scholarly journals MyD88 and beyond: a perspective on MyD88-targeted therapeutic approach for modulation of host immunity

2021 ◽  
Author(s):  
Kamal U. Saikh
Keyword(s):  
Innate Immunity ◽  
Small Molecule ◽  
Therapeutic Approach ◽  
Adaptor Proteins ◽  
Host Immunity ◽  
Type I ◽  
Type I Ifn ◽  
Immune Signaling ◽  
Tir Domain ◽  
Host Innate Immunity

Abstract The continuous emergence of infectious pathogens along with antimicrobial resistance creates a need for an alternative approach to treat infectious diseases. Targeting host factor(s) which are critically involved in immune signaling pathways for modulation of host immunity offers to treat a broad range of infectious diseases. Upon pathogen-associated ligands binding to the Toll-like/ IL-1R family, and other cellular receptors, followed by recruitment of intracellular signaling adaptor proteins, primarily MyD88, trigger the innate immune responses. But activation of host innate immunity strongly depends on the correct function of MyD88 which is tightly regulated. Dysregulation of MyD88 may cause an imbalance that culminates to a wide range of inflammation-associated syndromes and diseases. Furthermore, recent reports also describe that MyD88 upregulation with many viral infections is linked to decreased antiviral type I IFN response, and MyD88-deficient mice showed an increase in survivability. These reports suggest that MyD88 is also negatively involved via MyD88-independent pathways of immune signaling for antiviral type I IFN response. Because of its expanding role in controlling host immune signaling pathways, MyD88 has been recognized as a potential drug target in a broader drug discovery paradigm. Targeting BB-loop of MyD88, small molecule inhibitors were designed by structure-based approach which by blocking TIR–TIR domain homo-dimerization have shown promising therapeutic efficacy in attenuating MyD88-mediated inflammatory impact, and increased antiviral type I IFN response in experimental mouse model of diseases. In this review, we highlight the reports on MyD88-linked immune response and MyD88-targeted therapeutic approach with underlying mechanisms for controlling inflammation and antiviral type I IFN response. Highlights • Host innate immunity is activated upon PAMPs binding to PRRs followed by immune signaling through TIR domain–containing adaptor proteins mainly MyD88. • Structure-based approach led to develop small-molecule inhibitors which block TIR domain homodimerization of MyD88 and showed therapeutic efficacy in limiting severe inflammation-associated impact in mice. • Therapeutic intervention of MyD88 also showed an increase in antiviral effect with strong type I IFN signaling linked to increased phosphorylation of IRFs via MyD88–independent pathway. • MyD88 inhibitors might be potentially useful as a small-molecule therapeutics for modulation of host immunity against inflammatory diseases and antiviral therapy. • However, prior clinical use of more in-depth efforts should be focused for suitability of the approach in deploying to complex diseases including COPD and COVID-19 in limiting inflammation-associated syndrome to infection.

scholarly journals Virus Caused Imbalance of Type I IFN Responses and Inflammation in COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Jintao Zhang ◽  
Chunyuan Zhao ◽  
Wei Zhao
Keyword(s):  
Innate Immunity ◽  
Innate Immune System ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Antiviral Responses ◽  
Public Health Challenges ◽  
Host Innate Immunity ◽  
Efficient Elimination

The global expansion of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as one of the greatest public health challenges and imposes a great threat to human health. Innate immunity plays vital roles in eliminating viruses through initiating type I interferons (IFNs)-dependent antiviral responses and inducing inflammation. Therefore, optimal activation of innate immunity and balanced type I IFN responses and inflammation are beneficial for efficient elimination of invading viruses. However, SARS-CoV-2 manipulates the host’s innate immune system by multiple mechanisms, leading to aberrant type I IFN responses and excessive inflammation. In this review, we will emphasize the recent advances in the understanding of the crosstalk between host innate immunity and SARS-CoV-2 to explain the imbalance between inflammation and type I IFN responses caused by viral infection, and explore potential therapeutic targets for COVID-19.

scholarly journals PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor

2020 ◽  
Vol 94 (7) ◽  
Author(s):  
Chuan Xia ◽  
Jennifer J. Wolf ◽  
Chuankai Sun ◽  
Mengqiong Xu ◽  
Caleb J. Studstill ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Influenza Virus ◽  
Molecular Mechanism ◽  
Influenza A Virus ◽  
Influenza A ◽  
Type I Interferon ◽  
Type I ◽  
Type I Ifn ◽  
Host Type ◽  
Host Innate Immunity

ABSTRACT Influenza A virus (IAV) utilizes multiple strategies to confront or evade host type I interferon (IFN)-mediated antiviral responses in order to enhance its own propagation within the host. One such strategy is to induce the degradation of type I IFN receptor 1 (IFNAR1) by utilizing viral hemagglutinin (HA). However, the molecular mechanism behind this process is poorly understood. Here, we report that a cellular protein, poly(ADP-ribose) polymerase 1 (PARP1), plays a critical role in mediating IAV HA-induced degradation of IFNAR1. We identified PARP1 as an interacting partner for IAV HA through mass spectrometry analysis. This interaction was confirmed by coimmunoprecipitation analyses. Furthermore, confocal fluorescence microscopy showed altered localization of endogenous PARP1 upon transient IAV HA expression or during IAV infection. Knockdown or inhibition of PARP1 rescued IFNAR1 levels upon IAV infection or HA expression, exemplifying the importance of PARP1 for IAV-induced reduction of IFNAR1. Notably, PARP1 was crucial for the robust replication of IAV, which was associated with regulation of the type I IFN receptor signaling pathway. These results indicate that PARP1 promotes IAV replication by controlling viral HA-induced degradation of host type I IFN receptor. Altogether, these findings provide novel insight into interactions between influenza virus and the host innate immune response and reveal a new function for PARP1 during influenza virus infection. IMPORTANCE Influenza A virus (IAV) infections cause seasonal and pandemic influenza outbreaks, which pose a devastating global health concern. Despite the availability of antivirals against influenza, new IAV strains continue to persist by overcoming the therapeutics. Therefore, much emphasis in the field is placed on identifying new therapeutic targets that can more effectively control influenza. IAV utilizes several tactics to evade host innate immunity, which include the evasion of antiviral type I interferon (IFN) responses. Degradation of type I IFN receptor (IFNAR) is one known method of subversion, but the molecular mechanism for IFNAR downregulation during IAV infection remains unclear. Here, we have found that a host protein, poly(ADP-ribose) polymerase 1 (PARP1), facilitates IFNAR degradation and accelerates IAV replication. The findings reveal a novel cellular target for the potential development of antivirals against influenza, as well as expand our base of knowledge regarding interactions between influenza and the host innate immunity.

scholarly journals The Intestinal Microbiome Primes Host Innate Immunity Against Enteric Virus Systemic Infection Through Type I Interferon

2021 ◽  
Author(s):  
Xiao-Lian Yang ◽  
Gan Wang ◽  
Jin-Yan Xie ◽  
Han Li ◽  
Wei Liu ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Type I Interferon ◽  
Systemic Infection ◽  
Enteric Virus ◽  
Encephalomyocarditis Virus ◽  
Commensal Bacteria ◽  
Intestinal Microbiome ◽  
Type I ◽  
Type I Ifn ◽  
Host Innate Immunity

Abstract BackgroundIntestinal microbiomes are of vital importance in antagonizing systemic viral infection. However, very little literature has shown whether commensal bacteria play a crucial role in protecting enteric virus systemic infection from the aspect of modulating host innate immunity. Also, only a few specific commensal bacteria species have been revealed to be capable in regulating antiviral innate immune responses mediated by type I interferon (IFN). The underlying mechanisms have not yet been elucidated.ResultsWe utilized an enteric virus, encephalomyocarditis virus (EMCV) to inoculate PBS-treated or antibiotic cocktail-administrated mice (Abx) orally or intraperitoneally to examine the impact of microbiota depletion on virulence and viral replication in vivo. Microbiota depletion exacerbated the mortality, neuropathogenesis, viremia and viral burden in brain following EMCV infection. Furthermore, Abx-treated mice exhibited severely diminished macrophage activation and impaired type I IFN production and ISG expression in PBMC, spleen or brain. With the help of fecal bacterial 16S rRNA sequencing of PBS and Abx mice, we identified a single commensal bacterium Blautia coccoides (B. coccoides) that can restore macrophage- and IFNAR-dependent type I IFN responses to restrict systemic enteric virus infection.ConclusionOur present study demonstrates that intestinal microbiome is fundamental for protecting from enteric virus systemic infection through activating macrophages and type I IFN responses. Reconstitution with B. coccoides can inhibit enteric virus infection and mitigate its neuropathogenesis by activating IFN-I and ISG responses in macrophages via IFNAR- and STAT1-mediated signaling pathway.

scholarly journals 765 The first-in-class small molecule TREX1 inhibitor CPI-381 demonstrates type I IFN induction and sensitization of tumors to immune checkpoint blockade

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A800-A800
Author(s):  
Costa Salojin ◽  
Anna Gardberg ◽  
Valerie Vivat ◽  
Lei Cui ◽  
Jeffrey Lauer ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Tumor Growth ◽  
Small Molecule ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Type I ◽  
Type I Ifn ◽  
Syngeneic Tumor

BackgroundTREX1 is an exonuclease that functions as a negative regulator of innate immunity. TREX1 controls dsDNA sensing in tumor and immune cells by preventing aberrant dsDNA buildup that triggers STING-mediated Type 1 Interferon (IFN) induction leading to priming of the adaptive immune system. Loss of function mutations in TREX1 and genetic ablation of trex1 in mice lead to induction of IFNbeta-driven autoimmunity. Thus, TREX1 is a promising target to elicit IFN-mediated anti-tumor immunity.MethodsTo characterize TREX1 inhibitors we developed cell-based assays utilizing human HCT116 carcinoma and THP-1 monocytic Dual reporter cell lines to monitor IRF activity. Activation of cGAS was assessed by measuring cGAMP levels in B16F10 melanoma cells. The potency of TREX1 inhibitors in primary human dendritic cells (DC)s was analyzed by measuring IFNbeta induction by exogenous dsDNA. Analysis of tumor growth inhibition following TREX1 inhibitor treatment was conducted in mouse syngeneic tumor models. TREX1 activity was assessed by measuring degradation of a custom dsDNA substrate.ResultsWe report here the development of a small molecule TREX1 inhibitor, CPI-381, with nanomolar cellular potency, which translated into a robust induction of IRF reporter activity. We observed a significant increase in cGAMP production in B16F10 cells transfected with DNA in the presence of CPI-381, suggesting that CPI-381-mediated inhibition of TREX1 leads to the activation of dsDNA sensors, such as cGAS. Treatment of THP-1 cells with CPI-381 induced the expression of several key ISG involved in innate immunity. Moreover, inhibition of TREX1 with CPI-381 phenocopied the effect of TREX1 genetic deletion in primary human DCs by upregulating IFNbeta. To evaluate whether TREX1 negatively regulates IFNbeta production in syngeneic tumor models, we knocked down trex1 in B16F10, MB49, MC38, and CT26 murine cells. Accumulation of cytosolic dsDNA resulted in a substantial increase in IFNbeta secretion by all four TREX1-KO cell lines.In vivo efficacy studies with CPI-381 demonstrated reduced tumor growth in the MC38 syngeneic tumor model either alone or in combination with anti-PD1. We observed a reduction of TREX1 activity in CPI-381 treated tumors, confirming an inverse relationship between TREX1 intra-tumor activity and tumor growth, and efficient target engagement after systemic (oral) delivery.ConclusionsWe have developed a first-in-class, potent TREX1 inhibitor demonstrating excellent in vitro and in vivo potency via enhancement of cytosolic dsDNA sensing and induction of IFNbeta in cancer and immune cells. CPI-381-induced tumor-intrinsic TREX1 inhibition elicits antitumor immunity as a single agent and increases response to immune checkpoint blockade via mechanisms downstream of TREX1 that activate type I IFN signaling.Ethics ApprovalAll animal work was approved and conducted under the oversight of the Charles River Accelerator and Development Lab (CRADL, Cambridge, MA) Institutional Animal Care and Use Committee (protocol # 2021-1258).

scholarly journals Autophagy Contributes to Host Immunity and Protection against Zika Virus Infection via Type I IFN Signaling

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Yuyi Huang ◽  
Yujie Wang ◽  
Shuhui Meng ◽  
Zhuohang Chen ◽  
Haifan Kong ◽  
...  
Keyword(s):  
Virus Infection ◽  
Cell Line ◽  
Zika Virus ◽  
Fetal Brain ◽  
Host Immunity ◽  
Type I ◽  
Type I Ifn ◽  
Zikv Infection

Recent studies have indicated that the Zika virus (ZIKV) has a significant impact on the fetal brain, and autophagy is contributing to host immune response and defense against virus infection. Here, we demonstrate that ZIKV infection triggered increased LC3 punctuation in mouse monocyte-macrophage cell line (RAW264.7), mouse microglial cell line (BV2), and hindbrain tissues, proving the occurrence of autophagy both in vitro and in vivo. Interestingly, manual intervention of autophagy, like deficiency inhibited by 3-MA, can reduce viral clearance in RAW264.7 cells upon ZIKV infection. Besides, specific siRNA strategy confirmed that autophagy can be activated through Atg7-Atg5 and type I IFN signaling pathway upon ZIKV infection, while knocking down of Atg7 and Atg5 effectively decreased the ZIKV clearance in phagocytes. Furthermore, we analyzed that type I IFN signaling could contribute to autophagic clearance of invaded ZIKV in phagocytes. Taken together, our findings demonstrate that ZIKV-induced autophagy is favorable to activate host immunity, particularly through type I IFN signaling, which participates in host protection and defense against ZIKV infection.

scholarly journals Toll-Like Receptors and their Contribution to Innate Immunity: Focus on TLR4 Activation by Lipopolysaccharide

2014 ◽  
Vol 4 (1) ◽  
pp. 1-23 ◽  
Author(s):  
Maciej Czerkies ◽  
Katarzyna Kwiatkowska
Keyword(s):  
Innate Immunity ◽  
Ligand Binding ◽  
Transmembrane Domain ◽  
Adaptor Proteins ◽  
Type I Interferons ◽  
Type I ◽  
Toll Like Receptors ◽  
Signalling Cascades ◽  
Genes Encoding ◽  
Membrane Components

Summary Mechanisms of innate immunity are triggered as a result of recognition of evolutionarily conserved structures of microorganisms, named pathogen-associated molecular patterns. Their recognition is mediated by specialized receptors which initiate signalling cascades leading to expression of pro-inflammatory mediators and regulation of acquired immunity. Among several classes of such receptors, Toll-like receptors (TLRs) are extensively studied as they can sense an array of microbial cell wall and membrane components as well as single- and double-stranded RNA and DNA motifs typical for microorganisms. Each TLR consists of a ligand-binding domain containing leucine-rich repeats, a single transmembrane domain and a signalling TIR domain. After ligand binding, TLRs dimerize which facilitates the interaction of their TIR domains with adaptor proteins triggering signalling cascades. TLRs engage four common adaptor proteins, about ten signalling kinases, and a few transcription factors including NFκB, IRF and AP-1. In this review, special attention is paid to TLR4 activated by lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, since an exaggerated response to LPS may lead to potentially deadly septic shock. In recent years considerable progress has been made in the understanding of how the cooperation of several proteins, including CD14, TLR4/MD-2 complex and scavenger receptors, modulates the cell response to LPS. These studies have also revealed a dichotomy of signalling pathways triggered by TLR4 which depends on the participation of MyD88 and TRIF adaptor proteins and leads to the expression of genes encoding pro-inflammatory cytokines and type I interferons, respectively. The key event in the TRIF-dependent pathway is the internalization of activated TLR4.

scholarly journals Type I IFN Receptor Regulates Neutrophil Functions and Innate Immunity toLeishmaniaParasites

2010 ◽  
Vol 184 (12) ◽  
pp. 7047-7056 ◽  
Author(s):  
Lijun Xin ◽  
Diego A. Vargas-Inchaustegui ◽  
Sharon S. Raimer ◽  
Brent C. Kelly ◽  
Jiping Hu ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Type I ◽  
Type I Ifn

scholarly journals DDX3X Links NLRP11 to the Regulation of Type I Interferon Responses and NLRP3 Inflammasome Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Ioannis Kienes ◽  
Sarah Bauer ◽  
Clarissa Gottschild ◽  
Nora Mirza ◽  
Jens Pfannstiel ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Cytokine ◽  
Inflammasome Activation ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Central Target ◽  
Nlrp3 Inflammasome Activation ◽  
Lrr Domain

Tight regulation of inflammatory cytokine and interferon (IFN) production in innate immunity is pivotal for optimal control of pathogens and avoidance of immunopathology. The human Nod-like receptor (NLR) NLRP11 has been shown to regulate type I IFN and pro-inflammatory cytokine responses. Here, we identified the ATP-dependent RNA helicase DDX3X as a novel binding partner of NLRP11, using co-immunoprecipitation and LC-MS/MS. DDX3X is known to enhance type I IFN responses and NLRP3 inflammasome activation. We demonstrate that NLRP11 can abolish IKKϵ-mediated phosphorylation of DDX3X, resulting in lower type I IFN induction upon viral infection. These effects were dependent on the LRR domain of NLRP11 that we mapped as the interaction domain for DDX3X. In addition, NLRP11 also suppressed NLRP3-mediated caspase-1 activation in an LRR domain-dependent manner, suggesting that NLRP11 might sequester DDX3X and prevent it from promoting NLRP3-induced inflammasome activation. Taken together, our data revealed DDX3X as a central target of NLRP11, which can mediate the effects of NLRP11 on type I IFN induction as well as NLRP3 inflammasome activation. This expands our knowledge of the molecular mechanisms underlying NLRP11 function in innate immunity and suggests that both NLRP11 and DDX3X might be promising targets for modulation of innate immune responses.

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