scholarly journals The Early Activation ofCD8+T Cells Is Dependent on Type I IFN Signaling following Intramuscular Vaccination of Adenovirus Vector

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Masahisa Hemmi ◽  
Masashi Tachibana ◽  
Sayaka Tsuzuki ◽  
Masaki Shoji ◽  
Fuminori Sakurai ◽  
...  
Keyword(s):  
Immune Response ◽  
Lymph Nodes ◽  
Cytotoxic T Lymphocytes ◽  
Adenovirus Vector ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Early Activation ◽  
Innate Immune Signaling ◽  
Draining Lymph Nodes

Few of the vaccines in current use can induce antigen- (Ag-) specific immunity in both mucosal and systemic compartments. Hence, the development of vaccines that realize both mucosal and systemic protection against various pathogens is a high priority in global health. Recently, it has been reported that intramuscular (i.m.) vaccination of an adenovirus vector (Adv) can induce Ag-specific cytotoxic T lymphocytes (CTLs) in both systemic and gut mucosal compartments. We previously revealed that type I IFN signaling is required for the induction of gut mucosal CTLs, not systemic CTLs. However, the molecular mechanism via type I IFN signaling is largely unknown. Here, we report that type I IFN signaling following i.m. Adv vaccination is required for the expression of type I IFN in the inguinal lymph nodes (iLNs), which are the draining lymph nodes of the administration site. We also showed that the type I IFN signaling is indispensable for the early activation of CTLs in iLNs. These data suggested that type I IFN signaling has an important role in the translation of systemic innate immune response into mucosal adaptive immunity by amplifying the innate immune signaling and activating CTLs in the iLN.

scholarly journals miR-26a Inhibits Feline Herpesvirus 1 Replication by Targeting SOCS5 and Promoting Type I Interferon Signaling

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 2 ◽  
Author(s):  
Jikai Zhang ◽  
Zhijie Li ◽  
Jiapei Huang ◽  
Hang Yin ◽  
Jin Tian ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Infection ◽  
Innate Immune Response ◽  
Antiviral Response ◽  
Innate Immune ◽  
Host Cells ◽  
Type I ◽  
Type I Ifn ◽  
Feline Herpesvirus ◽  
Herpesvirus 1

In response to viral infection, host cells activate various antiviral responses to inhibit virus replication. While feline herpesvirus 1 (FHV-1) manipulates the host early innate immune response in many different ways, the host could activate the antiviral response to counteract it through some unknown mechanisms. MicroRNAs (miRNAs) which serve as a class of regulatory factors in the host, participate in the regulation of the host innate immune response against virus infection. In this study, we found that the expression levels of miR-26a were significantly upregulated upon FHV-1 infection. Furthermore, FHV-1 infection induced the expression of miR-26a via a cGAS-dependent pathway, and knockdown of cellular cGAS significantly blocked the expression of miR-26a induced by poly (dA:dT) or FHV-1 infection. Next, we investigated the biological function of miR-26a during viral infection. miR-26a was able to increase the phosphorylation of STAT1 and promote type I IFN signaling, thus inhibiting viral replication. The mechanism study showed that miR-26a directly targeted host SOCS5. Knockdown of SOCS5 increased the phosphorylation of STAT1 and enhanced the type I IFN-mediated antiviral response, and overexpression of suppressor of the cytokine signalling 5 (SOCS5) decreased the phosphorylation of STAT1 and inhibited the type I IFN-mediated antiviral response. Meanwhile, with the knockdown of SOCS5, the upregulated expression of phosphorylated STAT1 and the anti-virus effect induced by miR-26a were significantly inhibited. Taken together, our data demonstrated a new strategy of host miRNAs against FHV-1 infection by enhancing IFN antiviral signaling.

scholarly journals Defining the Immune Responses for SARS-CoV-2-Human Macrophage Interactions

2021 ◽  
Author(s):  
Mai Mostafa ◽  
Pravin Yeapuri ◽  
Jatin Machhi ◽  
Katherine Olson ◽  
Farah Shahjin ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Infection ◽  
Innate Immune Response ◽  
Human Monocyte ◽  
Innate Immune ◽  
Mononuclear Phagocytes ◽  
Human Macrophage ◽  
Type I ◽  
Innate Immune Signaling ◽  
Organ Tissue

Host innate immune response follows severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and it is the driver of the acute respiratory distress syndrome (ARDS) amongst other inflammatory end-organ morbidities. Such life-threatening coronavirus disease 2019 (COVID-19) is heralded by virus-induced activation of mononuclear phagocytes (MPs; monocytes, macrophages, and dendritic cells). MPs play substantial roles in aberrant immune secretory activities affecting profound systemic inflammation and end organ malfunctions. All follow an abortive viral infection. To elucidate SARS-CoV-2-MP interactions we investigated transcriptomic and proteomic profiles of human monocyte-derived macrophages. While expression of the SARS-CoV-2 receptor, the angiotensin-converting enzyme 2, paralleled monocyte-macrophage differentiation it failed to affect productive viral infection. In contrast, simple macrophage viral exposure led to robust pro-inflammatory cytokine and chemokine expression but attenuated type I interferon (IFN) activity. Both paralleled dysregulation of innate immune signaling pathways specifically those linked to IFN. We conclude that the SARS-CoV-2-infected host mounts a robust innate immune response characterized by a pro-inflammatory storm heralding consequent end-organ tissue damage.

scholarly journals Role of RIG-I-like receptors in innate immune sensing of Coxsackievirus B3 and encephalomyocarditis virus in murine macrophages and fibroblasts

2018 ◽  
Author(s):  
Esther Francisco ◽  
Mehul Suthar ◽  
Michael Gale ◽  
Amy B. Rosenfeld ◽  
Vincent R. Racaniello
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Coxsackievirus B3 ◽  
Innate Immune ◽  
Encephalomyocarditis Virus ◽  
Type I ◽  
Type I Ifn ◽  
Cell Type ◽  
Murine Macrophages ◽  
Picornavirus Infection

AbstractViral infections are sensed by pattern recognition receptors that trigger an innate immune response through the expression of interferons (IFNs) and other cytokines. Most RNA viruses are sensed by the RIG-I like receptors (RLR)s. The contributions of these receptors to sensing viruses of thePicornaviridaefamily were investigated. Encephalomyocarditis virus (EMCV) and Coxsackievirus B3 (CVB3), picornaviruses of theCardiovirusandEnterovirusgenera, are detected by both MDA5 and RIG-I in bone marrow derived macrophages. In macrophages from wild type mice, type I IFN is produced early after infection; IFNβ synthesis is reduced in the absence of each sensor, while IFNα production is reduced in the absence of MDA5. EMCV and CVB3 do not replicate in murine macrophages, and their detection is different in murine embryonic fibroblasts (MEFs), in which the viruses replicate to high titers. In MEFs RIG-I was essential for the expression of type I IFNs but contributes to increased yields of CVB3, while MDA5 inhibited CVB3 replication but in an IFN independent manner. These observations demonstrate that innate sensing of similar viruses by RLRs depends upon the cell type.ImportanceEnteroviruses such as Coxsackieviruses are the most common human respiratory pathogens. The host’s innate immune response, in particular that modulated by the production of type I and III interferons, is thought to restrict picornavirus infection. Two cytoplasmic proteins, MDA5 and RIG-I, are critical for initiating the early innate immune response against these viruses. Mutations within MDA5 encoding gene have been associated with the development of severe enterovirus associated respiratory illnesses in healthy children. To further understand how the innate immune response dependent upon MDA5 and Rig-I is initiated during picornavirus infection, macrophages from mice lacking MDA5 or RIG-I were infected with Coxsackievirus B3 (CVB3) and a related animal virus. RIG-I is essential for type I IFN production during CVB3 infection; when MDA5 is present, viral titers are reduced by an IFN-independent pathway. These observations demonstrate that innate sensing of viruses by MDA5 and RIG-I depends upon the cell type.

scholarly journals Expression kinetics and innate immune response after electroporation and lipid nanoparticle mediated delivery of a self-amplifying mRNA in the skin of mice

2019 ◽  
Author(s):  
Hanne Huysmans ◽  
Zifu Zhong ◽  
Joyca De Temmerman ◽  
Barbara L. Mui ◽  
Ying K. Tam ◽  
...  
Keyword(s):  
Immune Response ◽  
Protein Expression ◽  
Lymph Nodes ◽  
Innate Immune Response ◽  
Intradermal Injection ◽  
Innate Immune ◽  
Sharp Drop ◽  
Lipid Nanoparticle ◽  
Draining Lymph Nodes ◽  
Expression Kinetics

AbstractIn this work we studied the expression kinetics and innate immune response of a self-amplifying mRNA (sa-RNA) after electroporation and lipid nanoparticle (LNP) mediated delivery in the skin of mice. Intradermal electroporation of the sa-RNA resulted in a plateau-shaped expression with the plateau between day 3 and 10. The overall protein expression of sa-RNA was significant higher than that obtained after electroporation of pDNA or non-replication mRNAs. Moreover, intradermal electroporation of sa-RNA induced a short-lived innate immune response that did not affect the expression of the sa-RNA. A complete different expression profile and innate immune response was observed when LNPs were used. The expression peaked 24h after intradermal injection of sa-RNA-LNPs and subsequently showed a sharp drop. This drop can be explained by the strong innate immune response elicited by the sa-RNA-LNPs 4h after injection. Interestingly, sa-RNA-LNPs were able to transfection the draining lymph nodes after intradermal injection.

scholarly journals Defining the Innate Immune Responses for SARS-CoV-2-Human Macrophage Interactions

2021 ◽  
Vol 12 ◽  
Author(s):  
Mai M. Abdelmoaty ◽  
Pravin Yeapuri ◽  
Jatin Machhi ◽  
Katherine E. Olson ◽  
Farah Shahjin ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Human Monocyte ◽  
Innate Immune ◽  
Mononuclear Phagocytes ◽  
Human Macrophage ◽  
Type I ◽  
Innate Immune Signaling ◽  
Life Threatening ◽  
Organ Tissue

Host innate immune response follows severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and it is the driver of the acute respiratory distress syndrome (ARDS) amongst other inflammatory end-organ morbidities. Such life-threatening coronavirus disease 2019 (COVID-19) is heralded by virus-induced activation of mononuclear phagocytes (MPs; monocytes, macrophages, and dendritic cells). MPs play substantial roles in aberrant immune secretory activities affecting profound systemic inflammation and end-organ malfunctions. All follow the presence of persistent viral components and virions without evidence of viral replication. To elucidate SARS-CoV-2-MP interactions we investigated transcriptomic and proteomic profiles of human monocyte-derived macrophages. While expression of the SARS-CoV-2 receptor, the angiotensin-converting enzyme 2, paralleled monocyte-macrophage differentiation, it failed to affect productive viral infection. In contrast, simple macrophage viral exposure led to robust pro-inflammatory cytokine and chemokine expression but attenuated type I interferon (IFN) activity. Both paralleled dysregulation of innate immune signaling pathways, specifically those linked to IFN. We conclude that the SARS-CoV-2-infected host mounts a robust innate immune response characterized by a pro-inflammatory storm heralding end-organ tissue damage.

scholarly journals Defective early innate immune response to ectromelia virus in the draining lymph nodes of aged mice due to impaired dendritic cell accumulation

Aging Cell ◽  
2020 ◽  
Vol 19 (7) ◽  
Author(s):  
Colby Stotesbury ◽  
Eric B. Wong ◽  
Lingjuan Tang ◽  
Brian Montoya ◽  
Cory J. Knudson ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cell ◽  
Lymph Nodes ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Ectromelia Virus ◽  
Aged Mice ◽  
Cell Accumulation ◽  
Draining Lymph Nodes

scholarly journals Innate Immune Response to Adenoviral Vectors Is Mediated by both Toll-Like Receptor-Dependent and -Independent Pathways

2007 ◽  
Vol 81 (7) ◽  
pp. 3170-3180 ◽  
Author(s):  
Jiangao Zhu ◽  
Xiaopei Huang ◽  
Yiping Yang
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Adenoviral Vectors ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Adaptive Immune ◽  
Type I Ifns

ABSTRACT Recombinant adenoviral vectors have been widely used for gene therapy applications and as vaccine vehicles for treating infectious diseases such as human immunodeficiency virus disease. The innate immune response to adenoviruses represents the most significant hurdle in clinical application of adenoviral vectors for gene therapy, but it is an attractive feature for vaccine development. How adenovirus activates innate immunity remains largely unknown. Here we showed that adenovirus elicited innate immune response through the induction of high levels of type I interferons (IFNs) by both plasmacytoid dendritic cells (pDCs) and non-pDCs such as conventional DCs and macrophages. The innate immune recognition of adenovirus by pDCs was mediated by Toll-like receptor 9 (TLR9) and was dependent on MyD88, whereas that by non-pDCs was TLR independent through cytosolic sensing of adenoviral DNA. Furthermore, type I IFNs were pivotal in innate and adaptive immune responses to adenovirus in vivo, and type I IFN blockade diminished immune responses, resulting in more stable transgene expression and reduction of inflammation. These findings indicate that adenovirus activates innate immunity by its DNA through TLR-dependent and -independent pathways in a cell type-specific fashion, and they highlight a critical role for type I IFNs in innate and adaptive immune responses to adenoviral vectors. Our results that suggest strategies to interfere with type I IFN pathway may improve the outcome of adenovirus-mediated gene therapy, whereas approaches to activate the type I IFN pathway may enhance vaccine potency.

scholarly journals Corticosteroids and cellulose purification improve respectively the in vivo translation and vaccination efficacy of self-amplifying mRNAs

2020 ◽  
Author(s):  
Zifu Zhong ◽  
Séan Mc Cafferty ◽  
Lisa Opsomer ◽  
Haixiu Wang ◽  
Hanne Huysmans ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Biomedical Applications ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Therapeutic Platform ◽  
By Products

AbstractSynthetic mRNAs are an appealing therapeutic platform with multiple biomedical applications ranging from protein replacement therapy to vaccination. In comparison to conventional mRNA, synthetic self-amplifying mRNAs (sa-mRNAs) are gaining increased interest due to their higher and longer-lasting expression. However, sa-mRNAs also elicit an innate immune response, which may complicate the clinical translation of this platform. Approaches to reduce the innate immunity of sa-mRNAs have not been studied in detail. In this work we investigated the effect of several innate immune inhibitors and a novel cellulose-based mRNA purification approach on the type I interferon (IFN) response, translation and vaccination efficacy of our formerly developed sa-mRNA vaccine against Zika virus. Among the investigated inhibitors, we found that topical application of clobetasol at the sa-mRNA injection site was the most efficient in suppressing the type I IFN response and increasing the translation of sa-mRNA. However, clobetasol prevented the formation of antibodies against sa-mRNA encoded antigens and should therefore be avoided in a vaccination context. Residual dsRNA by-products of the in vitro transcription reaction are known inducers of immediate type I IFN responses. We additionally demonstrate drastic reduction of these dsRNA by-products upon cellulose-based purification, consequently reducing the innate immune response and improving sa-mRNA vaccination efficacy.

scholarly journals Emerging Alphaviruses Are Sensitive to Cellular States Induced by a Novel Small-Molecule Agonist of the STING Pathway

2017 ◽  
Vol 92 (6) ◽  
Author(s):  
Bryan Gall ◽  
Kara Pryke ◽  
Jinu Abraham ◽  
Nobuyo Mizuno ◽  
Sara Botto ◽  
...  
Keyword(s):  
Immune Response ◽  
Type I Interferon ◽  
Adaptor Protein ◽  
Human Cells ◽  
Innate Immune ◽  
Therapeutic Drug ◽  
Type I ◽  
Type I Ifn ◽  
Virus Growth

ABSTRACT The type I interferon (IFN) system represents an essential innate immune response that renders cells resistant to virus growth via the molecular actions of IFN-induced effector proteins. IFN-mediated cellular states inhibit growth of numerous and diverse virus types, including those of known pathogenicity as well as potentially emerging agents. As such, targeted pharmacologic activation of the IFN response may represent a novel therapeutic strategy to prevent infection or spread of clinically impactful viruses. In light of this, we employed a high-throughput screen to identify small molecules capable of permeating the cell and of activating IFN-dependent signaling processes. Here we report the identification and characterization of N -(methylcarbamoyl)-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]sulfanyl}-2-phenylacetamide (referred to as C11), a novel compound capable of inducing IFN secretion from human cells. Using reverse genetics-based loss-of-function assays, we show that C11 activates the type I IFN response in a manner that requires the adaptor protein STING but not the alternative adaptors MAVS and TRIF. Importantly, treatment of cells with C11 generated a cellular state that potently blocked replication of multiple emerging alphavirus types, including chikungunya, Ross River, Venezuelan equine encephalitis, Mayaro, and O'nyong-nyong viruses. The antiviral effects of C11 were subsequently abrogated in cells lacking STING or the type I IFN receptor, indicating that they are mediated, at least predominantly, by way of STING-mediated IFN secretion and subsequent autocrine/paracrine signaling. This work also allowed characterization of differential antiviral roles of innate immune signaling adaptors and IFN-mediated responses and identified MAVS as being crucial to cellular resistance to alphavirus infection. IMPORTANCE Due to the increase in emerging arthropod-borne viruses, such as chikungunya virus, that lack FDA-approved therapeutics and vaccines, it is important to better understand the signaling pathways that lead to clearance of virus. Here we show that C11 treatment makes human cells refractory to replication of a number of these viruses, which supports its value in increasing our understanding of the immune response and viral pathogenesis required to establish host infection. We also show that C11 depends on signaling through STING to produce antiviral type I interferon, which further supports its potential as a therapeutic drug or research tool.

scholarly journals Type I IFN innate immune response to adenovirus-mediated IFN-γ gene transfer contributes to the regression of cutaneous lymphomas

2007 ◽  
Vol 117 (10) ◽  
pp. 2834-2846 ◽  
Author(s):  
Mirjana Urosevic ◽  
Kazuyasu Fujii ◽  
Bastien Calmels ◽  
Elisabeth Laine ◽  
Nikita Kobert ◽  
...  
Keyword(s):  
Immune Response ◽  
Gene Transfer ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Cutaneous Lymphomas ◽  
Ifn Γ
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