Route of Infection Determines the Impact of Type I Interferons on Innate Immunity to Listeria monocytogenes

Tuberculosis (TB) is still an important global threat and although the causing organism has been discovered long ago, effective prevention strategies are lacking. Mycobacterium tuberculosis (MTB) is a unique pathogen with a complex host interaction. Understanding the immune responses upon infection with MTB is crucial for the development of new vaccination strategies and therapeutic targets for TB. Recently, it has been proposed that sensing bacterial nucleic acid in antigen-presenting cells via intracellular pattern recognition receptors (PRRs) is a central mechanism for initiating an effective host immune response. Here, we summarize key findings of the impact of mycobacterial RNA sensing for innate and adaptive host immunity after MTB infection, with emphasis on endosomal toll-like receptors (TLRs) and cytosolic sensors such as NLRP3 and RLRs, modulating T-cell differentiation through IL-12, IL-21, and type I interferons. Ultimately, these immunological pathways may impact immune memory and TB vaccine efficacy. The novel findings described here may change our current understanding of the host response to MTB and potentially impact clinical research, as well as future vaccination design. In this review, the current state of the art is summarized, and an outlook is given on how progress can be made.

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

Advances in Cell Biology ◽

10.2478/acb-2014-0001 ◽

2014 ◽

Vol 4 (1) ◽

pp. 1-23 ◽

Cited By ~ 8

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.

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Type I Interferons Increase Host Susceptibility to Trypanosoma cruzi Infection

Infection and Immunity ◽

10.1128/iai.01176-10 ◽

2011 ◽

Vol 79 (5) ◽

pp. 2112-2119 ◽

Cited By ~ 21

Author(s):

Anne-Danielle C. Chessler ◽

Kacey L. Caradonna ◽

Akram Da'dara ◽

Barbara A. Burleigh

Keyword(s):

Trypanosoma Cruzi ◽

Parasite Burden ◽

Host Susceptibility ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Content Type ◽

Type I Ifns ◽

Ifn Γ ◽

The Impact

ABSTRACTTrypanosoma cruzi, the protozoan parasite that causes human Chagas' disease, induces a type I interferon (IFN) (IFN-α/β) response during acute experimental infection in mice and in isolated primary cell types. To examine the potential impact of the type I IFN response in shaping outcomes in experimentalT. cruziinfection, groups of wild-type (WT) and type I IFN receptor-deficient (IFNAR−/−) 129sv/ev mice were infected with two differentT. cruzistrains under lethal and sublethal conditions and several parameters were measured during the acute stage of infection. The results demonstrate that type I IFNs are not required for early host protection againstT. cruzi. In contrast, under conditions of lethalT. cruzichallenge, WT mice succumbed to infection whereas IFNAR−/−mice were ultimately able to control parasite growth and survive.T. cruziclearance in and survival of IFNAR−/−mice were accompanied by higher levels of IFN-γ production by isolated splenocytes in response to parasite antigen. The suppression of IFN-γ in splenocytes from WT mice was independent of IL-10 levels. While the impact of type I IFNs on the production of IFN-γ and other cytokines/chemokines remains to be fully determined in the context ofT. cruziinfection, our data suggest that, under conditions of high parasite burden, type I IFNs negatively impact IFN-γ production, initiating a detrimental cycle that contributes to the ultimate failure to control infection. These findings are consistent with a growing theme in the microbial pathogenesis field in which type I IFNs can be detrimental to the host in a variety of nonviral pathogen infection models.

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Activation of STING signaling pathway effectively blocks human coronavirus infection

Journal of Virology ◽

10.1128/jvi.00490-21 ◽

2021 ◽

Author(s):

Wei Liu ◽

Hanako M. Reyes ◽

June F. Yang ◽

Yize Li ◽

Kathleen M. Stewart ◽

...

Keyword(s):

Signaling Pathway ◽

Broad Spectrum ◽

Type I Interferons ◽

Type I ◽

Immune Effector ◽

Innate Immune Effector ◽

Coronavirus Infection ◽

Novel Target ◽

Sting Pathway ◽

The Impact

The COVID-19 pandemic poses a serious global health threat. The rapid global spread of SARS-CoV-2 highlights an urgent need to develop effective therapeutics for blocking SARS-CoV-2 infection and spread. Stimulator of Interferon Genes (STING) is a chief element in host antiviral defense pathways. In this study, we examined the impact of the STING signaling pathway on coronavirus infection using the HCoV-OC43 model. We found that HCoV-OC43 infection did not stimulate the STING signaling pathway, but the activation of STING signaling effectively inhibits HCoV-OC43 infection to a much greater extent than that of type I interferons (IFNs). We also discovered that IRF3, the key STING downstream innate immune effector, is essential for this anti-coronavirus activity. In addition, we found that the amidobenzimidazole (ABZI)-based human STING agonist (diABZI) robustly blocks the infection of not only HCoV-OC43 but also SARS-CoV-2. Therefore, our study identifies the STING signaling pathway as a potential therapeutic target that could be exploited for developing broad-spectrum antiviral therapeutics against multiple coronavirus strains in order to face the challenge of future coronavirus outbreaks. Importance The highly infectious and lethal SARS-CoV-2 is posing an unprecedented threat to public health. Other coronaviruses are likely to jump from a non-human animal to humans in the future. Novel broad-spectrum antiviral therapeutics are therefore needed to control known pathogenic coronaviruses such as SARS-CoV-2 and its newly mutated variants, as well as future coronavirus outbreaks. STING signaling is a well-established host defense pathway, but its role in coronavirus infection remains unclear. In the present study, we found that activation of the STING signaling pathway robustly inhibits infection of HCoV-OC43 and SARS-CoV-2. These results identified the STING pathway as a novel target for controlling the spread of known pathogenic coronaviruses as well as emerging coronavirus outbreaks.

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Impact of STING Inflammatory Signaling during Intracellular Bacterial Infections

Cells ◽

10.3390/cells11010074 ◽

2021 ◽

Vol 11 (1) ◽

pp. 74

Author(s):

Erika S. Guimarães ◽

Fabio V. Marinho ◽

Nina M. G. P. de Queiroz ◽

Maísa M. Antunes ◽

Sergio C. Oliveira

Keyword(s):

Immune Responses ◽

Bacterial Infections ◽

Inflammatory Responses ◽

Metabolic Reprogramming ◽

Host Cells ◽

Type I Interferons ◽

Type I ◽

Bacterial Survival ◽

Inflammatory Profile ◽

The Impact

The early detection of bacterial pathogens through immune sensors is an essential step in innate immunity. STING (Stimulator of Interferon Genes) has emerged as a key mediator of inflammation in the setting of infection by connecting pathogen cytosolic recognition with immune responses. STING detects bacteria by directly recognizing cyclic dinucleotides or indirectly by bacterial genomic DNA sensing through the cyclic GMP-AMP synthase (cGAS). Upon activation, STING triggers a plethora of powerful signaling pathways, including the production of type I interferons and proinflammatory cytokines. STING activation has also been associated with the induction of endoplasmic reticulum (ER) stress and the associated inflammatory responses. Recent reports indicate that STING-dependent pathways participate in the metabolic reprogramming of macrophages and contribute to the establishment and maintenance of a robust inflammatory profile. The induction of this inflammatory state is typically antimicrobial and related to pathogen clearance. However, depending on the infection, STING-mediated immune responses can be detrimental to the host, facilitating bacterial survival, indicating an intricate balance between immune signaling and inflammation during bacterial infections. In this paper, we review recent insights regarding the role of STING in inducing an inflammatory profile upon intracellular bacterial entry in host cells and discuss the impact of STING signaling on the outcome of infection. Unraveling the STING-mediated inflammatory responses can enable a better understanding of the pathogenesis of certain bacterial diseases and reveal the potential of new antimicrobial therapy.

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.633769 ◽

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.

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Extensive evolutionary and functional diversity among mammalian AIM2-like receptors

Journal of Experimental Medicine ◽

10.1084/jem.20121960 ◽

2012 ◽

Vol 209 (11) ◽

pp. 1969-1983 ◽

Cited By ~ 136

Author(s):

Rebecca L. Brunette ◽

Janet M. Young ◽

Deborah G. Whitley ◽

Igor E. Brodsky ◽

Harmit S. Malik ◽

...

Keyword(s):

Innate Immunity ◽

Phylogenetic Analysis ◽

Gene Family ◽

Functional Diversity ◽

Innate Immune ◽

Type I Interferons ◽

Type I ◽

Antiviral Responses ◽

Immune Detection ◽

Dependent Type

Innate immune detection of nucleic acids is important for initiation of antiviral responses. Detection of intracellular DNA activates STING-dependent type I interferons (IFNs) and the ASC-dependent inflammasome. Certain members of the AIM2-like receptor (ALR) gene family contribute to each of these pathways, but most ALRs remain uncharacterized. Here, we identify five novel murine ALRs and perform a phylogenetic analysis of mammalian ALRs, revealing a remarkable diversification of these receptors among mammals. We characterize the expression, localization, and functions of the murine and human ALRs and identify novel activators of STING-dependent IFNs and the ASC-dependent inflammasome. These findings validate ALRs as key activators of the antiviral response and provide an evolutionary and functional framework for understanding their roles in innate immunity.

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When human guanylate-binding proteins meet viral infections

Journal of Biomedical Science ◽

10.1186/s12929-021-00716-8 ◽

2021 ◽

Vol 28 (1) ◽

Author(s):

Rongzhao Zhang ◽

Zhixin Li ◽

Yan-Dong Tang ◽

Chenhe Su ◽

Chunfu Zheng

Keyword(s):

Innate Immunity ◽

Viral Infection ◽

Binding Proteins ◽

Molecular Mechanisms ◽

Viral Infections ◽

Innate Immune ◽

Type I Interferons ◽

Type I ◽

Downstream Signaling ◽

Antiviral Innate Immunity

AbstractInnate immunity is the first line of host defense against viral infection. After invading into the cells, pathogen-associated-molecular-patterns derived from viruses are recognized by pattern recognition receptors to activate the downstream signaling pathways to induce the production of type I interferons (IFN-I) and inflammatory cytokines, which play critical functions in the host antiviral innate immune responses. Guanylate-binding proteins (GBPs) are IFN-inducible antiviral effectors belonging to the guanosine triphosphatases family. In addition to exerting direct antiviral functions against certain viruses, a few GBPs also exhibit regulatory roles on the host antiviral innate immunity. However, our understanding of the underlying molecular mechanisms of GBPs' roles in viral infection and host antiviral innate immune signaling is still very limited. Therefore, here we present an updated overview of the functions of GBPs during viral infection and in antiviral innate immunity, and highlight discrepancies in reported findings and current challenges for future studies, which will advance our understanding of the functions of GBPs and provide a scientific and theoretical basis for the regulation of antiviral innate immunity.

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