An Overview of Recent Insights into the Response of TLR to SARS-CoV-2 Infection and the Potential of TLR Agonists as SARS-CoV-2 Vaccine Adjuvants

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to coronavirus disease (COVID-19), a global health pandemic causing millions of deaths worldwide. However, the immunopathogenesis of COVID-19, particularly the interaction between SARS-CoV-2 and host innate immunity, remains unclear. The innate immune system acts as the first line of host defense, which is critical for the initial detection of invading pathogens and the activation and shaping of adaptive immunity. Toll-like receptors (TLRs) are key sensors of innate immunity that recognize pathogen-associated molecular patterns and activate downstream signaling for pro-inflammatory cytokine and chemokine production. However, TLRs may also act as a double-edged sword, and dysregulated TLR responses may enhance immune-mediated pathology, instead of providing protection. Therefore, a proper understanding of the interaction between TLRs and SARS-CoV-2 is of great importance for devising therapeutic and preventive strategies. The use of TLR agonists as vaccine adjuvants for human disease is a promising approach that could be applied in the investigation of COVID-19 vaccines. In this review, we discuss the recent progress in our understanding of host innate immune responses in SARS-CoV-2 infection, with particular focus on TLR response. In addition, we discuss the use of TLR agonists as vaccine adjuvants in enhancing the efficacy of COVID-19 vaccine.

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The neuropeptide receptor NMUR-1 regulates the specificity of C. elegans innate immunity against pathogen infection

10.1101/2021.05.06.442992 ◽

2021 ◽

Author(s):

Phillip Wibisono ◽

Shawndra Wibisono ◽

Jan Watteyne ◽

Chia-Hui Chen ◽

Durai Sellegounder ◽

...

Keyword(s):

Innate Immunity ◽

Immune System ◽

Immune Responses ◽

Adaptive Immune System ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Genes ◽

C Elegans ◽

Adaptive Immune ◽

Functional Assays

A key question in current immunology is how the innate immune system generates high levels of specificity. Like most invertebrates, Caenorhabditis elegans does not have an adaptive immune system and relies solely on innate immunity to defend itself against pathogen attacks, yet it can still differentiate different pathogens and launch distinct innate immune responses. Here, we have found that functional loss of NMUR-1, a neuronal GPCR homologous to mammalian receptors for the neuropeptide neuromedin U, has diverse effects on C. elegans survival against various bacterial pathogens. Transcriptomic analyses and functional assays revealed that NMUR-1 modulates C. elegans transcription activity by regulating the expression of transcription factors, which, in turn, controls the expression of distinct immune genes in response to different pathogens. Our study has uncovered a molecular basis for the specificity of C. elegans innate immunity that could provide mechanistic insights into understanding the specificity of vertebrate innate immunity.

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Introns encode dsRNAs undetected by RIG-I/MDA5/interferons and sensed via RNase L

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2102134118 ◽

2021 ◽

Vol 118 (46) ◽

pp. e2102134118

Author(s):

Alisha Chitrakar ◽

Kristina Solorio-Kirpichyan ◽

Eliza Prangley ◽

Sneha Rath ◽

Jin Du ◽

...

Keyword(s):

Innate Immunity ◽

Immune Responses ◽

Innate Immune ◽

Rna Decay ◽

Antiviral Defense ◽

Rnase L ◽

Innate Immune Responses ◽

Double Stranded Rna ◽

Turn On ◽

Nuclear Rna

Double-stranded RNA (dsRNA), a hallmark viral material that activates antiviral interferon (IFN) responses, can appear in human cells also in the absence of viruses. We identify phosphorothioate DNAs (PS DNAs) as triggers of such endogenous dsRNA (endo-dsRNA). PS DNAs inhibit decay of nuclear RNAs and induce endo-dsRNA via accumulation of high levels of intronic and intergenic inverted retroelements (IIIR). IIIRs activate endo-dsRNA responses distinct from antiviral defense programs. IIIRs do not turn on transcriptional RIG-I/MDA5/IFN signaling, but they trigger the dsRNA-sensing pathways of OAS3/RNase L and PKR. Thus, nuclear RNA decay and nuclear-cytosolic RNA sorting actively protect from these innate immune responses to self. Our data suggest that the OAS3/RNase L and PKR arms of innate immunity diverge from antiviral IFN responses and monitor nuclear RNA decay by sensing cytosolic escape of IIIRs. OAS3 provides a receptor for IIIRs, whereas RNase L cleaves IIIR-carrying introns and intergenic RNAs.

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Immunologic Consequences of Hypoxia during Critical Illness

Anesthesiology ◽

10.1097/aln.0000000000001163 ◽

2016 ◽

Vol 125 (1) ◽

pp. 237-249 ◽

Cited By ~ 10

Author(s):

Harmke D. Kiers ◽

Gert-Jan Scheffer ◽

Johannes G. van der Hoeven ◽

Holger K. Eltzschig ◽

Peter Pickkers ◽

...

Keyword(s):

Immune Responses ◽

Signaling Pathways ◽

Daily Practice ◽

Innate Immune ◽

Protective Effects ◽

Innate Immune Responses ◽

Downstream Signaling ◽

Pathogen Clearance ◽

Pharmacologic Modulation ◽

Oxygen Status

Abstract Hypoxia and immunity are highly intertwined at clinical, cellular, and molecular levels. The prevention of tissue hypoxia and modulation of systemic inflammation are cornerstones of daily practice in the intensive care unit. Potentially, immunologic effects of hypoxia may contribute to outcome and represent possible therapeutic targets. Hypoxia and activation of downstream signaling pathways result in enhanced innate immune responses, aimed to augment pathogen clearance. On the other hand, hypoxia also exerts antiinflammatory and tissue-protective effects in lymphocytes and other tissues. Although human data on the net immunologic effects of hypoxia and pharmacologic modulation of downstream pathways are limited, preclinical data support the concept of tailoring the immune response through modulation of the oxygen status or pharmacologic modulation of hypoxia-signaling pathways in critically ill patients.

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Innate Immune Response against Hepatitis C Virus: Targets for Vaccine Adjuvants

Vaccines ◽

10.3390/vaccines8020313 ◽

2020 ◽

Vol 8 (2) ◽

pp. 313

Author(s):

Daniel Sepulveda-Crespo ◽

Salvador Resino ◽

Isidoro Martinez

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Innate Immune Response ◽

Vaccine Development ◽

Innate Immune ◽

World Health ◽

Cell Immune Response ◽

Vaccine Adjuvants

Despite successful treatments, hepatitis C virus (HCV) infections continue to be a significant world health problem. High treatment costs, the high number of undiagnosed individuals, and the difficulty to access to treatment, particularly in marginalized susceptible populations, make it improbable to achieve the global control of the virus in the absence of an effective preventive vaccine. Current vaccine development is mostly focused on weakly immunogenic subunits, such as surface glycoproteins or non-structural proteins, in the case of HCV. Adjuvants are critical components of vaccine formulations that increase immunogenic performance. As we learn more information about how adjuvants work, it is becoming clear that proper stimulation of innate immunity is crucial to achieving a successful immunization. Several hepatic cell types participate in the early innate immune response and the subsequent inflammation and activation of the adaptive response, principally hepatocytes, and antigen-presenting cells (Kupffer cells, and dendritic cells). Innate pattern recognition receptors on these cells, mainly toll-like receptors, are targets for new promising adjuvants. Moreover, complex adjuvants that stimulate different components of the innate immunity are showing encouraging results and are being incorporated in current vaccines. Recent studies on HCV-vaccine adjuvants have shown that the induction of a strong T- and B-cell immune response might be enhanced by choosing the right adjuvant.

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Flagellin from Recombinant Attenuated Salmonella enterica Serovar Typhimurium Reveals a Fundamental Role in Chicken Innate Immunity

Clinical and Vaccine Immunology ◽

10.1128/cvi.05569-11 ◽

2012 ◽

Vol 19 (3) ◽

pp. 304-312 ◽

Cited By ~ 6

Author(s):

Zhiming Pan ◽

Qiuxia Cong ◽

Shizhong Geng ◽

Qiang Fang ◽

Xilong Kang ◽

...

Keyword(s):

Innate Immunity ◽

Immune Responses ◽

Salmonella Enterica ◽

Rational Design ◽

Bacterial Load ◽

Innate Immune ◽

Innate Immune Responses ◽

Content Type ◽

Serovar Typhimurium

ABSTRACTRecombinant attenuatedSalmonellavaccines have been extensively studied, with a focus on eliciting specific immune responses against foreign antigens. However, very little is known about the innate immune responses, particularly the role of flagellin, in the induction of innate immunity triggered by recombinant attenuatedSalmonellain chickens. In the present report, we describe twoSalmonella entericaserovar Typhimurium vaccine strains, wild-type (WT) or flagellin-deficient (flhD)Salmonella, both expressing the fusion protein (F) gene of Newcastle disease virus. We examined the bacterial load and spatiotemporal kinetics of expression of inflammatory cytokine, chemokine, and Toll-like receptor 5 (TLR5) genes in the cecum, spleen, liver, and heterophils following oral immunization of chickens with the twoSalmonellastrains. TheflhDmutant exhibited an enhanced ability to establish systemic infection compared to the WT. In contrast, the WT strain induced higher levels of interleukin-1β (IL-1β), CXCLi2, and TLR5 mRNAs in cecum, the spleen, and the heterophils than theflhDmutant at different times postinfection. Collectively, the present data reveal a fundamental role of flagellin in the innate immune responses induced by recombinant attenuatedSalmonellavaccines in chickens that should be considered for the rational design of novel vaccines for poultry.

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CD14 is a coreceptor of Toll-like receptors 7 and 9

Journal of Experimental Medicine ◽

10.1084/jem.20101111 ◽

2010 ◽

Vol 207 (12) ◽

pp. 2689-2701 ◽

Cited By ~ 130

Author(s):

Christoph L. Baumann ◽

Irene M. Aspalter ◽

Omar Sharif ◽

Andreas Pichlmair ◽

Stephan Blüml ◽

...

Keyword(s):

Nucleic Acid ◽

Nucleic Acids ◽

Innate Immune ◽

Confocal Imaging ◽

Acid Uptake ◽

Innate Immune Responses ◽

Toll Like Receptors ◽

Molecular Patterns ◽

Cluster Of Differentiation

Recognition of pathogens by the innate immune system requires proteins that detect conserved molecular patterns. Nucleic acids are recognized by cytoplasmic sensors as well as by endosomal Toll-like receptors (TLRs). It has become evident that TLRs require additional proteins to be activated by their respective ligands. In this study, we show that CD14 (cluster of differentiation 14) constitutively interacts with the MyD88-dependent TLR7 and TLR9. CD14 was necessary for TLR7- and TLR9-dependent induction of proinflammatory cytokines in vitro and for TLR9-dependent innate immune responses in mice. CD14 associated with TLR9 stimulatory DNA in precipitation experiments and confocal imaging. The absence of CD14 led to reduced nucleic acid uptake in macrophages. Additionally, CD14 played a role in the stimulation of TLRs by viruses. Using various types of vesicular stomatitis virus, we showed that CD14 is dispensable for viral uptake but is required for the triggering of TLR-dependent cytokine responses. These data show that CD14 has a dual role in nucleic acid–mediated TLR activation: it promotes the selective uptake of nucleic acids, and it acts as a coreceptor for endosomal TLR activation.

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Evolving Perspectives on Innate Immune Mechanisms of IPF

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.676569 ◽

2021 ◽

Vol 8 ◽

Author(s):

Genta Ishikawa ◽

Angela Liu ◽

Erica L. Herzog

Keyword(s):

Innate Immunity ◽

Genetic Factors ◽

Suppressor Cells ◽

Innate Immune ◽

Lymphoid Cells ◽

Animal Modeling ◽

Myeloid Suppressor Cells ◽

Disease Outcomes ◽

Molecular Patterns

While epithelial-fibroblast interactions are viewed as the primary drivers of Idiopathic Pulmonary Fibrosis (IPF), evidence gleaned from animal modeling and human studies implicates innate immunity as well. To provide perspective on this topic, this review synthesizes the available data regarding the complex role of innate immunity in IPF. The role of substances present in the fibrotic microenvironment including pathogen associated molecular patterns (PAMPs) derived from invading or commensal microbes, and danger associated molecular patterns (DAMPs) derived from injured cells and tissues will be discussed along with the proposed contribution of innate immune populations such as macrophages, neutrophils, fibrocytes, myeloid suppressor cells, and innate lymphoid cells. Each component will be considered in the context of its relationship to environmental and genetic factors, disease outcomes, and potential therapies. We conclude with discussion of unanswered questions and opportunities for future study in this area.

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“Corneal Nerves, CD11c+ Dendritic Cells and Their Impact on Ocular Immune Privilege”

Frontiers in Immunology ◽

10.3389/fimmu.2021.701935 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jerry Y. Niederkorn

Keyword(s):

Immune Responses ◽

Inflammatory Diseases ◽

Innate Immune ◽

Immune Privilege ◽

Innate Immune Responses ◽

Regulatory Processes ◽

Immune Mediated ◽

Corneal Nerves ◽

The Central Nervous System ◽

The Brain

The eye and the brain have limited capacities for regeneration and as such, immune-mediated inflammation can produce devastating consequences in the form of neurodegenerative diseases of the central nervous system or blindness as a result of ocular inflammatory diseases such as uveitis. Accordingly, both the eye and the brain are designed to limit immune responses and inflammation – a condition known as “immune privilege”. Immune privilege is sustained by physiological, anatomical, and regulatory processes that conspire to restrict both adaptive and innate immune responses.

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Integrated role of microRNA-30e-5p through targeting negative regulators of innate immune pathways during HBV infection and SLE

10.1101/2020.02.29.969014 ◽

2020 ◽

Author(s):

Richa Mishra ◽

Sanjana Bhattacharya ◽

Bhupendra S Rawat ◽

Ashish Kumar ◽

Akhilesh Kumar ◽

...

Keyword(s):

Innate Immunity ◽

Mouse Model ◽

Immune Responses ◽

Therapeutic Potential ◽

Innate Immune ◽

Locked Nucleic Acid ◽

Type I ◽

Innate Immune Responses ◽

Negative Regulators

AbstractPrecise regulation of innate immunity is crucial for the development of appropriate host immunity against microbial infections and the maintenance of immune homeostasis. The microRNAs are small non-coding RNA, post-transcriptional regulator of multiple genes and act as a rheostat for protein expression. Here, we identified microRNA(miR)-30e-5p (miR-30e) induced by the hepatitis B virus (HBV) and other viruses that act as a master regulator for innate immune responses. Moreover, pegylated type I interferons treatment to HBV patients for viral reduction also reduces the miRNA. Additionally, we have also shown the immuno-pathological effects of miR-30e in systemic lupus erythematous (SLE) patients and SLE mouse model. Mechanistically, the miR-30e targets multiple negative regulators namely TRIM38, TANK, ATG5, ATG12, BECN1, SOCS1, SOCS3 of innate immune signaling pathways and enhances innate immune responses. Furthermore, sequestering of endogenous miR-30e in PBMCs of SLE patients and SLE mouse model respectively by the introduction of antagomir and locked nucleic acid based inhibitor significantly reduces type I interferon and pro-inflammatory cytokines. Collectively, our study demonstrates the novel role of miR-30e in innate immunity and its prognostic and therapeutic potential in infectious and autoimmune diseases.

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Perillaldehyde Inhibition of cGAS Reduces dsDNA-Induced Interferon Response

Frontiers in Immunology ◽

10.3389/fimmu.2021.655637 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lei Chu ◽

Chenhui Li ◽

Yongxing Li ◽

Qiuya Yu ◽

Huansha Yu ◽

...

Keyword(s):

Innate Immunity ◽

Herpes Simplex ◽

Immune Responses ◽

Therapeutic Benefit ◽

Perilla Frutescens ◽

Innate Immune ◽

Interferon Response ◽

Innate Immune Responses ◽

Simplex Virus

Cyclic GMP-AMP synthase (cGAS), serving as a primary sensor of intracellular DNA, is essential to initiate anti-microbial innate immunity. Inappropriate activation of cGAS by self-DNA promotes severe autoinflammatory diseases such as Aicardi–Goutières syndrome (AGS); thus, inhibition of cGAS may provide therapeutic benefit in anti-autoimmunity. Here we report that perillaldehyde (PAH), a natural monoterpenoid compound derived from Perilla frutescens, suppresses cytosolic-DNA-induced innate immune responses by inhibiting cGAS activity. Mice treated with PAH are more susceptible to herpes simplex virus type 1 (HSV-1) infection. Moreover, administration with PAH markedly ameliorates self-DNA-induced autoinflammatory responses in a mouse model of AGS. Collectively, our study reveals that PAH can effectively inhibit cGAS-STING signaling and could be developed toward the treatment of cGAS-mediated autoimmune diseases.

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