Transcriptome Profiling of the Virus-Induced Innate Immune Response in Pteropus vampyrus and Its Attenuation by Nipah Virus Interferon Antagonist Functions

ABSTRACTBats are important reservoirs for several viruses, many of which cause lethal infections in humans but have reduced pathogenicity in bats. As the innate immune response is critical for controlling viruses, the nature of this response in bats and how it may differ from that in other mammals are of great interest. Using next-generation transcriptome sequencing (mRNA-seq), we profiled the transcriptional response ofPteropus vampyrusbat kidney (PVK) cells to Newcastle disease virus (NDV), an avian paramyxovirus known to elicit a strong innate immune response in mammalian cells. ThePteropusgenus is a known reservoir of Nipah virus (NiV) and Hendra virus (HeV). Analysis of the 200 to 300 regulated genes showed that genes for interferon (IFN) and antiviral pathways are highly upregulated in NDV-infected PVK cells, including genes for beta IFN, RIG-I, MDA5, ISG15, and IRF1. NDV-infected cells also upregulated several genes not previously characterized to be antiviral, such as RND1, SERTAD1, CHAC1, and MORC3. In fact, we show that MORC3 is induced by both IFN and NDV infection in PVK cells but is not induced by either stimulus in human A549 cells. In contrast to NDV infection, HeV and NiV infection of PVK cells failed to induce these innate immune response genes. Likewise, an attenuated response was observed in PVK cells infected with recombinant NDVs expressing the NiV IFN antagonist proteins V and W. This study provides the first global profile of a robust virus-induced innate immune response in bats and indicates that henipavirus IFN antagonist mechanisms are likely active in bat cells.IMPORTANCEBats are the reservoir host for many highly pathogenic human viruses, including henipaviruses, lyssaviruses, severe acute respiratory syndrome coronavirus, and filoviruses, and many other viruses have also been isolated from bats. Viral infections are reportedly asymptomatic or heavily attenuated in bat populations. Despite their ecological importance to viral maintenance, research into their immune system and mechanisms for viral control has only recently begun. Nipah virus and Hendra virus are two paramyxoviruses associated with high mortality rates in humans and whose reservoir is thePteropusgenus of bats. Greater knowledge of the innate immune response ofP. vampyrusbats to viral infection may elucidate how bats serve as a reservoir for so many viruses.

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The transcription factors TFEB and TFE3 link the FLCN-AMPK signaling axis to innate immune response and pathogen resistance

10.1101/463430 ◽

2018 ◽

Author(s):

Leeanna El-Houjeiri ◽

Elite Possik ◽

Tarika Vijayaraghavan ◽

Mathieu Paquette ◽

José A Martina ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Mammalian Cells ◽

Pathogen Resistance ◽

Innate Immune ◽

Negative Regulator ◽

Energy Status ◽

Rapid Reduction ◽

Coupling Energy ◽

Mtorc1 Signaling

AbstractTFEB and TFE3 are transcriptional regulators of the innate immune response, but the mechanisms regulating their activation upon pathogen infection are poorly elucidated. UsingC. elegansand mammalian models, we report that the master metabolic modulator 5’-AMP-activated protein kinase (AMPK) and its negative regulator Folliculin (FLCN) act upstream of TFEB/TFE3 in the innate immune response, independently of the mTORC1 signaling pathway. In nematodes, loss of FLCN or overexpression of AMPK conferred pathogen resistanceviaactivation of TFEB/TFE3-dependent antimicrobial genes, while ablation of total AMPK activity abolished this phenotype. Similarly, in mammalian cells, loss of FLCN or pharmacological activation of AMPK induced TFEB/TFE3-dependent pro-inflammatory cytokine expression. Importantly, a rapid reduction in cellular ATP levels in murine macrophages was observed upon lipopolysaccharide (LPS) treatment accompanied by an acute AMPK activation and TFEB nuclear localization. These results uncover an ancient, highly conserved and pharmacologically actionable mechanism coupling energy status with innate immunity.

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Ursodeoxycholic Acid (UDCA) Mitigates the Host Inflammatory Response during Clostridioides difficile Infection by Altering Gut Bile Acids

Infection and Immunity ◽

10.1128/iai.00045-20 ◽

2020 ◽

Vol 88 (6) ◽

Author(s):

Jenessa A. Winston ◽

Alissa J. Rivera ◽

Jingwei Cai ◽

Rajani Thanissery ◽

Stephanie A. Montgomery ◽

...

Keyword(s):

Immune Response ◽

Bile Acid ◽

Inflammatory Response ◽

Innate Immune Response ◽

Innate Immune ◽

Colonization Resistance ◽

Content Type ◽

Clostridioides Difficile

ABSTRACT Clostridioides difficile infection (CDI) is associated with increasing morbidity and mortality posing an urgent threat to public health. Recurrence of CDI after successful treatment with antibiotics is high, thus necessitating discovery of novel therapeutics against this enteric pathogen. Administration of the secondary bile acid ursodeoxycholic acid (UDCA; ursodiol) inhibits the life cycles of various strains of C. difficile in vitro, suggesting that the FDA-approved formulation of UDCA, known as ursodiol, may be able to restore colonization resistance against C. difficile in vivo. However, the mechanism(s) by which ursodiol is able to restore colonization resistance against C. difficile remains unknown. Here, we confirmed that ursodiol inhibits C. difficile R20291 spore germination and outgrowth, growth, and toxin activity in a dose-dependent manner in vitro. In a murine model of CDI, exogenous administration of ursodiol resulted in significant alterations in the bile acid metabolome with little to no changes in gut microbial community structure. Ursodiol pretreatment resulted in attenuation of CDI pathogenesis early in the course of disease, which coincided with alterations in the cecal and colonic inflammatory transcriptome, bile acid-activated receptors nuclear farnesoid X receptor (FXR) and transmembrane G-protein-coupled membrane receptor 5 (TGR5), which are able to modulate the innate immune response through signaling pathways such as NF-κB. Although ursodiol pretreatment did not result in a consistent decrease in the C. difficile life cycle in vivo, it was able to attenuate an overly robust inflammatory response that is detrimental to the host during CDI. Ursodiol remains a viable nonantibiotic treatment and/or prevention strategy against CDI. Likewise, modulation of the host innate immune response via bile acid-activated receptors FXR and TGR5 represents a new potential treatment strategy for patients with CDI.

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Role of miRNA-146a in the regulation of the innate immune response and cancer

Biochemical Society Transactions ◽

10.1042/bst0361211 ◽

2008 ◽

Vol 36 (6) ◽

pp. 1211-1215 ◽

Cited By ~ 135

Author(s):

Andrew E. Williams ◽

Mark M. Perry ◽

Sterghios A. Moschos ◽

Hanna M. Larner-Svensson ◽

Mark A. Lindsay

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Mammalian Cells ◽

Mrna Translation ◽

Nuclear Factor Κb ◽

Causal Link ◽

Innate Immune ◽

Major Function ◽

Biological Responses

In mammalian cells, miRNAs (microRNAs) are the most abundant family of small non-coding RNAs that regulate mRNA translation through the RNA interference pathway. In general, it appears that the major function of miRNAs is in development, differentiation and homoeostasis, which is indicated by studies showing aberrant miRNA expression during the development of cancer. Interestingly, changes in the expression of miR-146a have been implicated in both the development of multiple cancers and in the negative regulation of inflammation induced via the innate immune response. Furthermore, miR-146a expression is driven by the transcription factor NF-κB (nuclear factor κB), which has been implicated as an important causal link between inflammation and carcinogenesis. In the present article, we review the evidence for a role of miR-146a in innate immunity and cancer and assess whether changes in miR-146a might link these two biological responses.

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Promotion of Colonization and Virulence by Cholera Toxin Is Dependent on Neutrophils

Infection and Immunity ◽

10.1128/iai.00422-13 ◽

2013 ◽

Vol 81 (9) ◽

pp. 3338-3345 ◽

Cited By ~ 12

Author(s):

Jessica Queen ◽

Karla J. F. Satchell

Keyword(s):

Immune Response ◽

Cholera Toxin ◽

Innate Immune Response ◽

Host Response ◽

Survival Rates ◽

Innate Immune ◽

Infection Model ◽

High Dose ◽

Content Type ◽

Inflammatory Protein

ABSTRACTThe innate immune response toVibrio choleraeinfection is poorly understood, but this knowledge is critical for the design of safe, effective vaccines. Using an adult mouse intestinal infection model, this study examines the contribution of neutrophils to host immunity, as well as the effect of cholera toxin and other secreted factors on this response. Depletion of neutrophils from mice with anti-Ly6G IA8 monoclonal antibody led to similar survival rates of mice infected with low or moderate doses of toxigenicV. choleraeEl Tor O1. At a high dose, neutropenic mice showed increased rates of survival compared to neutrophil-replete animals. Expression of cholera toxin was found to be protective to the neutropenic host, and this phenotype can be replicated by the administration of purified toxin. Neutrophils do not effectively clear colonizing bacteria from the small intestine, nor do they alter induction of early immune-modulating signals. In both neutropenic and neutrophil-replete animals, the local response to infection is characterized by expression of interleukin 6 (IL-6), IL-10, and macrophage inflammatory protein 2 alpha (MIP-2). Overall, these data indicate that the innate immune response to toxigenicV. choleraeinfection differs dramatically from the host response to nontoxigenic infection or vaccination, where neutrophils are protective to the host. In the absence of neutrophils, cholera toxin induces immunomodulatory effects that increase host survival. In cholera toxin-producing strains, similar to nontoxigenic infection, accessory toxins are critical to virulence, indicating that cholera toxin and the other secreted toxins modulate the host response by different mechanisms, with both contributing to bacterial persistence and virulence.

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Leptospira interrogans Catalase Is Required for Resistance to H2O2and for Virulence

Infection and Immunity ◽

10.1128/iai.00466-12 ◽

2012 ◽

Vol 80 (11) ◽

pp. 3892-3899 ◽

Cited By ~ 64

Author(s):

Azad Eshghi ◽

Kristel Lourdault ◽

Gerald L. Murray ◽

Thanatchaporn Bartpho ◽

Rasana W. Sermswan ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Immune Response ◽

Innate Immune Response ◽

Reactive Oxygen ◽

Innate Immune ◽

Leptospira Interrogans ◽

Oxygen Species ◽

Content Type ◽

Host Innate Immune Response

ABSTRACTPathogenicLeptospiraspp. are likely to encounter higher concentrations of reactive oxygen species induced by the host innate immune response. In this study, we characterizedLeptospira interroganscatalase (KatE), the only annotated catalase found within pathogenicLeptospiraspecies, by assessing its role in resistance to H2O2-induced oxidative stress and during infection in hamsters. PathogenicL. interrogansbacteria had a 50-fold-higher survival rate under H2O2-induced oxidative stress than did saprophyticL. biflexabacteria, and this was predominantly catalase dependent. We also characterized KatE, the only annotated catalase found within pathogenicLeptospiraspecies. Catalase assays performed with recombinant KatE confirmed specific catalase activity, while protein fractionation experiments localized KatE to the bacterial periplasmic space. The insertional inactivation ofkatEin pathogenicLeptospirabacteria drastically diminished leptospiral viability in the presence of extracellular H2O2and reduced virulence in an acute-infection model. Combined, these results suggest thatL. interrogansKatE confersin vivoresistance to reactive oxygen species induced by the host innate immune response.

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Cytotoxicity of, and innate immune response to, size-controlled polypyrrole nanoparticles in mammalian cells

Biomaterials ◽

10.1016/j.biomaterials.2010.11.080 ◽

2011 ◽

Vol 32 (9) ◽

pp. 2342-2350 ◽

Cited By ~ 73

Author(s):

Sojin Kim ◽

Wan-Kyu Oh ◽

Yoon Seon Jeong ◽

Jin-Yong Hong ◽

Bo-Ram Cho ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Mammalian Cells ◽

Innate Immune ◽

Polypyrrole Nanoparticles ◽

Size Controlled

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Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity

Journal of General Virology ◽

10.1099/vir.0.055921-0 ◽

2013 ◽

Vol 94 (11) ◽

pp. 2367-2392 ◽

Cited By ~ 185

Author(s):

Geoffrey L. Smith ◽

Camilla T. O. Benfield ◽

Carlos Maluquer de Motes ◽

Michela Mazzon ◽

Stuart W. J. Ember ◽

...

Keyword(s):

Immune Response ◽

Vaccinia Virus ◽

Innate Immune Response ◽

Immune Evasion ◽

Mammalian Cells ◽

Innate Immune ◽

Gene Encoding ◽

Cytokines And Chemokines ◽

Host Innate Immune Response ◽

New Hosts

Virus infection of mammalian cells is sensed by pattern recognition receptors and leads to an innate immune response that restricts virus replication and induces adaptive immunity. In response, viruses have evolved many countermeasures that enable them to replicate and be transmitted to new hosts, despite the host innate immune response. Poxviruses, such as vaccinia virus (VACV), have large DNA genomes and encode many proteins that are dedicated to host immune evasion. Some of these proteins are secreted from the infected cell, where they bind and neutralize complement factors, interferons, cytokines and chemokines. Other VACV proteins function inside cells to inhibit apoptosis or signalling pathways that lead to the production of interferons and pro-inflammatory cytokines and chemokines. In this review, these VACV immunomodulatory proteins are described and the potential to create more immunogenic VACV strains by manipulation of the gene encoding these proteins is discussed.

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Deficiency in Translesion DNA Polymerase ζ Induces an Innate Immune Response

10.1101/2020.03.02.972513 ◽

2020 ◽

Cited By ~ 1

Author(s):

Sara K. Martin ◽

Junya Tomida ◽

Richard D. Wood

Keyword(s):

Immune Response ◽

Dna Polymerase ◽

Innate Immune Response ◽

Mammalian Cells ◽

Dna Lesions ◽

Innate Immune ◽

Protective Function ◽

Interferon Stimulated Genes ◽

Protein Levels ◽

Genomic Stress

ABSTRACTDNA polymerase pol ζ is regarded as a specialized DNA polymerase for bypass of DNA lesions. In mammalian cells, pol ζ also contributes to genomic stability during normal DNA replication. Disruption of Rev3l (the catalytic subunit of pol ζ) is toxic to cells and mice, with increased constitutive chromosome damage, including micronuclei. As the cellular manifestations of this genomic stress have remained unexplored, we measured genome-wide transcriptional changes by RNA-seq in pol ζ-defective cells. Expression of 1117 transcripts was altered by 4-fold or more in Rev3l knockout mouse embryonic fibroblasts (MEFs), with a pattern showing an induction of an innate immune response. We validated the increased expression of known interferon-stimulated genes (ISG) at the mRNA and protein levels. We found that the cGAS-STING axis, which senses cytosolic DNA, drives ISG expression in Rev3l knockout MEFs. These results reveal a new genome protective function of pol ζ and indicate that inhibition of pol ζ may be therapeutically useful by simultaneously increasing sensitivity to genotoxins and inducing a cytotoxic innate immune response.

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Staphylococcus aureus Biofilm-Conditioned Medium Impairs Macrophage-Mediated Antibiofilm Immune Response by Upregulating KLF2 Expression

Infection and Immunity ◽

10.1128/iai.00643-18 ◽

2019 ◽

Vol 87 (4) ◽

Cited By ~ 7

Author(s):

Talib Alboslemy ◽

Bing Yu ◽

Tara Rogers ◽

Min-Ho Kim

Keyword(s):

Staphylococcus Aureus ◽

Immune Response ◽

Conditioned Medium ◽

Innate Immune Response ◽

Immune Defense ◽

Innate Immune ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Content Type ◽

Cell Functions

ABSTRACT Staphylococcus aureus infections associated with the formation of biofilms on medical implants or host tissue play a critical role in the persistence of chronic infections. One critical mechanism of biofilm infection that leads to persistent infection lies in the capacity of biofilms to evade the macrophage-mediated innate immune response. It is now increasingly apparent that microorganisms exploit the negative regulatory mechanisms of the pattern recognition receptor (PRR)-mediated inflammatory response to subvert host cell functions by using various virulence factors. However, the detailed molecular mechanism, along with the identity of a target molecule, underlying the evasion of the macrophage-mediated innate immune response against S. aureus infection associated with biofilm formation remains to be elucidated. Here, using an in vitro culture model of murine macrophage-like RAW 264.7 cells, we demonstrate that S. aureus biofilm-conditioned medium significantly attenuated the capacity for macrophage bactericidal and proinflammatory responses. Importantly, the responses were associated with attenuated activation of NF-κB and increased expression of Kruppel-like factor 2 (KLF2) in RAW 264.7 cells. Small interfering RNA (siRNA)-mediated silencing of KLF2 in RAW 264.7 cells could restore the activation of NF-κB toward the bactericidal activity and generation of proinflammatory cytokines in the presence of S. aureus biofilm-conditioned medium. Collectively, our results suggest that factors secreted from S. aureus biofilms might exploit the KLF2-dependent negative regulatory mechanism to subvert macrophage-mediated innate immune defense against S. aureus biofilms.

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Identification of PGN_1123 as the Gene Encoding Lipid A Deacylase, an Enzyme Required for Toll-Like Receptor 4 Evasion, inPorphyromonas gingivalis

Journal of Bacteriology ◽

10.1128/jb.00683-18 ◽

2019 ◽

Vol 201 (11) ◽

Cited By ~ 3

Author(s):

Sumita Jain ◽

Ana M. Chang ◽

Manjot Singh ◽

Jeffrey S. McLean ◽

Stephen R. Coats ◽

...

Keyword(s):

Immune Response ◽

Porphyromonas Gingivalis ◽

Innate Immune Response ◽

Lipid A ◽

Innate Immune ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Gene Encoding ◽

Content Type ◽

Chronic Inflammatory Condition

ABSTRACTRemoval of one acyl chain from bacterial lipid A by deacylase activity is a mechanism used by many pathogenic bacteria to evade the host's Toll-like receptor 4 (TLR4)-mediated innate immune response. InPorphyromonas gingivalis, a periodontal pathogen, lipid A deacylase activity converts a majority of the initially synthesized penta-acylated lipid A, a TLR4 agonist, to tetra-acylated structures, which effectively evade TLR4 sensing by being either inert or antagonistic at TLR4. In this paper, we report successful identification of the gene that encodes theP. gingivalislipid A deacylase enzyme. This gene, PGN_1123 inP. gingivalis33277, is highly conserved withinP. gingivalis, and putative orthologs are phylogenetically restricted to theBacteroidetesphylum. Lipid A of ΔPGN_1123 mutants is penta-acylated and devoid of tetra-acylated structures, and the mutant strain provokes a strong TLR4-mediated proinflammatory response, in contrast to the negligible response elicited by wild-typeP. gingivalis. Heterologous expression of PGN_1123 inBacteroides thetaiotaomicronpromoted lipid A deacylation, confirming that PGN_1123 encodes the lipid A deacylase enzyme.IMPORTANCEPeriodontitis, commonly referred to as gum disease, is a chronic inflammatory condition that affects a large proportion of the population.Porphyromonas gingivalisis a bacterium closely associated with periodontitis, although how and if it is a cause for the disease are not known. It has a formidable capacity to dampen the host's innate immune response, enabling its persistence in diseased sites and triggering microbial dysbiosis in animal models of infection.P. gingivalisis particularly adept at evading the host's TLR4-mediated innate immune response by modifying the structure of lipid A, the TLR4 ligand. In this paper, we report identification of the gene encoding lipid A deacylase, a key enzyme that modifies lipid A to TLR4-evasive structures.

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