (A/Puerto Rico/08/1934) expressing different NS1 proteins from human and avian origin. We found that these viruses induced a clearly distinct phenotype in DCs. Specifically, viruses expressing NS1 from human IAV (either H1N1 or H3N2) induced higher levels of expression of type I (IFN-α and IFN-β) and type III (IFN-λ1 to IFNλ3) IFNs than viruses expressing avian IAV NS1 proteins (H5N1, H7N9, and H7N2), but the differences observed in the expression levels of proinflammatory cytokines like tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6) were not significant. In addition, using imaging flow cytometry, we found that human and avian NS1 proteins segregate based on their subcellular trafficking dynamics, which might be associated with the different innate immune profile induced in DCs by viruses expressing those NS1 proteins. Innate immune responses induced by our panel of IAV recombinant viruses were also characterized in normal human bronchial epithelial cells, and the results were consistent with those in DCs. Altogether, our results reveal an increased ability of NS1 from avian viruses to antagonize innate immune responses in human primary cells compared to the ability of NS1 from human viruses, which could contribute to the severe disease induced by avian IAV in humans. IMPORTANCE Influenza A viruses (IAVs) cause seasonal epidemics which result in an important health and economic burden. Wild aquatic birds are the natural host of IAV. However, IAV can infect diverse hosts, including humans, domestic poultry, pigs, and others. IAVs circulating in animals occasionally cross the species barrier, infecting humans, which results in mild to very severe disease. In some cases, these viruses can acquire the ability to be transmitted among humans and initiate a pandemic. The nonstructural 1 (NS1) protein of IAV is an important antagonist of the innate immune response. In this study, using recombinant viruses and primary human cells, we show that NS1 proteins from human and avian hosts show intrinsic differences in the modulation of the innate immunity in human dendritic cells and epithelial cells, as well as different cellular localization dynamics in infected cells.

scholarly journals NOD1-Mediated Mucosal Host Defense againstHelicobacter pylori

2010 ◽  
Vol 2010 ◽  
pp. 1-6 ◽  
Author(s):  
Tomohiro Watanabe ◽  
Naoki Asano ◽  
Atsushi Kitani ◽  
Ivan J. Fuss ◽  
Tsutomu Chiba ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Immune Responses ◽  
Host Defense ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Gastric Epithelial Cells ◽  
Innate Immune Responses ◽  
Cytokines And Chemokines ◽  
H Pylori ◽  
Oligomerization Domain

Infection of the stomach withHelicobacter pyloriis an important risk factor for gastritis, peptic ulcer, and gastric carcinoma. Although it has been well established that persistent colonization byH. pyloriis associated with adaptive Th1 responses, the innate immune responses leading to these Th1 responses are poorly defined. Recent studies have shown that the activation of nucleotide-binding oligomerization domain 1 (NOD1) in gastric epithelial cells plays an important role in innate immune responses againstH. pylori. The detection ofH. pylori-derived ligands by cytosolic NOD1 induces several host defense factors, including antimicrobial peptides, cytokines, and chemokines. In this paper, we review the molecular mechanisms by which NOD1 contributes to mucosal host defense againstH. pyloriinfection of the stomach.

Stimulation of innate immune responses by malarial glycosylphosphatidylinositol via pattern recognition receptors

Parasitology ◽  
2005 ◽  
Vol 130 (S1) ◽  
pp. S45-S62 ◽  
Author(s):  
T. NEBL ◽  
M. J. DE VEER ◽  
L. SCHOFIELD
Keyword(s):  
Pattern Recognition ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Severe Disease ◽  
Pattern Recognition Receptors ◽  
Innate Immune ◽  
Proinflammatory Responses ◽  
Cellular Immune

The glycosylphosphatidylinositol (GPI) anchor ofPlasmodium falciparumis thought to function as a critical toxin that contributes to severe malarial pathogenesis by eliciting the production of proinflammatory responses by the innate immune system of mammalian hosts. Analysis of the fine structure ofP. falciparumGPI suggests a requirement for the presence of both core glycan and lipid moieties in the recognition and signalling of parasite glycolipids by host immune cells. It has been demonstrated that GPI anchors of various parasitic protozoa can mediate cellular immune responses via members of the Toll-like family of pattern recognition receptors (TLRs). Recent studies indicate that GPI anchors ofP. falciparumand other protozoa are preferentially recognized by TLR-2, involving the MyD88-dependent activation of specific signalling pathways that mediate the production of proinflammatory cytokines and nitric oxide from host macrophagesin vitro. However, the contribution of malaria GPI toxin to severe disease syndromes and the role of specific TLRs or other pattern recognition receptors in innate immunityin vivois only just beginning to be characterized. A better understanding of the molecular mechanisms underlying severe malarial pathogenesis may yet lead to substantial new insights with important implications for the development of novel therapeutics for malaria treatment.

Coagulation and innate immune responses: can we view them separately?

Blood ◽  
2009 ◽  
Vol 114 (12) ◽  
pp. 2367-2374 ◽  
Author(s):  
Mieke Delvaeye ◽  
Edward M. Conway
Keyword(s):  
Immune Responses ◽  
Defense Mechanisms ◽  
Horseshoe Crab ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Living Fossil ◽  
Potential Impact ◽  
Hemostatic Disorders ◽  
New Strategies

Abstract The horseshoe crab is often referred to as a “living fossil,” representative of the oldest classes of arthropods, almost identical to species in existence more than 500 million years ago. Comparative analyses of the defense mechanisms used by the horseshoe crab that allowed it to survive mostly unchanged throughout the millennia reveal a common ancestry of the coagulation and innate immune systems that are totally integrated—indeed, almost inseparable. In human biology, we traditionally view the hemostatic pathways and those regulating innate immune responses to infections and tissue damage as entirely separate entities. But are they? The last couple of decades have revealed a remarkable degree of interplay between these systems, and the linking cellular and molecular mechanisms are rapidly being delineated. In this review, we present some of the major points of intersection between coagulation and innate immunity. We attempt to highlight the potential impact of these findings by identifying recently established paradigms that will hopefully result in the emergence of new strategies to treat a range of inflammatory and hemostatic disorders.

scholarly journals Mitochondria: powering the innate immune response to Mycobacterium tuberculosis infection

2021 ◽  
Author(s):  
Kristin L. Patrick ◽  
Robert O. Watson
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Bacterial Pathogen ◽  
Tuberculosis Patient ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Type I ◽  
Innate Immune Responses ◽  
Mycobacterium Tuberculosis Infection

Within the last decade, we have learned that damaged mitochondria activate many of the same innate immune pathways that evolved to sense and respond to intracellular pathogens. These shared responses include cytosolic nucleic acid sensing and type I interferon (IFN) expression, inflammasome activation that leads to pyroptosis, and selective autophagy (called mitophagy when mitochondria are the cargo). Because mitochondria were once bacteria, parallels between how cells respond to mitochondrial and bacterial ligands are not altogether surprising. However, the potential for crosstalk or synergy between bacteria- and mitochondria-driven innate immune responses during infection remains poorly understood. This interplay is particularly striking—and intriguing—in the context of infection with the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb). Multiple studies point to a role for Mtb infection and/or specific Mtb virulence factors in disrupting the mitochondrial network in macrophages leading to metabolic changes and triggering potent innate immune responses. Research from our labs and others argues that mutations in mitochondrial genes can exacerbate mycobacterial disease severity by hyper-activating innate responses or activating them at the wrong time. Indeed, growing evidence supports a model whereby different mitochondrial defects or mutations alter Mtb infection outcomes in distinct ways. By synthesizing the current literature in this minireview, we hope to gain insight into the molecular mechanisms driving, and consequences of, mitochondrial-dependent immune polarization so that we might better predict tuberculosis patient outcomes and develop host-directed therapeutics designed to correct these imbalances.

scholarly journals The role of mitophagy in innate immune responses triggered by mitochondrial stress

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Yinjuan Song ◽  
Yang Zhou ◽  
Xiangmei Zhou
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Immune Evasion ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Acid Oxidation ◽  
Innate Immune Responses ◽  
Mitochondrial Stress ◽  
Cellular Organelles

Abstract Mitochondria are important cellular organelles involved in many different functions, from energy generation and fatty acid oxidation to cell death regulation and immune responses. Accumulating evidence indicates that mitochondrial stress acts as a key trigger of innate immune responses. Critically, the dysfunctional mitochondria can be selectively eliminated by mitophagy. The elimination of dysfunctional mitochondria may function as an effective way employed by mitophagy to keep the immune system in check. In addition, mitophagy can be utilized by pathogens for immune evasion. In this review, we summarize how mitochondrial stress triggers innate immune responses and the roles of mitophagy in innate immunity and in infection, as well as the molecular mechanisms of mitophagy. Graphical abstract

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