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

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.

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.704633 ◽

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.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1707840114 ◽

2017 ◽

Vol 114 (42) ◽

pp. 11205-11210 ◽

Cited By ~ 33

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.

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Roles of Shiga Toxins in Immunopathology

Toxins ◽

10.3390/toxins11040212 ◽

2019 ◽

Vol 11 (4) ◽

pp. 212 ◽

Cited By ~ 17

Author(s):

Moo-Seung Lee ◽

Vernon Tesh

Keyword(s):

Immune Responses ◽

Stress Responses ◽

Innate Immune ◽

Organ Injury ◽

Innate Immune Responses ◽

Shiga Toxins ◽

Shigella Species ◽

Lethal Complications ◽

Uremic Syndrome ◽

Cellular Immune

Shigella species and Shiga toxin-producing Escherichia coli (STEC) are agents of bloody diarrhea that may progress to potentially lethal complications such as diarrhea-associated hemolytic uremic syndrome (D+HUS) and neurological disorders. The bacteria share the ability to produce virulence factors called Shiga toxins (Stxs). Research over the past two decades has identified Stxs as multifunctional toxins capable of inducing cell stress responses in addition to their canonical ribotoxic function inhibiting protein synthesis. Notably, Stxs are not only potent inducers of cell death, but also activate innate immune responses that may lead to inflammation, and these effects may increase the severity of organ injury in patients infected with Stx-producing bacteria. In the intestines, kidneys, and central nervous system, excessive or uncontrolled host innate and cellular immune responses triggered by Stxs may result in sensitization of cells to toxin mediated damage, leading to immunopathology and increased morbidity and mortality in animal models (including primates) and human patients. Here, we review studies describing Stx-induced innate immune responses that may be associated with tissue damage, inflammation, and complement activation. We speculate on how these processes may contribute to immunopathological responses to the toxins.

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Induction of the Type I IFN Response by Human Metapneumovirus Lacking SH, G, or M2.2 Expression

Proceedings ◽

10.3390/proceedings2020050143 ◽

2020 ◽

Vol 50 (1) ◽

pp. 143

Author(s):

Kevin Groen ◽

Stefan van Nieuwkoop ◽

Ron Fouchier ◽

Bernadette van den Hoogen

Keyword(s):

Immune Response ◽

Next Generation Sequencing ◽

Immune Responses ◽

A549 Cells ◽

Innate Immune ◽

Innate Immune Responses ◽

Phenotypic Analysis ◽

Hmpv Infection ◽

Generation Sequencing

The human metapneumovirus (HMPV), a member of the Pneumoviridae family, is a major cause of respiratory illness, primarily in young children, the elderly, and immunocompromised individuals. Having a fundamental understanding of the viral evasion of innate immune responses is crucial for the rational design of antiviral therapies. Several studies have reported on how HMPV subverts innate immune responses, with roles for SH, G, and M2.2 proteins. However, these studies often conflict. It has also been reported that eliminating the M2.2 ORF results in insertions and deletions around the M2.2 ORF, which could result in an M2.2-independent interaction with the immune system. We aimed to investigate how HMPV interacts with the innate immune response. Therefore, recombinant viruses lacking M2.2, SH, or G protein expression were generated either by deletion or by ablation of protein expression through mutations. Phenotypic analysis revealed that viruses lacking M2.2 expression are attenuated on interferon-competent A549 cells, but not on interferon-deficient cells. Deletion of ORFs compared to ablation of expression through mutations did not result in differences in replication kinetics. Viruses lacking M2.2 expression induced interferon-ẞ protein production, indicating interferon-antagonistic functions of the M2.2 protein, as previously reported. Phenotypic analysis of A549 cells knocked out for RIG-I, MAVS, and PKR revealed the role of RIG-I in the immune response towards HMPV. Next-generation sequencing analysis of viruses lacking M2.2 expression but not G or SH expression showed hypermutation throughout the virus genome. The hypermutation patterns suggest a role for adenosine deaminase acting on RNA (ADAR) editing. We addressed the question of whether RIG-I activation by viruses lacking M2.2 expression is due to hypermutated genomes or the absence of M2.2 as an interferon antagonist. Additionally, we investigated the role of ADAR in HMPV infection. We present our data on the possible influence of ADAR in HMPV infection by next-generation sequencing of viral stocks in cell knockdowns of ADAR generated by CRISPR-interference.

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NOD1-Mediated Mucosal Host Defense againstHelicobacter pylori

International Journal of Inflammation ◽

10.4061/2010/476482 ◽

2010 ◽

Vol 2010 ◽

pp. 1-6 ◽

Cited By ~ 13

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.

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SpyCatcher-SpyTagged ApxIA Toxoid and the Immune-Modulating Yeast Ghost Shells

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2020.2992 ◽

2020 ◽

Vol 16 (11) ◽

pp. 1644-1657

Author(s):

Seonhyung Lee ◽

Beom-Ku Han ◽

Yang-Hoon Kim ◽

Ji-Young Ahn

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Mass Spectrometry Analysis ◽

Cytotoxic Activities ◽

Raw 264.7 Macrophages ◽

Spectrometry Analysis ◽

Cellular Immune Responses ◽

Histocompatibility Complex ◽

Tnf Α ◽

Cellular Immune

Actinobacillus pleuropneumoniaesecretes the hemolytic cytotoxins ApxI, ApxII, ApxIII, and ApxIV, which cause pleurop- neumonia in swine. Of these, ApxI is the most toxic. ApxIA, a repeats-in-toxin toxin-like protein, has strong hemolytic and cytotoxic activities. This study aimed to develop an immune modulator ApxIA toxoid, with a Spytag/Spycatcher pair (SC::ST pair), in yeast ghost shells (YGSs). These YGSs were utilized as ApxIA toxoid delivery platforms for -glucan components that can be recognized by the innate immune system. The SC::ST pair was used to conjugate the ApxIA toxoid to YGSs. The YGS-SC::ST-ToxApxIA was successfully phagocytosed by RAW 264.7 macrophages cells, without any toxicity. Further investigation revealed that YGS-SC::ST-ToxApxIA led to defective immune responses, in addition to increased levels of cytokines IL-1β, TNF-α, and IL-10. A membrane proteomic analysis, to determine preferential major histocompatibility complex binding of ApxIA-derived peptides, was performed and four ApxIA peptides were successfully identified by liquid chromatography with tandem mass spectrometry analysis. The identified peptides may serve as poten- tial vaccine candidates in immunobiology studies of A. pleuropneumoniae. Our results indicate that YGS-SC::ST-ToxApxIA can prevent A. pleuropneumoniae pleuropneumonia (APP) by inducing both humoral and cellular immune responses.

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

Viruses ◽

10.3390/v12040455 ◽

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.

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

Parasitology ◽

10.1017/s0031182005008152 ◽

2005 ◽

Vol 130 (S1) ◽

pp. S45-S62 ◽

Cited By ~ 63

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.

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Mosquito Phenoloxidase and Defensin Colocalize in Melanization Innate Immune Responses

Journal of Histochemistry & Cytochemistry ◽

10.1369/jhc.4a6564.2005 ◽

2005 ◽

Vol 53 (6) ◽

pp. 689-698 ◽

Cited By ~ 25

Author(s):

Julián F. Hillyer ◽

Bruce M. Christensen

Keyword(s):

Immune Responses ◽

Micrococcus Luteus ◽

Innate Immune ◽

Innate Immune Responses ◽

Melanin Biosynthesis ◽

Immune Reactions ◽

Transmission Electron ◽

Cellular Immune ◽

Rate Limiting

Mosquitoes mount strong humoral and cellular immune responses against foreign organisms. Two components of the mosquito immune response that have received much attention are the phenoloxidase cascade that leads to melanization and antimicrobial peptides. The purpose of the current study was to use immunocytochemistry and transmission electron microscopy to identify the location of the melanization rate-limiting enzyme phenoloxidase and the antimicrobial peptide defensin in innate immune reactions against Escherichia coli and Micrococcus luteus by the mosquito Aedes aegypti. Our results show that both phenoloxidase and defensin are present at the sites of melanin biosynthesis in immune reactions against bacteria. Furthermore, both proteins are often present inside the same melanotic capsules. When hemocytes were analyzed, phenoloxidase was present in the cytosol of oenocytoids, but no significant amounts of defensin were detected inside any hemocytes. In summary, these data show that phenoloxidase and defensin colocalize in melanization reactions against bacteria and argue for further studies into the potential role of defensin in phenoloxidase-based melanization innate immune responses in mosquitoes.

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

Blood ◽

10.1182/blood-2009-05-199208 ◽

2009 ◽

Vol 114 (12) ◽

pp. 2367-2374 ◽

Cited By ~ 158

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.

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