scholarly journals Oral streptococci subvert the host innate immune response through hydrogen peroxide

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Yi Ling Tang ◽  
Tiow Suan Sim ◽  
Kai Soo Tan
Keyword(s):  
Hydrogen Peroxide ◽  
Immune Response ◽  
Innate Immune Response ◽  
Mammalian Cells ◽  
Innate Immune ◽  
Related Factor ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Oral Streptococci ◽  
Periodontal Health

AbstractIn periodontal health, oral streptococci constitute up to 80% of the plaque biofilm. Yet, destructive inflammatory events of the periodontium are rare. This observation suggests that oral streptococci may possess mechanisms to co-exist with the host. However, the mechanisms employed by oral streptococci to modulate the innate immune response have not been well studied. One of the key virulence factors produced by oral streptococci is hydrogen peroxide (H2O2). In mammalian cells, H2O2 triggers the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key pathway mediating antioxidant defence. This study aimed to determine (1) if H2O2 producing oral streptococci activated the Nrf2 pathway in macrophages, and (2) if the activation of Nrf2 influenced the innate immune response. We found that oral streptococci downregulated the innate immune response in a H2O2 dependent manner through the activation of the Nrf2. The activation of the Nrf2 signalling pathway led to the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NFĸB), the key transcription factor regulating pro-inflammatory response. This study showed for the first time that oral streptococci are unlikely passive bystanders but could play an active role in the maintenance of periodontal health by preventing overt inflammation.

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

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.

Differential modulation of innate immune response by epinephrine and estradiol

2017 ◽  
Vol 30 (3) ◽  
Author(s):  
Sona Margaryan ◽  
Armenuhi Hyusyan ◽  
Anush Martirosyan ◽  
Shushan Sargsian ◽  
Gayane Manukyan
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Dependent Manner ◽  
Induced Expression ◽  
Short Term Exposure ◽  
Tnf Α ◽  
Vitro Effect ◽  
Dose Dependent

AbstractBackgroundAlthough it is widely accepted that catecholamines and estrogens influence immunity and have consequences for health, their effect on innate immunity (e.g. monocytes and neutrophils) is still not fully investigated.Materials and methodsOur study aimed to analyze the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, monocyte chemoattractant protein (MCP)-1 and IL-8 by whole blood cells following short-term exposure to epinephrine (Epi) and 17β-estradiol (E2) in the presence or absence of lipopolysaccharide (LPS). We also evaluated the in vitro effect of these hormones on expression of β2 integrin (CD11b/CD18) and L-selectin (CD62L) by circulating neutrophils and monocytes in the blood of healthy subjects.ResultsEpi has shown a potential to modulate the production of pro-inflammatory mediators. Its exposure resulted in significantly increased production of IL-8 in a dose-dependent manner. On the contrary, a dose-dependent suppression of LPS-induced production of IL-1β, IL-8, and MCP-1 by Epi was observed. In neutrophils, a modest rise in CD11b expression was observed after Epi exposure. Simultaneously, Epi suppressed LPS-induced expression of CD11b and CD18. In monocytes, Epi suppressed LPS-induced expression of C11b. E2 inhibited LPS-induced TNF-α production and caused a significant decrease in CD62L expression in both cell populations. No significant changes were observed after double exposure of cells with Epi and E2.ConclusionsThus, our results show that Epi and E2 differentially modulate the innate immune response and have a dual effect on cytokine modulation. The findings suggest that the observed immunoregulatory role of Epi and E2 may influence the outcome in endotoxin responses and can be critical in the regulation of inflammatory responses.

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

2008 ◽  
Vol 36 (6) ◽  
pp. 1211-1215 ◽  
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.

scholarly journals The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression

Oncogene ◽  
2020 ◽  
Vol 39 (44) ◽  
pp. 6841-6855 ◽  
Author(s):  
Christina Jessen ◽  
Julia K. C. Kreß ◽  
Apoorva Baluapuri ◽  
Anita Hufnagel ◽  
Werner Schmitz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Transcription Factor ◽  
Prostaglandin E2 ◽  
Innate Immune Response ◽  
Stress Responses ◽  
Melanoma Cells ◽  
Innate Immune ◽  
Dependent Manner

AbstractThe transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H2O2 or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.

scholarly journals TRAF6 and TAK1 contribute to SAMHD1-mediated negative regulation of NF-κB signaling

2020 ◽  
Author(s):  
Constanza E. Espada ◽  
Corine St. Gelais ◽  
Serena Bonifati ◽  
Victoria V. Maksimova ◽  
Michael P. Cahill ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Transforming Growth Factor ◽  
Negative Regulation ◽  
Innate Immune ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Intracellular Dntp ◽  
Hiv 1

Sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) restricts HIV-1 replication by limiting the intracellular dNTP pool. SAMHD1 also suppresses the activation of NF-κB in response to viral infections and inflammatory stimuli. However, the mechanisms by which SAMHD1 negatively regulates this pathway remain unclear. Here we show that SAMHD1-mediated suppression of NF-κB activation is modulated by two key mediators of NF-κB signaling, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and transforming growth factor-ß-activated kinase-1 (TAK1). We compared NF-κB activation stimulated by interleukin (IL)-1ß in monocytic THP-1 control and SAMHD1 knockout (KO) cells with and without partial TRAF6 knockdown (KD), or in cells treated with TAK1 inhibitors. Relative to control cells, IL-1ß-treated SAMHD1 KO cells showed increased phosphorylation of the inhibitor of NF-κB (IκBα), an indication of pathway activation, and elevated levels of TNF-α mRNA. Moreover, SAMHD1 KO combined with TRAF6 KD or pharmacological TAK1 inhibition reduced IκBα phosphorylation and TNF-α mRNA to the level of control cells. SAMHD1 KO cells infected with single-cycle HIV-1 showed elevated infection and TNF-α mRNA levels compared to control cells, and the effects were significantly reduced by TRAF6 KD or TAK1 inhibition. We further demonstrated that overexpressed SAMHD1 inhibited TRAF6-stimulated NF-κB reporter activity in HEK293T cells in a dose-dependent manner. SAMHD1 contains a nuclear localization signal (NLS), but an NLS-defective SAMHD1 exhibited a suppressive effect similar to the wild-type protein. Our data suggest that the TRAF6-TAK1 axis contributes to SAMHD1-mediated suppression of NF-κB activation and HIV-1 infection. Importance Cells respond to pathogen infection by activating a complex innate immune signaling pathway, which culminates in the activation of transcription factors and secretion of a family of functionally and genetically related cytokines. However, excessive immune activation may cause tissue damage and detrimental effects on the host. Therefore, in order to maintain host homeostasis, the innate immune response is tightly regulated during viral infection. We have reported SAMHD1 as a novel negative regulator of the innate immune response. Here, we provide new insights into SAMHD1-mediated negative regulation of the NF-κB pathway at the TRAF6-TAK1 checkpoint. We show that SAMHD1 inhibits TAK1 activation and TRAF6 signaling in response to proinflammatory stimuli. Interestingly, TRAF6 knockdown in SAMHD1-deficient cells significantly inhibited HIV-1 infection and activation of NF-κB induced by virus infection. Our research reveals a new negative regulatory mechanism by which SAMHD1 participates in the maintenance of cellular homeostasis during HIV-1 infection and inflammation.

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

Biomaterials ◽  
2011 ◽  
Vol 32 (9) ◽  
pp. 2342-2350 ◽  
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

scholarly journals Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity

2013 ◽  
Vol 94 (11) ◽  
pp. 2367-2392 ◽  
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.

scholarly journals Deficiency in Translesion DNA Polymerase ζ Induces an Innate Immune Response

2020 ◽  
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.

scholarly journals A Chemokine-Degrading Extracellular Protease Made by Group A Streptococcus Alters Pathogenesis by Enhancing Evasion of the Innate Immune Response

2008 ◽  
Vol 76 (3) ◽  
pp. 978-985 ◽  
Author(s):  
Paul Sumby ◽  
Shizhen Zhang ◽  
Adeline R. Whitney ◽  
Fabiana Falugi ◽  
Guido Grandi ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Group A Streptococcus ◽  
Cell Envelope ◽  
Innate Immune ◽  
Infection Model ◽  
Dependent Manner ◽  
Wild Type ◽  
Group A

ABSTRACT Circumvention of the host innate immune response is critical for bacterial pathogens to infect and cause disease. Here we demonstrate that the group A Streptococcus (GAS; Streptococcus pyogenes) protease SpyCEP (S. pyogenes cell envelope protease) cleaves granulocyte chemotactic protein 2 (GCP-2) and growth-related oncogene alpha (GROα), two potent chemokines made abundantly in human tonsils. Cleavage of GCP-2 and GROα by SpyCEP abrogated their abilities to prime neutrophils for activation, detrimentally altering the innate immune response. SpyCEP expression is negatively regulated by the signal transduction system CovR/S. Purified recombinant CovR bound the spyCEP gene promoter region in vitro, indicating direct regulation. Immunoreactive SpyCEP protein was present in the culture supernatants of covR/S mutant GAS strains but not in supernatants from wild-type strains. However, wild-type GAS strains do express SpyCEP, where it is localized to the cell wall. Strain MGAS2221, an organism representative of the highly virulent and globally disseminated M1T1 GAS clone, differed significantly from its isogenic spyCEP mutant derivative strain in a mouse soft tissue infection model. Interestingly, and in contrast to previous studies, the isogenic mutant strain generated lesions of larger size than those formed following infection with the parent strain. The data indicate that SpyCEP contributes to GAS virulence in a strain- and disease-dependent manner.

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

2015 ◽  
Vol 89 (15) ◽  
pp. 7550-7566 ◽  
Author(s):  
Nicole B. Glennon ◽  
Omar Jabado ◽  
Michael K. Lo ◽  
Megan L. Shaw
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Mammalian Cells ◽  
Nipah Virus ◽  
A549 Cells ◽  
Hendra Virus ◽  
Innate Immune ◽  
Viral Control ◽  
Content Type ◽  
Pteropus Vampyrus

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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