scholarly journals The NF-κB Pathway: Modulation by Entamoeba histolytica and Other Protozoan Parasites

2021 ◽  
Vol 11 ◽  
Author(s):  
Attinder Chadha ◽  
Kris Chadee
Keyword(s):  
Immune Responses ◽  
Entamoeba Histolytica ◽  
Nuclear Factor Κb ◽  
Host Cells ◽  
Innate Immune Responses ◽  
Host Defenses ◽  
Protozoan Parasites ◽  
Multiple Strategies ◽  
Inflammatory Caspases ◽  
Inside Out

Protozoan parasites have led to worldwide devastation because of their ability to cause infectious diseases. They have evolved as successful pathogens in part because of their remarkable and sophisticated ways to evade innate host defenses. This holds true for both intracellular and extracellular parasites that deploy multiple strategies to circumvent innate host defenses for their survival. The different strategies protozoan parasites use include hijacking the host cellular signaling pathways and transcription factors. In particular, the nuclear factor-κB (NF-κB) pathway seems to be an attractive target for different pathogens owing to their central role in regulating prompt innate immune responses in host defense. NF-κB is a ubiquitous transcription factor that plays an indispensable role not only in regulating immediate immune responses against invading pathogens but is also a critical regulator of cell proliferation and survival. The major immunomodulatory components include parasite surface and secreted proteins/enzymes and stimulation of host cells intracellular pathways and inflammatory caspases that directly or indirectly interfere with the NF-κB pathway to thwart immune responses that are directed for containment and/or elimination of the pathogen. To showcase how protozoan parasites exploits the NF-κB signaling pathway, this review highlights recent advances from Entamoeba histolytica and other protozoan parasites in contact with host cells that induce outside-in and inside-out signaling to modulate NF-κB in disease pathogenesis and survival in the host.

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 Enterotoxigenic Escherichia coli Prevents Host NF-κB Activation by Targeting IκBα Polyubiquitination

2012 ◽  
Vol 80 (12) ◽  
pp. 4417-4425 ◽  
Author(s):  
Xiaogang Wang ◽  
Philip R. Hardwidge
Keyword(s):  
Escherichia Coli ◽  
Immune Responses ◽  
Diarrheal Disease ◽  
Innate Immune ◽  
Host Cells ◽  
Enterotoxigenic Escherichia Coli ◽  
Host Responses ◽  
Innate Immune Responses ◽  
Content Type ◽  
Heat Stable

ABSTRACTThe NF-κB pathway regulates innate immune responses to infection. NF-κB is activated after pathogen-associated molecular patterns are detected, leading to the induction of proinflammatory host responses. As a countermeasure, bacterial pathogens have evolved mechanisms to subvert NF-κB signaling. EnterotoxigenicEscherichia coli(ETEC) causes diarrheal disease and significant morbidity and mortality for humans in developing nations. The extent to which this important pathogen subverts innate immune responses by directly targeting the NF-κB pathway is an understudied topic. Here we report that ETEC secretes a heat-stable, proteinaceous factor that blocks NF-κB signaling normally induced by tumor necrosis factor (TNF), interleukin-1β, and flagellin. Pretreating intestinal epithelial cells with ETEC supernatant significantly blocked the degradation of the NF-κB inhibitor IκBα without affecting IκBα phosphorylation. Data from immunoprecipitation experiments suggest that the ETEC factor functions by preventing IκBα polyubiquitination. Inhibiting clathrin function blocked the activity of the secreted ETEC factor, suggesting that this yet-uncharacterized activity may utilize clathrin-dependent endocytosis to enter host cells. These data suggest that ETEC evades the host innate immune response by directly modulating NF-κB signaling.

scholarly journals The Solute Carrier Transporter SLC15A3 Participates in Antiviral Innate Immune Responses against Herpes Simplex Virus-1

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Longzhen He ◽  
Baocheng Wang ◽  
Yuanyuan Li ◽  
Leqing Zhu ◽  
Peiling Li ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Innate Immune ◽  
Host Cells ◽  
Type I ◽  
Innate Immune Responses ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

The innate immune response is the first line defense against viral infections. Novel genes involved in this system are continuing to emerge. SLC15A3, a proton-coupled histidine and di-tripeptide transporter that was previously found in lysosomes, has been reported to inhibit chikungunya viral replication in host cells. In this study, we found that SLC15A3 was significantly induced by DNA virus herpes simplex virus-1(HSV-1) in monocytes from human peripheral blood mononuclear cells. Aside from monocytes, it can also be induced by HSV-1 in 293T, HeLa cells, and HaCaT cells. Overexpression of SLC15A3 in 293T cells inhibits HSV-1 replication and enhances type I and type III interferon (IFN) responses, while silencing SLC15A3 leads to enhanced HSV-1 replication with reduced IFN production. Moreover, we found that SLC15A3 interacted with MAVS and STING and potentiated MAVS- and STING-mediated IFN production. These results demonstrate that SLC15A3 participates in anti-HSV-1 innate immune responses by regulating MAVS- and STING-mediated signaling pathways.

scholarly journals Meta-analysis of immune induced gene expression changes in diverse Drosophila melanogaster innate immune responses

2021 ◽  
Author(s):  
Ashley L Waring ◽  
Joshua Hill ◽  
Brooke M Allen ◽  
Nicholas M Bretz ◽  
Nguyen Le ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drosophila Melanogaster ◽  
Immune Responses ◽  
Meta Analysis ◽  
Nuclear Factor Κb ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Response Factors ◽  
Induced Genes ◽  
Conserved Gene

Background: Organisms are commonly infected by a diverse array of pathogen types including bacteria, fungi, viruses, and parasites, and mount functionally distinct responses to each of these varied immune challenges. Host immune responses are characterized by the induction of gene expression in response to infection. However, the extent to which expression changes are shared among responses to distinct pathogens is largely unknown. Results: We performed meta-analysis of gene expression data collected from Drosophila melanogaster following infection with a wide array of pathogens. We identified 62 genes that are significantly induced by infection. While many of these infection-induced genes encode known immune response factors, we also identified 21 genes that have not been previously associated with host immunity. Examination of the upstream flanking sequences of the infection-induced genes lead to the identification of two conserved enhancer sites. These sites correspond to conserved binding sites for GATA and nuclear factor κB (NFκB) family transcription factors and are associated with higher levels of transcript induction. We further identified 31 genes with predicted functions in metabolism and organismal development that are significantly downregulated following infection by diverse pathogens. Conclusions: Our study identifies conserved gene expression changes in Drosophila melanogaster following infection with varied pathogens, and transcription factor families that may regulate this immune induction. These findings provide new insight into transcriptional changes that accompany Drosophila immunity. They may suggest possible roles for the differentially regulated genes in innate immune responses to diverse classes of pathogens, and serve to identify candidate genes for further empirical study of these processes.

scholarly journals Great balls of fire: activation and signalling of inflammatory caspases

2021 ◽  
Author(s):  
Georgia Bateman ◽  
Benjamin Hill ◽  
Ryan Knight ◽  
Dave Boucher
Keyword(s):  
Immune Responses ◽  
Inflammatory Cell ◽  
Current Knowledge ◽  
Cysteine Proteases ◽  
Innate Immune ◽  
Caspase Activity ◽  
Innate Immune Responses ◽  
Caspase Activation ◽  
Biochemical Processes ◽  
Inflammatory Caspases

Innate immune responses are tightly regulated by various pathways to control infections and maintain homeostasis. One of these pathways, the inflammasome pathway, activates a family of cysteine proteases called inflammatory caspases. They orchestrate an immune response by cleaving specific cellular substrates. Canonical inflammasomes activate caspase-1, whereas non-canonical inflammasomes activate caspase-4 and -5 in humans and caspase-11 in mice. Caspases are highly specific enzymes that select their substrates through diverse mechanisms. During inflammation, caspase activity is responsible for the secretion of inflammatory cytokines and the execution of a form of lytic and inflammatory cell death called pyroptosis. This review aims to bring together our current knowledge of the biochemical processes behind inflammatory caspase activation, substrate specificity, and substrate signalling.

scholarly journals Targeted Mitochondrial Therapy With Over-Expressed MAVS Protein From Mesenchymal Stem Cells: A New Therapeutic Approach for COVID-19

2021 ◽  
Vol 9 ◽  
Author(s):  
Amirhesam Babajani ◽  
Pooya Hosseini-Monfared ◽  
Samin Abbaspour ◽  
Elham Jamshidi ◽  
Hassan Niknejad
Keyword(s):  
Stem Cells ◽  
Immune Response ◽  
Mesenchymal Stem Cells ◽  
Immune Responses ◽  
Pulmonary Involvement ◽  
Innate Immune ◽  
Host Cells ◽  
Innate Immune Responses ◽  
Mitochondrial Antiviral Signaling ◽  
And Control

The SARS-CoV-2, the virus that causes COVID-19, has infected millions of people worldwide. The symptoms of this disease are primarily due to pulmonary involvement, uncontrolled tissue inflammation, and inadequate immune response against the invader virus. Impaired interferon (IFN) production is one of the leading causes of the immune system’s inability to control the replication of the SARS-CoV-2. Mitochondria play an essential role in developing and maintaining innate cellular immunity and IFN production. Mitochondrial function is impaired during cellular stress, affecting cell bioenergy and innate immune responses. The mitochondrial antiviral-signaling protein (MAVS), located in the outer membrane of mitochondria, is one of the key elements in engaging the innate immune system and interferon production. Transferring healthy mitochondria to the damaged cells by mesenchymal stem cells (MSCs) is a proposed option for regenerative medicine and a viable treatment approach to many diseases. In addition to mitochondrial transport, these cells can regulate inflammation, repair the damaged tissue, and control the pathogenesis of COVID-19. The immune regulatory nature of MSCs dramatically reduces the probability of an immune rejection. In order to induce an appropriate immune response against the SARS-CoV-2, we hypothesize to donate mitochondria to the host cells of the virus. We consider MSCs as an appropriate biological carrier for mitochondria. Besides, enhancing the expression of MAVS protein in MSCs and promoting the expression of SARS-CoV-2 viral spike protein as a specific ligand for ACE2+ cells will improve IFN production and innate immune responses in a targeted manner.

scholarly journals Crosstalk Between NDP52 and LUBAC in Innate Immune Responses, Cell Death, and Xenophagy

2021 ◽  
Vol 12 ◽  
Author(s):  
Hirohisa Miyashita ◽  
Daisuke Oikawa ◽  
Seigo Terawaki ◽  
Daijiro Kabata ◽  
Ayumi Shintani ◽  
...  
Keyword(s):  
Immune Responses ◽  
Hela Cells ◽  
Nuclear Factor Κb ◽  
Suppressive Effect ◽  
Innate Immune ◽  
Bacterial Invasion ◽  
Innate Immune Responses ◽  
Apoptotic Pathway ◽  
Ubiquitin Chain ◽  
Tnf Α

Nuclear dot protein 52 kDa (NDP52, also known as CALCOCO2) functions as a selective autophagy receptor. The linear ubiquitin chain assembly complex (LUBAC) specifically generates the N-terminal Met1-linked linear ubiquitin chain, and regulates innate immune responses, such as nuclear factor-κB (NF-κB), interferon (IFN) antiviral, and apoptotic pathways. Although NDP52 and LUBAC cooperatively regulate bacterial invasion-induced xenophagy, their functional crosstalk remains enigmatic. Here we show that NDP52 suppresses canonical NF-κB signaling through the broad specificity of ubiquitin-binding at the C-terminal UBZ domain. Upon TNF-α-stimulation, NDP52 associates with LUBAC through the HOIP subunit, but does not disturb its ubiquitin ligase activity, and has a modest suppressive effect on NF-κB activation by functioning as a component of TNF-α receptor signaling complex I. NDP52 also regulates the TNF-α-induced apoptotic pathway, but not doxorubicin-induced intrinsic apoptosis. A chemical inhibitor of LUBAC (HOIPIN-8) cancelled the increased activation of the NF-κB and IFN antiviral pathways, and enhanced apoptosis in NDP52-knockout and -knockdown HeLa cells. Upon Salmonella-infection, colocalization of Salmonella, LC3, and linear ubiquitin was detected in parental HeLa cells to induce xenophagy. Treatment with HOIPIN-8 disturbed the colocalization and facilitated Salmonella expansion. In contrast, HOIPIN-8 showed little effect on the colocalization of LC3 and Salmonella in NDP52-knockout cells, suggesting that NDP52 is a weak regulator in LUBAC-mediated xenophagy. These results indicate that the crosstalk between NDP52 and LUBAC regulates innate immune responses, apoptosis, and xenophagy.

Modeling and analysis of innate immune responses induced by the host cells against hepatitis C virus infection

2015 ◽  
Vol 7 (5) ◽  
pp. 544-559 ◽  
Author(s):  
Ayesha Obaid ◽  
Jamil Ahmad ◽  
Anam Naz ◽  
Faryal Mehwish Awan ◽  
Rehan Zafar Paracha ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Immune Responses ◽  
Innate Immune ◽  
Host Cells ◽  
Innate Immune Responses ◽  
Hepatitis C Virus Infection ◽  
Modeling And Analysis

scholarly journals Hacking the host: exploitation of macrophage polarization by intracellular bacterial pathogens

2020 ◽  
Vol 78 (1) ◽  
Author(s):  
Joseph D Thiriot ◽  
Yazmin B Martinez-Martinez ◽  
Janice J Endsley ◽  
Alfredo G Torres
Keyword(s):  
Immune Responses ◽  
Bacterial Pathogens ◽  
Macrophage Polarization ◽  
Polarization State ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Host Defenses ◽  
M2 Polarization ◽  
Integral Role ◽  
Macrophage Plasticity

ABSTRACT Macrophages play an integral role in host defenses against intracellular bacterial pathogens. A remarkable plasticity allows for adaptation to the needs of the host to orchestrate versatile innate immune responses to a variety of microbial threats. Several bacterial pathogens have adapted to macrophage plasticity and modulate the classical (M1) or alternative (M2) activation bias towards a polarization state that increases fitness for intracellular survival. Here, we summarize the current understanding of the host macrophage and intracellular bacterial interface; highlighting the roles of M1/M2 polarization in host defense and the mechanisms employed by several important intracellular pathogens to modulate macrophage polarization to favor persistence or proliferation. Understanding macrophage polarization in the context of disease caused by different bacterial pathogens is important for the identification of targets for therapeutic intervention.

scholarly journals Unique and complementary suppression of cGAS-STING and RNA sensing- triggered innate immune responses by SARS-CoV-2 proteins

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yajuan Rui ◽  
Jiaming Su ◽  
Si Shen ◽  
Ying Hu ◽  
Dingbo Huang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Nuclear Factor Κb ◽  
Innate Immune ◽  
Nuclear Accumulation ◽  
Innate Immune Responses ◽  
Structural Protein ◽  
Viral Protease ◽  
Downstream Signaling ◽  
Efficient Replication

AbstractThe emergence of SARS-CoV-2 has resulted in the COVID-19 pandemic, leading to millions of infections and hundreds of thousands of human deaths. The efficient replication and population spread of SARS-CoV-2 indicates an effective evasion of human innate immune responses, although the viral proteins responsible for this immune evasion are not clear. In this study, we identified SARS-CoV-2 structural proteins, accessory proteins, and the main viral protease as potent inhibitors of host innate immune responses of distinct pathways. In particular, the main viral protease was a potent inhibitor of both the RLR and cGAS-STING pathways. Viral accessory protein ORF3a had the unique ability to inhibit STING, but not the RLR response. On the other hand, structural protein N was a unique RLR inhibitor. ORF3a bound STING in a unique fashion and blocked the nuclear accumulation of p65 to inhibit nuclear factor-κB signaling. 3CL of SARS-CoV-2 inhibited K63-ubiquitin modification of STING to disrupt the assembly of the STING functional complex and downstream signaling. Diverse vertebrate STINGs, including those from humans, mice, and chickens, could be inhibited by ORF3a and 3CL of SARS-CoV-2. The existence of more effective innate immune suppressors in pathogenic coronaviruses may allow them to replicate more efficiently in vivo. Since evasion of host innate immune responses is essential for the survival of all viruses, our study provides insights into the design of therapeutic agents against SARS-CoV-2.

Sign in / Sign up

Export Citation Format

Share Document