scholarly journals How dendritic cells sense and respond to viral infections

2021 ◽  
Vol 135 (19) ◽  
pp. 2217-2242
Author(s):  
Laura Marongiu ◽  
Mihai Valache ◽  
Fabio A. Facchini ◽  
Francesca Granucci
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Viral Infections ◽  
Adaptive Immune Response ◽  
Type I Interferons ◽  
Type I ◽  
Viral Pathogens ◽  
Cross Presentation ◽  
Antiviral Responses ◽  
Sense And Respond

Abstract The ability of dendritic cells (DCs) to sense viral pathogens and orchestrate a proper immune response makes them one of the key players in antiviral immunity. Different DC subsets have complementing functions during viral infections, some specialize in antigen presentation and cross-presentation and others in the production of cytokines with antiviral activity, such as type I interferons. In this review, we summarize the latest updates concerning the role of DCs in viral infections, with particular focus on the complex interplay between DC subsets and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Despite being initiated by a vast array of immune receptors, DC-mediated antiviral responses often converge towards the same endpoint, that is the production of proinflammatory cytokines and the activation of an adaptive immune response. Nonetheless, the inherent migratory properties of DCs make them a double-edged sword and often viral recognition by DCs results in further viral dissemination. Here we illustrate these various aspects of the antiviral functions of DCs and also provide a brief overview of novel antiviral vaccination strategies based on DCs targeting.

scholarly journals How fragile we are. Influence of STimulator of INterferon Genes, STING, variants on pathogen recognition and immune response efficiency

2021 ◽  
Author(s):  
Jeremy Morere ◽  
Cecilia Hognon ◽  
Tom Miclot ◽  
Tao Jiang ◽  
Elise Dumont ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Dynamical Behavior ◽  
Structural Features ◽  
Type I Interferons ◽  
Machine Learning Techniques ◽  
Type I ◽  
Interaction Patterns

The STimulator of INterferon Genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP upon the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines which are crucial for protecting cells from infections. STING signaling pathway can also influence both tumor-suppressive and tumor-promoting mechanisms, rendering it an appealing target for drug design. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the differential molecular mechanisms exhibited by these variants is of utmost importance notably towards personalized medicine treatments against diseases such as viral infections (COVID-19, Dengue...), cancers, or auto-inflammatory diseases. Owing to micro-seconds scale molecular modeling simulations and post-processing by contacts analysis and Machine Learning techniques, we reveal the dynamical behavior of four STING variants (wild type, G230A, R293Q, and G230A-R293Q) and we rationalize the variability of efficiency observed experimentally. Our results show that the decrease of STING activity is linked to a stiffening of key-structural features of the binding cavity, together with changes of the interaction patterns within the protein.

scholarly journals HIV-1 Vpr Degrades TET2 to Suppress IRF7 and Interferon Expression in Plasmacytoid Dendritic Cells

2019 ◽  
Author(s):  
Qi Wang ◽  
Li-Chung Tsao ◽  
Lei Lv ◽  
Yanping Xu ◽  
Liang Cheng ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Viral Infections ◽  
Constitutive Expression ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Type I ◽  
Restriction Factors ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Hiv 1

AbstractPlasmacytoid dendritic cells (pDCs) are the major source of type I interferons (IFN-I) in rapid response to viral infections, with constitutive expression of interferon regulatory factor 7 (IRF7). HIV-1 expresses several accessory proteins to counteract specific IFN-induced host restriction factors. As one abundant virion-associated protein, HIV-1 Vpr remains enigmatic in enhancing HIV-1 infection via unclear mechanisms. Here we report that Vpr impaired IFN-I induction in pDCs to enhance HIV-1 replication in CD4+ T cells. Blockade of IFN-I signaling abrogated the effect of Vpr on HIV-1 replication. Virion-associated Vpr suppressed IFN-I induction in pDC by TLR7 agonists. Modulation of IFN-I induction by Vpr was genetically dependent on its activity of TET2 degradation. We further demonstrate that Vpr-mediated TET2 degradation reduced expression of IRF7 in pDCs. Finally, degradation of TET2 in pDCs by Vpr reduced the demethylation level of the IRF7 promoter via CXXC5-dependent recruitment. We conclude that HIV-1 Vpr functions to promote HIV-1 replication by suppressing TET2-dependent IRF7 expression and IFN-I induction in pDCs. The Vpr-TET2-IRF7 axis provides a novel therapeutic target to control HIV-1 infection.

Respiratory and gastrointestinal epithelial modulation of the immune response during viral infection

2011 ◽  
Vol 18 (1) ◽  
pp. 179-189 ◽  
Author(s):  
Paul M Fitch ◽  
Paul Henderson ◽  
Jürgen Schwarze
Keyword(s):  
Immune Response ◽  
Human Body ◽  
World Wide ◽  
Viral Infections ◽  
Adaptive Immune Response ◽  
Significant Morbidity ◽  
Viral Pathogens ◽  
Adaptive Immune ◽  
Adaptive Interface ◽  
Portal Of Entry

Respiratory and enteric viral infections cause significant morbidity and mortality world-wide and represent a major socio-economic burden. Many of these viruses have received unprecedented public and media interest in recent years. A popular public misconception is that viruses are a threat to which the human body has only limited defences. However, the majority of primary and secondary exposures to virus are asymptomatic or induce only minor symptoms. The mucosal epithelial surfaces are the main portal of entry for viral pathogens and are centrally involved in the initiation, maintenance and polarisation of the innate and adaptive immune response to infection. This review describes the defences employed by the epithelium of the respiratory and gastrointestinal tracts during viral infections with focus on epithelial modulation of the immune response at the innate/adaptive interface.

scholarly journals Deletion of Irf3 and Irf7 Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection

2016 ◽  
Vol 9 (2) ◽  
pp. 145-161 ◽  
Author(s):  
Bastian Hatesuer ◽  
Hang Thi Thu Hoang ◽  
Peggy Riese ◽  
Stephanie Trittel ◽  
Ingo Gerhauser ◽  
...  
Keyword(s):  
Immune Response ◽  
Knockout Mice ◽  
Influenza A ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Adaptive Immune Response ◽  
Strong Increase ◽  
Type I ◽  
Influenza A Viruses ◽  
Double Knockout

The interferon (IFN) pathway plays an essential role in the innate immune response following viral infections and subsequent shaping of adaptive immunity. Infections with influenza A viruses (IAV) activate the IFN pathway after the recognition of pathogen-specific molecular patterns by respective pattern recognition receptors. The IFN regulatory factors IRF3 and IRF7 are key players in the regulation of type I and III IFN genes. In this study, we analyzed the role of IRF3 and IRF7 for the host response to IAV infections in Irf3-/-, Irf7-/-, and Irf3-/-Irf7-/- knockout mice. While the absence of IRF3 had only a moderate impact on IFN expression, deletion of IRF7 completely abolished IFNα production after infection. In contrast, lack of both IRF3 and IRF7 resulted in the absence of both IFNα and IFNβ after IAV infection. In addition, IAV infection of double knockout mice resulted in a strong increase of mortality associated with a massive influx of granulocytes in the lung and reduced activation of the adaptive immune response.

scholarly journals Human plasmacytoid dendritic cells are equipped with antigen-presenting and tumoricidal capacities

Blood ◽  
2012 ◽  
Vol 120 (19) ◽  
pp. 3936-3944 ◽  
Author(s):  
Jurjen Tel ◽  
Evelien L. Smits ◽  
Sébastien Anguille ◽  
Rubin N. Joshi ◽  
Carl G. Figdor ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Viral Infections ◽  
Cell Subset ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Human Interferon ◽  
Target Cells ◽  
Type I ◽  
Dendritic Cell Subset ◽  
Antigen Presenting

Abstract Human plasmacytoid dendritic cells (pDCs) represent a highly specialized naturally occurring dendritic-cell subset and are the main producers of type I interferons (IFNs) in response to viral infections. We show that human pDCs activated by the preventive vaccine FSME specifically up-regulate CD56 on their surface, a marker that was thought to be specific for NK cells and associated with cytolytic effector functions. We observed that FSME-activated pDCs specifically lysed NK target cells and expressed cytotoxic molecules, such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and granzyme B. Elevated levels of these molecules coincided with the expression of CD56, indicative for skewing human pDCs toward an interferon-producing killer DC subset. Detailed phenotypical and functional analysis revealed that pDCs attained a mature phenotype, secreted proinflammatory cytokines, and had the capacity to present antigens and stimulate T cells. Here, we report on the generation of CD56+ human interferon producing killer pDCs with the capacity to present antigens. These findings aid in deciphering the role for pDCs in antitumor immunity and present a promising prospect of developing antitumor therapy using pDCs.

scholarly journals Functional modulation of plazmacytoid dendritic cells during viral infections

2018 ◽  
Vol 72 ◽  
pp. 264-277
Author(s):  
Lidia Szulc-Dąbrowska ◽  
Piotr Wojtyniak ◽  
Diana Papiernik ◽  
Justyna Struzik
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Dendritic Cells ◽  
Nucleic Acids ◽  
Viral Infections ◽  
Type I ◽  
Term Survival ◽  
Antiviral Immune Response ◽  
Type I Ifns ◽  
Immunodeficiency Virus

Plasmacytoid dendritic cells (pDCs), also known as interferon (IFN)-producing cells (IPCs), represent a unique cell population of innate immunity due to their ability to produce high amounts of type I IFNs in response to viral infections. The pDCs recognize viral nucleic acids via Toll-like receptor (TLR)7 and TLR9 localized in endosomal compartments. Type I IFNs, secreted by activated pDCs through the recognition of foreign nucleic acids, not only exhibit a direct antiviral activity but also activate NK cells, induce myeloid DC (mDC) maturation, promote T cell long-term survival and memory formation, polarization of Th1 cells, cytolytic activity of CD8+ T lymphocytes and IFN-γ production. Therefore, pDCs link innate and adaptive immunity to mount an effective antiviral immune response. The pDCs, which act as the main cells of innate immunity that produce type I IFNs, play an important role in controlling viral infections, including human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), lymphocytic choriomeningitis virus (LCMV), hepatitis C virus (HCV), hepatitis B virus (HBV), respiratory syncytial virus (RSV) and herpes simplex virus (HSV) infections. However, some of these viruses can infect and even replicate productively in pDCs, resulting in modulation and functional impairment of these cells. Thus, viruses evade host antiviral immune response to mediate a persistent infection.

scholarly journals Production of IFNβ by Conventional Dendritic Cells after Stimulation with Viral Compounds and IFNβ-Independent IFNAR1-Signaling Pathways are Associated with Aggravation of Polymicrobial Sepsis

2019 ◽  
Vol 20 (18) ◽  
pp. 4410 ◽  
Author(s):  
Magdalena Howe ◽  
Jens Bauer ◽  
Anja Schulze ◽  
Sonja Kropp ◽  
Richard M. Locksley ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Viral Infections ◽  
Expression Patterns ◽  
Primary Source ◽  
Polymicrobial Sepsis ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Altered Expression

Viral infections are associated with increased incidence of severe sepsis. Particularly during the early stages, type I interferons (IFNs) are known mediators of detrimental effects. However, the functional role of early interferon β (IFNβ) and its cellular source during sepsis in the context of preexisting viral infections has not been defined. Using the colon ascendens stent peritonitis (CASP) model, we demonstrate that IFNβ−/− and type I IFN receptor (IFNAR1)−/− mice were less susceptible to sepsis after pre-stimulation with the viral mimetic poly(I:C). Wild type (WT) mice treated with poly(I:C) exhibited altered expression patterns of TNF and IL-12p40 during CASP which were dependent on IFNβ or IFNAR1, suggesting a mechanism for the increased sepsis susceptibility of WT mice. Using a double cytokine reporter mouse model, we present novel data on the simultaneous expression of IFNβ and IL-12p40 on a single cell level during polymicrobial sepsis in vivo. Conventional dendritic cells (cDCs) were identified as primary source of IFNβ and the protective cytokine IL-12p40 after CASP surgery irrespective of poly(I:C) pre-stimulation. These data demonstrated that if polymicrobial sepsis is preceded by a viral infection, IFNβ and IL-12p40 are expressed by polyfunctional cDCs suggesting that these cells can play both detrimental and beneficial roles during sepsis development.

scholarly journals RIOK3 Is an Adaptor Protein Required for IRF3-Mediated Antiviral Type I Interferon Production

2014 ◽  
Vol 88 (14) ◽  
pp. 7987-7997 ◽  
Author(s):  
Jun Feng ◽  
Paul D. De Jesus ◽  
Victoria Su ◽  
Stephanie Han ◽  
Danyang Gong ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Type I Interferon ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Antiviral Responses ◽  
Interferon Pathway ◽  
Irf3 Activation

ABSTRACTDetection of cytosolic nucleic acids by pattern recognition receptors leads to the induction of type I interferons (IFNs) and elicits the innate immune response. We report here the identification of RIOK3 as a novel adaptor protein that is essential for the cytosolic nucleic acid-induced type I IFN production and for the antiviral response to gammaherpesvirus through two independent kinome-wide RNA interference screens. RIOK3 knockdown blocks both cytosolic double-stranded B-form DNA and double-stranded RNA-induced IRF3 activation and IFN-β production. In contrast, the overexpression of RIOK3 activates IRF3 and induces IFN-β. RIOK3 functions downstream of TBK1 and upstream of IRF3 activation. Furthermore, RIOK3 physically interacts with both IRF3 and TBK1 and is necessary for the interaction between TBK1 and IRF3. In addition, global transcriptome analysis shows that the expression of many gene involved antiviral responses is dependent on RIOK3. Thus, knockdown of RIOK3 inhibits cellular antiviral responses against both DNA and RNA viruses (herpesvirus and influenza A virus). Our data suggest that RIOK3 plays a critical role in the antiviral type I IFN pathway by bridging TBK1 and IRF3.IMPORTANCEThe innate immune response, such as the production of type I interferons, acts as the first line of defense, limiting infectious pathogens directly and shaping the adaptive immune response. In this study, we identified RIOK3 as a novel regulator of the antiviral type I interferon pathway. Specifically, we found that RIOK3 physically interacts with TBK1 and IRF3 and bridges the functions between TBK1 and IRF3 in the activation of type I interferon pathway. The identification of a cellular kinase that plays a role the type I interferon pathway adds another level of complexity in the regulation of innate immunity and will have implications for developing novel strategies to combat viral infection.

scholarly journals Type I Interferon Production of Plasmacytoid Dendritic Cells under Control

2021 ◽  
Vol 22 (8) ◽  
pp. 4190
Author(s):  
Dóra Bencze ◽  
Tünde Fekete ◽  
Kitti Pázmándi
Keyword(s):  
Dendritic Cells ◽  
Viral Infections ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Tumor Resistance ◽  
Endogenous Factors ◽  
Associated Diseases ◽  
Type I Ifns

One of the most powerful and multifaceted cytokines produced by immune cells are type I interferons (IFNs), the basal secretion of which contributes to the maintenance of immune homeostasis, while their activation-induced production is essential to effective immune responses. Although, each cell is capable of producing type I IFNs, plasmacytoid dendritic cells (pDCs) possess a unique ability to rapidly produce large amounts of them. Importantly, type I IFNs have a prominent role in the pathomechanism of various pDC-associated diseases. Deficiency in type I IFN production increases the risk of more severe viral infections and the development of certain allergic reactions, and supports tumor resistance; nevertheless, its overproduction promotes autoimmune reactions. Therefore, the tight regulation of type I IFN responses of pDCs is essential to maintain an adequate level of immune response without causing adverse effects. Here, our goal was to summarize those endogenous factors that can influence the type I IFN responses of pDCs, and thus might serve as possible therapeutic targets in pDC-associated diseases. Furthermore, we briefly discuss the current therapeutic approaches targeting the pDC-type I IFN axis in viral infections, cancer, autoimmunity, and allergy, together with their limitations defined by the Janus-faced nature of pDC-derived type I IFNs.

scholarly journals Learning from Bats to Escape from Potent or Severe Viral Infections

2021 ◽  
Author(s):  
Vijay Kumar
Keyword(s):  
Immune Response ◽  
Crucial Role ◽  
Viral Infections ◽  
Adaptive Immune Response ◽  
Severe Infection ◽  
Viral Pathogens ◽  
Adaptive Immune ◽  
Serious Infections ◽  
Animal Reservoirs

The COVID-19 pandemic that started in December 2019 in Wuhan city, China has created chaos all over the world with over 185 million infection cases and 4 million deaths world-wide. The pathogen behind COVID-19 has been identified as severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) that is more close to the previous SARS-CoV responsible for SARS epidemic 2002–2003. Although, SARS-CoV-2 also differs from SARS-CoV in many aspects as indicated by genetic studies. For example, SARS-CoV does not have a furin binding domain or site, whereas its presence in SARS-CoV-2 spike (S) protein increases its potential for infectivity. The horseshoe bats (Rhinolphus species) from China are considered as primary animal reservoirs for SARS-CoV and SARS-CoV-2. However, along with CoVs, bats also harbor many other viral pathogens (Ebola, Nipah, and Hendra viruses) without having serious infections. The bat physiology plays a crucial role in harboring these viruses along with adaptations to longevity and slow aging process. The immune system plays a crucial role in the clearance or establishment of the infection. Present chapter discusses different immunological aspects (innate immune response comprising the virus recognizing pattern recognition receptors (PRRs), type 1 interferon production, pro- and anti-inflammatory immune response, and adaptive immune response) that help bats to control viral infection without getting a severe infection as compared to other mammals, including humans.

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