scholarly journals Interaction of TLR4 and TLR8 in the Innate Immune Response against Mycobacterium Tuberculosis

2021 ◽  
Vol 22 (4) ◽  
pp. 1560
Author(s):  
Shruthi Thada ◽  
Gabor L. Horvath ◽  
Mario M. Müller ◽  
Nickel Dittrich ◽  
Melanie L. Conrad ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Vaccine Development ◽  
Docking Studies ◽  
Innate Immune ◽  
Therapeutic Interventions ◽  
Type I ◽  
Snp Analysis ◽  
Nucleotide Polymorphisms ◽  
Type I Ifns ◽  
Tlr4 Ligand

The interaction and crosstalk of Toll-like receptors (TLRs) is an established pathway in which the innate immune system recognises and fights pathogens. In a single nucleotide polymorphisms (SNP) analysis of an Indian cohort, we found evidence for both TLR4-399T and TRL8-1A conveying increased susceptibility towards tuberculosis (TB) in an interdependent manner, even though there is no established TLR4 ligand present in Mycobacterium tuberculosis (Mtb), which is the causative pathogen of TB. Docking studies revealed that TLR4 and TLR8 can build a heterodimer, allowing interaction with TLR8 ligands. The conformational change of TLR4-399T might impair this interaction. With immunoprecipitation and mass spectrometry, we precipitated TLR4 with TLR8-targeted antibodies, indicating heterodimerisation. Confocal microscopy confirmed a high co-localisation frequency of TLR4 and TLR8 that further increased upon TLR8 stimulation. The heterodimerisation of TLR4 and TLR8 led to an induction of IL12p40, NF-κB, and IRF3. TLR4-399T in interaction with TLR8 induced an increased NF-κB response as compared to TLR4-399C, which was potentially caused by an alteration of subsequent immunological pathways involving type I IFNs. In summary, we present evidence that the heterodimerisation of TLR4 and TLR8 at the endosome is involved in Mtb recognition via TLR8 ligands, such as microbial RNA, which induces a Th1 response. These findings may lead to novel targets for therapeutic interventions and vaccine development regarding TB.

RNA sensors as a mechanism of innate immune evasion among SARS-CoV2, HIV and Nipah viruses

2021 ◽  
Vol 22 ◽  
Author(s):  
Dalia Cicily Kattiparambil Dixon ◽  
Chameli Ratan ◽  
Bhagyalakshmi Nair ◽  
Sabitha Mangalath ◽  
Rachy Abraham ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Innate Immune Response ◽  
Vaccine Development ◽  
Innate Immune ◽  
Interferon Response ◽  
Host Immune System ◽  
Type I ◽  
Adaptive Responses ◽  
Rna Sensors

: Innate immunity is the first line of defence elicited by the host immune system to fight against invading pathogens such as viruses and bacteria. From this elementary immune response, the more complex antigen-specific adaptive responses are recruited to provide a long-lasting memory against the pathogens. Innate immunity gets activated when the host cell utilizes a diverse set of receptors known as pattern recognition receptors (PRR) to recognize the viruses that have penetrated the host and respond with cellular processes like complement system, phagocytosis, cytokine release and inflammation and destruction of NK cells. Viral RNA or DNA or viral intermediate products are recognized by receptors like toll-like receptors(TLRs), nucleotide oligomerization domain(NOD)-like receptors (NLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) thereby, inducing type I interferon response (IFN) and other proinflammatory cytokines in infected cells or other immune cells. But certain viruses can evade the host innate immune response to replicate efficiently, triggering the spread of the viral infection. The present review describes the similarity in the mechanism chosen by viruses from different families -HIV, SARS-CoV2 and Nipah viruses to evade the innate immune response and how efficiently they establish the infection in the host. The review also addresses the stages of developments of various vaccines against these viral diseases and the challenges encountered by the researchers during vaccine development.

scholarly journals Lessons from Bacillus Calmette-Guérin: Harnessing Trained Immunity for Vaccine Development

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2109
Author(s):  
Samuel T. Pasco ◽  
Juan Anguita
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Vaccine Development ◽  
Vaccine Design ◽  
Innate Immune ◽  
Bacillus Calmette Guerin ◽  
Adaptive Immune Responses ◽  
Trained Immunity ◽  
Adaptive Immune ◽  
Potential Methods

Vaccine design traditionally focuses on inducing adaptive immune responses against a sole target pathogen. Considering that many microbes evade innate immune mechanisms to initiate infection, and in light of the discovery of epigenetically mediated innate immune training, the paradigm of vaccine design has the potential to change. The Bacillus Calmette-Guérin (BCG) vaccine induces some level of protection against Mycobacterium tuberculosis (Mtb) while stimulating trained immunity that correlates with lower mortality and increased protection against unrelated pathogens. This review will explore BCG-induced trained immunity, including the required pathways to establish this phenotype. Additionally, potential methods to improve or expand BCG trained immunity effects through alternative vaccine delivery and formulation methods will be discussed. Finally, advances in new anti-Mtb vaccines, other antimicrobial uses for BCG, and “innate memory-based vaccines” will be examined.

scholarly journals Broadly neutralizing antibodies and vaccine design against HIV-1 infection

2019 ◽  
Vol 14 (1) ◽  
pp. 30-42 ◽  
Author(s):  
Qian Wang ◽  
Linqi Zhang
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Vaccine Design ◽  
Therapeutic Interventions ◽  
Type I ◽  
Broadly Neutralizing Antibodies ◽  
Dynamic Studies ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Remarkable Progress

AbstractRemarkable progress has been achieved for prophylactic and therapeutic interventions against human immunodeficiency virus type I (HIV-1) through antiretroviral therapy. However, vaccine development has remained challenging. Recent discoveries in broadly neutralizing monoclonal antibodies (bNAbs) has led to the development of multiple novel vaccine approaches for inducing bNAbs-like antibody response. Structural and dynamic studies revealed several vulnerable sites and states of the HIV-1 envelop glycoprotein (Env) during infection. Our review aims to highlight these discoveries and rejuvenate our endeavor in HIV-1 vaccine design and development.

scholarly journals Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1

2015 ◽  
Vol 90 (5) ◽  
pp. 2403-2417 ◽  
Author(s):  
Chuan Xia ◽  
Madhuvanthi Vijayan ◽  
Curtis J. Pritzl ◽  
Serge Y. Fuchs ◽  
Adrian B. McDermott ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Influenza A Virus ◽  
Influenza A ◽  
Type I Interferon ◽  
Innate Immune ◽  
Host Cells ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns ◽  
Ha Protein

ABSTRACTInfluenza A virus (IAV) employs diverse strategies to circumvent type I interferon (IFN) responses, particularly by inhibiting the synthesis of type I IFNs. However, it is poorly understood if and how IAV regulates the type I IFN receptor (IFNAR)-mediated signaling mode. In this study, we demonstrate that IAV induces the degradation of IFNAR subunit 1 (IFNAR1) to attenuate the type I IFN-induced antiviral signaling pathway. Following infection, the level of IFNAR1 protein, but not mRNA, decreased. Indeed, IFNAR1 was phosphorylated and ubiquitinated by IAV infection, which resulted in IFNAR1 elimination. The transiently overexpressed IFNAR1 displayed antiviral activity by inhibiting virus replication. Importantly, the hemagglutinin (HA) protein of IAV was proved to trigger the ubiquitination of IFNAR1, diminishing the levels of IFNAR1. Further, influenza A viral HA1 subunit, but not HA2 subunit, downregulated IFNAR1. However, viral HA-mediated degradation of IFNAR1 was not caused by the endoplasmic reticulum (ER) stress response. IAV HA robustly reduced cellular sensitivity to type I IFNs, suppressing the activation of STAT1/STAT2 and induction of IFN-stimulated antiviral proteins. Taken together, our findings suggest that IAV HA causes IFNAR1 degradation, which in turn helps the virus escape the powerful innate immune system. Thus, the research elucidated an influenza viral mechanism for eluding the IFNAR signaling pathway, which could provide new insights into the interplay between influenza virus and host innate immunity.IMPORTANCEInfluenza A virus (IAV) infection causes significant morbidity and mortality worldwide and remains a major health concern. When triggered by influenza viral infection, host cells produce type I interferon (IFN) to block viral replication. Although IAV was shown to have diverse strategies to evade this powerful, IFN-mediated antiviral response, it is not well-defined if IAV manipulates the IFN receptor-mediated signaling pathway. Here, we uncovered that influenza viral hemagglutinin (HA) protein causes the degradation of type I IFN receptor subunit 1 (IFNAR1). HA promoted phosphorylation and polyubiquitination of IFNAR1, which facilitated the degradation of this receptor. The HA-mediated elimination of IFNAR1 notably decreased the cells' sensitivities to type I IFNs, as demonstrated by the diminished expression of IFN-induced antiviral genes. This discovery could help us understand how IAV regulates the host innate immune response to create an environment optimized for viral survival in host cells.

scholarly journals Herpes Simplex Virus 1 UL36USP Antagonizes Type I Interferon-Mediated Antiviral Innate Immunity

2018 ◽  
Vol 92 (19) ◽  
Author(s):  
Hui Yuan ◽  
Jia You ◽  
Hongjuan You ◽  
Chunfu Zheng
Keyword(s):  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Herpes Simplex Virus 1 ◽  
Type I Ifns ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Simplex Virus ◽  
Antiviral Innate Immunity ◽  
Hsv 1

ABSTRACT Type I interferons (IFNs), as major components of the innate immune system, play a vital role in host resistance to a variety of pathogens. Canonical signaling mediated by type I IFNs activates the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway through binding to the IFN-α/β receptor (IFNAR), resulting in transcription of IFN-stimulated genes (ISGs). However, viruses have evolved multiple strategies to evade this process. Here, we report that herpes simplex virus 1 (HSV-1) ubiquitin-specific protease (UL36USP) abrogates the type I IFN-mediated signaling pathway independent of its deubiquitinase (DUB) activity. In this study, ectopically expressed UL36USP inhibited IFN-β-induced activation of ISRE promoter and transcription of ISGs, and overexpression of UL36USP lacking DUB activity did not influence this effect. Furthermore, UL36USP was demonstrated to antagonize IFN-β-induced activation of JAKs and STATs via specifically binding to the IFNAR2 subunit and blocking the interaction between JAK1 and IFNAR2. More importantly, knockdown of HSV-1 UL36USP restored the formation of JAK1-IFNAR2 complex. These findings underline the roles of UL36USP-IFNAR2 interaction in counteracting the type I IFN-mediated signaling pathway and reveal a novel evasion mechanism of antiviral innate immunity by HSV-1. IMPORTANCE Type I IFNs mediate transcription of numerous antiviral genes, creating a remarkable antiviral state in the host. Viruses have evolved various mechanisms to evade this response. Our results indicated that HSV-1 encodes a ubiquitin-specific protease (UL36USP) as an antagonist to subvert type I IFN-mediated signaling. UL36USP was identified to significantly inhibit IFN-β-induced signaling independent of its deubiquitinase (DUB) activity. The underlying mechanism of UL36USP antagonizing type I IFN-mediated signaling was to specifically bind with IFNAR2 and disassociate JAK1 from IFNAR2. For the first time, we identify UL36USP as a crucial suppressor for HSV-1 to evade type I IFN-mediated signaling. Our findings also provide new insights into the innate immune evasion by HSV-1 and will facilitate our understanding of host-virus interplay.

scholarly journals Interleukin-1- and Type I Interferon-Dependent Enhanced Immunogenicity of an NYVAC-HIV-1 Env-Gag-Pol-Nef Vaccine Vector with Dual Deletions of Type I and Type II Interferon-Binding Proteins

2015 ◽  
Vol 89 (7) ◽  
pp. 3819-3832 ◽  
Author(s):  
Julie Delaloye ◽  
Abdelali Filali-Mouhim ◽  
Mark J. Cameron ◽  
Elias K. Haddad ◽  
Alexandre Harari ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Hiv Vaccine ◽  
Innate Immune ◽  
Vaccine Vector ◽  
Type I ◽  
Type Ii ◽  
Type I Ifns ◽  
Attractive Candidate ◽  
Immunogenic Properties ◽  
Hiv 1

ABSTRACTNYVAC, a highly attenuated, replication-restricted poxvirus, is a safe and immunogenic vaccine vector. Deletion of immune evasion genes from the poxvirus genome is an attractive strategy for improving the immunogenic properties of poxviruses. Using systems biology approaches, we describe herein the enhanced immunological profile of NYVAC vectors expressing the HIV-1 clade Cenv,gag,pol, andnefgenes (NYVAC-C) with single or double deletions of genes encoding type I (ΔB19R) or type II (ΔB8R) interferon (IFN)-binding proteins. Transcriptomic analyses of human monocytes infected with NYVAC-C, NYVAC-C with theB19Rdeletion (NYVAC-C-ΔB19R), or NYVAC-C withB8RandB19Rdeletions (NYVAC-C-ΔB8RB19R) revealed a concerted upregulation of innate immune pathways (IFN-stimulated genes [ISGs]) of increasing magnitude with NYVAC-C-ΔB19R and NYVAC-C-ΔB8RB19R than with NYVAC-C. Deletion ofB8RandB19Rresulted in an enhanced activation of IRF3, IRF7, and STAT1 and the robust production of type I IFNs and of ISGs, whose expression was inhibited by anti-type I IFN antibodies. Interestingly, NYVAC-C-ΔB8RB19R induced the production of much higher levels of proinflammatory cytokines (tumor necrosis factor [TNF], interleukin-6 [IL-6], and IL-8) than NYVAC-C or NYVAC-C-ΔB19R as well as a strong inflammasome response (caspase-1 and IL-1β) in infected monocytes. Top network analyses showed that this broad response mediated by the deletion ofB8RandB19Rwas organized around two upregulated gene expression nodes (TNF and IRF7). Consistent with these findings, monocytes infected with NYVAC-C-ΔB8RB19R induced a stronger type I IFN-dependent and IL-1-dependent allogeneic CD4+T cell response than monocytes infected with NYVAC-C or NYVAC-C-ΔB19R. Dual deletion of type I and type II IFN immune evasion genes in NYVAC markedly enhanced its immunogenic properties via its induction of the increased expression of type I IFNs and IL-1β and make it an attractive candidate HIV vaccine vector.IMPORTANCENYVAC is a replication-deficient poxvirus developed as a vaccine vector against HIV. NYVAC expresses several genes known to impair the host immune defenses by interfering with innate immune receptors, cytokines, or interferons. Given the crucial role played by interferons against viruses, we postulated that targeting the type I and type II decoy receptors used by poxvirus to subvert the host innate immune response would be an attractive approach to improve the immunogenicity of NYVAC vectors. Using systems biology approaches, we report that deletion of type I and type II IFN immune evasion genes in NYVAC poxvirus resulted in the robust expression of type I IFNs and interferon-stimulated genes (ISGs), a strong activation of the inflammasome, and upregulated expression of IL-1β and proinflammatory cytokines. Dual deletion of type I and type II IFN immune evasion genes in NYVAC poxvirus improves its immunogenic profile and makes it an attractive candidate HIV vaccine vector.

Innate immune sensing of cancer: clues from an identified role for type I IFNs

2012 ◽  
Vol 61 (8) ◽  
pp. 1343-1347 ◽  
Author(s):  
Thomas F. Gajewski ◽  
Mercedes B. Fuertes ◽  
Seng-Ryong Woo
Keyword(s):  
Innate Immune ◽  
Type I ◽  
Type I Ifns ◽  
Immune Sensing ◽  
Innate Immune Sensing

scholarly journals Chemical exposures affect innate immune response to SARS-CoV-2

2021 ◽  
Author(s):  
Olatunbosun Arowolo ◽  
Leonid Pobezinsky ◽  
Alexander Suvorov
Keyword(s):  
Molecular Mechanisms ◽  
Chemical Compounds ◽  
Pathological Response ◽  
Innate Immune ◽  
Therapeutic Interventions ◽  
Type I ◽  
Death Rates ◽  
Chemical Exposures ◽  
Human Immune ◽  
First Time

Abstract Severe outcomes of COVID-19 are associated with pathological response of the immune system to the SARS-CoV-2 infection. Emerging evidence suggests that interaction may exist between COVID-19 pathogenesis and a broad range of xenobiotics, resulting in significant increases in death rates in highly exposed populations. Therefore, a better understanding of the molecular basis of the interaction between SARS-CoV-2 infection and chemical exposures may open opportunities for better preventive and therapeutic interventions. We attempted to gain mechanistic knowledge on the interaction between SARS-CoV-2 infection and chemical exposures using in-silico approach, where we identified genes and molecular pathways affected by both chemical exposures and SARS-CoV-2 in human immune cells (T-cells, B-cells, NK-cells, dendritic, and monocyte cells). Our findings demonstrate for the first time that overlapping molecular mechanisms affected by a broad range of chemical exposures and COVID-19 are linked to IFN type I/II signaling pathways and the process of antigen presentation. Based on our data, we also predict that exposures to various chemical compounds will predominantly impact the population of monocytes during the response against COVID-19.

scholarly journals Correction: Type I IFNs facilitate innate immune control of the opportunistic bacteria Burkholderia cenocepacia in the macrophage cytosol

2021 ◽  
Vol 17 (8) ◽  
pp. e1009821
Author(s):  
Michael G. Dorrington ◽  
Clinton J. Bradfield ◽  
Justin B. Lack ◽  
Bin Lin ◽  
Sinu P. John ◽  
...  
Keyword(s):  
Innate Immune ◽  
Burkholderia Cenocepacia ◽  
Type I ◽  
Immune Control ◽  
Type I Ifns ◽  
Opportunistic Bacteria

Type-I IFN promotes humoral immunity in viral vector vaccination

2021 ◽  
Author(s):  
Chaojie Zhong ◽  
Fengliang Liu ◽  
Renee J. Hajnik ◽  
Lei Yao ◽  
Kangjing Chen ◽  
...  
Keyword(s):  
Humoral Immunity ◽  
Viral Vectors ◽  
Vaccine Development ◽  
Viral Vector ◽  
T Cell Response ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Type I ◽  
Type I Ifn ◽  
Immune Pathways

Recombinant viral vectors are an important platform for vaccine delivery. Our recent study has demonstrated distinct innate immune profiles in responding to viral vectors of different families (e.g., adenovirus vs. poxvirus): while human Ad5 vector is minimally innate immune stimulatory, the poxviral vector ALVAC induces strong innate response and stimulates type-I IFN and inflammasome activation. However, impact of the innate immune signaling on vaccine-induced adaptive immunity in viral vector vaccination is less clear. Here, we showed that Modified Vaccinia Ankara (MVA), another poxviral vector, stimulated type-I IFN response in innate immune cells through cGAS-STING. Using MVA-HIV vaccine as a model, we found that type-I IFN signaling promoted the generation of humoral immunity in MVA-HIV vaccination in vivo . Following vaccination, type-I IFN receptor knockout (IFNAR1-/-) mice produced significantly lower levels of total and HIV gp120-specific antibodies compared to the wild-type (WT) mice. Consistent with the antibody response, type-I IFN signaling deficiency also led to reduced levels of plasma cells and memory-like B cells compared to those in WT mice. Furthermore, analysis of vaccine-induced CD4 T cells showed that type-I IFN signaling also promoted the generation of vaccine-specific CD4 T-cell response and T follicular helper (Tfh) response in mice. Together, our data indicate a role of type-I IFN signaling in promoting humoral immunity in poxviral vector vaccination. The study suggests that modulating type-I IFN and its associated innate immune pathways will likely affect vaccine efficacy. IMPORTANCE Viral vectors, including MVA, are an important antigen delivery platform and have been commonly used in vaccine development. Understanding the innate host-viral vector interactions and its impact on vaccine-induced immunity is critical but understudied. Using MVA-HIV vaccination of WT and IFNAR1-/- mice as a model, our study reports that type-I IFN signaling promotes humoral immunity in MVA vaccination, including vaccine-induced antibody, B-cell, and Tfh responses. Findings of the present study provide insights not only for basic understanding of host-viral vector interactions, but also for improving vaccine design by potentially modulating type-I IFN and its associated innate immune pathways in viral vector vaccination.

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