scholarly journals Modeling Virus-Induced Inflammation in Zebrafish: A Balance Between Infection Control and Excessive Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Con Sullivan ◽  
Brandy-Lee Soos ◽  
Paul J. Millard ◽  
Carol H. Kim ◽  
Benjamin L. King
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Inflammatory Response ◽  
Viral Infection ◽  
Innate Immune Response ◽  
Innate Immune System ◽  
Innate Immune ◽  
Zebrafish Model ◽  
Infection Models

The inflammatory response to viral infection in humans is a dynamic process with complex cell interactions that are governed by the immune system and influenced by both host and viral factors. Due to this complexity, the relative contributions of the virus and host factors are best studied in vivo using animal models. In this review, we describe how the zebrafish (Danio rerio) has been used as a powerful model to study host-virus interactions and inflammation by combining robust forward and reverse genetic tools with in vivo imaging of transparent embryos and larvae. The innate immune system has an essential role in the initial inflammatory response to viral infection. Focused studies of the innate immune response to viral infection are possible using the zebrafish model as there is a 4-6 week timeframe during development where they have a functional innate immune system dominated by neutrophils and macrophages. During this timeframe, zebrafish lack a functional adaptive immune system, so it is possible to study the innate immune response in isolation. Sequencing of the zebrafish genome has revealed significant genetic conservation with the human genome, and multiple studies have revealed both functional conservation of genes, including those critical to host cell infection and host cell inflammatory response. In addition to studying several fish viruses, zebrafish infection models have been developed for several human viruses, including influenza A, noroviruses, chikungunya, Zika, dengue, herpes simplex virus type 1, Sindbis, and hepatitis C virus. The development of these diverse viral infection models, coupled with the inherent strengths of the zebrafish model, particularly as it relates to our understanding of macrophage and neutrophil biology, offers opportunities for far more intensive studies aimed at understanding conserved host responses to viral infection. In this context, we review aspects relating to the evolution of innate immunity, including the evolution of viral pattern recognition receptors, interferons and interferon receptors, and non-coding RNAs.

scholarly journals Tumour viruses and innate immunity

2017 ◽  
Vol 372 (1732) ◽  
pp. 20160267 ◽  
Author(s):  
Sharon E. Hopcraft ◽  
Blossom Damania
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Viral Infection ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Host Cells ◽  
Oncogenic Viruses ◽  
Barr Virus ◽  
Human T Cell ◽  
Epstein Barr

Host cells sense viral infection through pattern recognition receptors (PRRs), which detect pathogen-associated molecular patterns (PAMPs) and stimulate an innate immune response. PRRs are localized to several different cellular compartments and are stimulated by viral proteins and nucleic acids. PRR activation initiates signal transduction events that ultimately result in an inflammatory response. Human tumour viruses, which include Kaposi's sarcoma-associated herpesvirus, Epstein–Barr virus, human papillomavirus, hepatitis C virus, hepatitis B virus, human T-cell lymphotropic virus type 1 and Merkel cell polyomavirus, are detected by several different PRRs. These viruses engage in a variety of mechanisms to evade the innate immune response, including downregulating PRRs, inhibiting PRR signalling, and disrupting the activation of transcription factors critical for mediating the inflammatory response, among others. This review will describe tumour virus PAMPs and the PRRs responsible for detecting viral infection, PRR signalling pathways, and the mechanisms by which tumour viruses evade the host innate immune system. This article is part of the themed issue ‘Human oncogenic viruses’.

scholarly journals Ursodeoxycholic Acid (UDCA) Mitigates the Host Inflammatory Response during Clostridioides difficile Infection by Altering Gut Bile Acids

2020 ◽  
Vol 88 (6) ◽  
Author(s):  
Jenessa A. Winston ◽  
Alissa J. Rivera ◽  
Jingwei Cai ◽  
Rajani Thanissery ◽  
Stephanie A. Montgomery ◽  
...  
Keyword(s):  
Immune Response ◽  
Bile Acid ◽  
Inflammatory Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Colonization Resistance ◽  
Content Type ◽  
Clostridioides Difficile

ABSTRACT Clostridioides difficile infection (CDI) is associated with increasing morbidity and mortality posing an urgent threat to public health. Recurrence of CDI after successful treatment with antibiotics is high, thus necessitating discovery of novel therapeutics against this enteric pathogen. Administration of the secondary bile acid ursodeoxycholic acid (UDCA; ursodiol) inhibits the life cycles of various strains of C. difficile in vitro, suggesting that the FDA-approved formulation of UDCA, known as ursodiol, may be able to restore colonization resistance against C. difficile in vivo. However, the mechanism(s) by which ursodiol is able to restore colonization resistance against C. difficile remains unknown. Here, we confirmed that ursodiol inhibits C. difficile R20291 spore germination and outgrowth, growth, and toxin activity in a dose-dependent manner in vitro. In a murine model of CDI, exogenous administration of ursodiol resulted in significant alterations in the bile acid metabolome with little to no changes in gut microbial community structure. Ursodiol pretreatment resulted in attenuation of CDI pathogenesis early in the course of disease, which coincided with alterations in the cecal and colonic inflammatory transcriptome, bile acid-activated receptors nuclear farnesoid X receptor (FXR) and transmembrane G-protein-coupled membrane receptor 5 (TGR5), which are able to modulate the innate immune response through signaling pathways such as NF-κB. Although ursodiol pretreatment did not result in a consistent decrease in the C. difficile life cycle in vivo, it was able to attenuate an overly robust inflammatory response that is detrimental to the host during CDI. Ursodiol remains a viable nonantibiotic treatment and/or prevention strategy against CDI. Likewise, modulation of the host innate immune response via bile acid-activated receptors FXR and TGR5 represents a new potential treatment strategy for patients with CDI.

scholarly journals Insights into Innate Immune Response Against SARS-CoV-2 Infection

2021 ◽  
Vol 29 (3) ◽  
pp. 255-269
Author(s):  
Adina Huțanu ◽  
Anca Meda Georgescu ◽  
Akos Vince Andrejkovits ◽  
William Au ◽  
Minodora Dobreanu
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Innate Immune Response ◽  
Innate Immune System ◽  
Time Course ◽  
Adaptive Immune Response ◽  
Innate Immune ◽  
Interferon Response ◽  
Humoral Factors ◽  
Key Steps

Abstract The innate immune system is mandatory for the activation of antiviral host defense and eradication of the infection. In this regard, dendritic cells, natural killer cells, macrophages, neutrophils representing the cellular component, and cytokines, interferons, complement or Toll-Like Receptors, representing the mediators of unspecific response act together for both activation of the adaptive immune response and viral clearance. Of great importance is the proper functioning of the innate immune response from the very beginning. For instance, in the early stages of viral infection, the defective interferon response leads to uncontrolled viral replication and pathogen evasion, while hypersecretion during the later stages of infection generates hyperinflammation. This cascade activation of systemic inflammation culminates with cytokine storm syndrome and hypercoagulability state, due to a close interconnection between them. Thus an unbalanced reaction, either under- or over- stimulation of the innate immune system will lead to an uncoordinated response and unfavorable disease outcomes. Since both cellular and humoral factors are involved in the time-course of the innate immune response, in this review we aimed to address their gradual involvement in the antiviral response with emphasis on key steps in SARS-CoV-2 infection.

scholarly journals MiR-146b Mediates Endotoxin Tolerance in Human Phagocytes

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Tiziana Ada Renzi ◽  
Marcello Rubino ◽  
Laura Gornati ◽  
Cecilia Garlanda ◽  
Massimo Locati ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Inflammatory Response ◽  
Innate Immune Response ◽  
Endotoxin Tolerance ◽  
Innate Immune ◽  
Human Monocytes ◽  
Key Factors ◽  
Tlr Signaling ◽  
Tolerant State

A proper regulation of the innate immune response is fundamental to keep the immune system in check and avoid a chronic status of inflammation. As they act as negative modulators of TLR signaling pathways, miRNAs have been recently involved in the control of the inflammatory response. However, their role in the context of endotoxin tolerance is just beginning to be explored. We here show that miR-146b is upregulated in human monocytes tolerized by LPS, IL-10, or TGFβpriming and demonstrate that its transcription is driven by STAT3 and RUNX3, key factors downstream of IL-10 and TGFβsignaling. Our study also found that IFNγ, known to revert LPS tolerant state, inhibits miR-146b expression. Finally, we provide evidence that miR-146b levels have a profound effect on the tolerant state, thus candidating miR-146b as a molecular mediator of endotoxin tolerance.

The role of the innate immune system on pulmonary infections

2019 ◽  
Vol 400 (4) ◽  
pp. 443-456 ◽  
Author(s):  
Michelle Galeas-Pena ◽  
Nathaniel McLaughlin ◽  
Derek Pociask
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Innate Immune Response ◽  
Innate Immune System ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Resistant Bacteria ◽  
Upper Respiratory Tract ◽  
Phagocytic Cells ◽  
Mucus Production

Abstract Inhalation is required for respiration and life in all vertebrates. This process is not without risk, as it potentially exposes the host to environmental pathogens with every breath. This makes the upper respiratory tract one of the most common routes of infection and one of the leading causes of morbidity and mortality in the world. To combat this, the lung relies on the innate immune defenses. In contrast to the adaptive immune system, the innate immune system does not require sensitization, previous exposure or priming to attack foreign particles. In the lung, the innate immune response starts with the epithelial barrier and mucus production and is reinforced by phagocytic cells and T cells. These cells are vital for the production of cytokines, chemokines and anti-microbial peptides that are critical for clearance of infectious agents. In this review, we discuss all aspects of the innate immune response, with a special emphasis on ways to target aspects of the immune response to combat antibiotic resistant bacteria.

A “Loss-of-Tolerance” Phenotype of the Liver Macrophage System to LPS Induces Overwhelming Systemic Inflammation and Early Death in a Knockout-Transgenic Mouse Model of Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2337-2337
Author(s):  
Steffen E. Meiler ◽  
Ilka Theruvath ◽  
Marlene Wade ◽  
C. Alvin Head
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Innate Immune System ◽  
Innate Immune ◽  
Cell Disease ◽  
Liver Macrophage ◽  
Tnf Α

Abstract Infections and death from fulminant sepsis remain a constant threat to patients with sickle cell disease (SCD). Established explanations include an impaired ability to contain and eliminate pathogenic organisms due to defects in spleen function and adaptive immunity. To the contrary, very little is known about the “first-line” response of the innate immune system after contact with pathogen associated cell components. An escalated immune (inflammatory) response to microbial structures would provide an alternative mechanism to explain increased rates of infectious complications and septic death in sickle cell patients. To test this hypothesis, knockout-transgenic mice homozygous for the human β-sickle globin gene (SS) were treated with a low dose of the canonical infectious stimulus lipopolysaccharide (0.5 μg/g bw; i.p.; 22°C) and compared to heterozygous sickle trait (ST) and C57BL/6 animals. Phenotypically, sickle mice appeared much sicker after LPS and displayed strict seclusion behavior, cessation of food intake, and physiological signs of stress. Body core (rectal) temperature decreased precipitously and irreversibly in sickle animals (~12°C/8hrs vs. ~2°C/8hrs [ST and C57BL/6]) followed by rapid death (50%/12h; 100%/48h vs 0% [ST; C57BL/6]). Analysis of the LD50 demonstrated an ~500-fold increased sensitivity to LPS in sickle mice (0.05 μg/g vs 25 μg/g [ST]). Serum cytokines (TNF-α, IL-6) were dramatically up-regulated in SS mice compared to control (TNF-α: 16-fold/2 hr post LPS, 100-fold/3 hr post LPS). Organ-specific immunohistochemical analysis of the marker cytokine TNF-α in liver, bone marrow, spleen, lung, and kidney four hrs after LPS revealed an astonishingly super-induced expression in the liver of sickle animals compared to controls. The liver of sickle animals showed several areas of coagulative liver necrosis unrelated to LPS and consistent with ischemic injury from recurrent sickle-mediated vascular occlusion. Immunoreactivity to TNF-α was most pronounced in areas of liver injury and mostly restricted to large macrophages (F4/80 +) surrounded by a T-lymphocytic (CD3+) infiltrate. In vitro analysis of Kupffer cells to serial concentrations of LPS recapitulated the in vivo results, demonstrating up to 20-fold larger TNF-α levels in cells derived from sickle livers. To further elucidate the role of the liver macrophage in the in vivo immune response to LPS, sickle animals were challenged with LPS forty-eight hrs after Kupffer cell depletion with Gadolinium Chloride. Sickle mice treated with Gadolinium experienced enhanced survival and an ~90% reduction in serum TNF-α levels. In summary, the present study offers new insights into the responsiveness of the innate immune system in SCD to the highly conserved bacterial cell component, lipopolysaccharide. Unexpectedly, these data suggest that the liver macrophage in SCD, typically a cell type tolerant to the pro-inflammatory effects of LPS, has a cardinal role in orchestrating an excessive and harmful innate immune response to bacterial infections. Further studies will have to determine the immune response to other conserved bacterial structures and relate these findings to the human form of SCD.

scholarly journals Released Tryptophanyl-tRNA Synthetase Stimulates Innate Immune Responses against Viral Infection

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Hyun-Cheol Lee ◽  
Eun-Seo Lee ◽  
Md Bashir Uddin ◽  
Tae-Hwan Kim ◽  
Jae-Hoon Kim ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Viral Infection ◽  
Innate Immune Response ◽  
Trna Synthetase ◽  
Innate Immune ◽  
Full Length ◽  
Type I ◽  
Innate Immune Responses

ABSTRACT Tryptophanyl-tRNA synthetase (WRS) is one of the aminoacyl-tRNA synthetases (ARSs) that possesses noncanonical functions. Full-length WRS is released during bacterial infection and primes the Toll-like receptor 4 (TLR4)-myeloid differentiation factor 2 (MD2) complex to elicit innate immune responses. However, the role of WRS in viral infection remains unknown. Here, we show that full-length WRS is secreted by immune cells in the early phase of viral infection and functions as an antiviral cytokine. Treatment of cells with recombinant WRS protein promotes the production of inflammatory cytokines and type I interferons (IFNs) and curtails virus replication in THP-1 and Raw264.7 cells but not in TLR4−/− or MD2−/− bone marrow-derived macrophages (BMDMs). Intravenous and intranasal administration of recombinant WRS protein induces an innate immune response and blocks viral replication in vivo. These findings suggest that secreted full-length WRS has a noncanonical role in inducing innate immune responses to viral infection as well as to bacterial infection. IMPORTANCE ARSs are essential enzymes in translation that link specific amino acids to their cognate tRNAs. In higher eukaryotes, some ARSs possess additional, noncanonical functions in the regulation of cell metabolism. Here, we report a novel noncanonical function of WRS in antiviral defense. WRS is rapidly secreted in response to viral infection and primes the innate immune response by inducing the secretion of proinflammatory cytokines and type I IFNs, resulting in the inhibition of virus replication both in vitro and in vivo. Thus, we consider WRS to be a member of the antiviral innate immune response. The results of this study enhance our understanding of host defense systems and provide additional information on the noncanonical functions of ARSs.

scholarly journals An Overview on the Field of Micro- and Nanotechnologies for Synthetic Peptide-Based Vaccines

2011 ◽  
Vol 2011 ◽  
pp. 1-18 ◽  
Author(s):  
Aiala Salvador ◽  
Manoli Igartua ◽  
Rosa Maria Hernández ◽  
José Luis Pedraz
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Innate Immune System ◽  
Synthetic Peptide ◽  
Vaccine Delivery ◽  
Delivery Systems ◽  
Innate Immune ◽  
Cross Presentation ◽  
Antigen Presenting

The development of synthetic peptide-based vaccines has many advantages in comparison with vaccines based on live attenuated organisms, inactivated or killed organism, or toxins. Peptide-based vaccines cannot revert to a virulent form, allow a better conservation, and are produced more easily and safely. However, they generate a weaker immune response than other vaccines, and the inclusion of adjuvants and/or the use of vaccine delivery systems is almost always needed. Among vaccine delivery systems, micro- and nanoparticulated ones are attractive, because their particulate nature can increase cross-presentation of the peptide. In addition, they can be passively or actively targeted to antigen presenting cells. Furthermore, particulate adjuvants are able to directly activate innate immune system in vivo. Here, we summarize micro- and nanoparticulated vaccine delivery systems used in the field of synthetic peptide-based vaccines as well as strategies to increase their immunogenicity.

scholarly journals How the Innate Immune System Fights for Your Health

2021 ◽  
Vol 9 ◽  
Author(s):  
Mieke C. Louwe ◽  
Pål Aukrust
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Innate Immune Response ◽  
Innate Immune System ◽  
The Body ◽  
Innate Immune ◽  
Response Activation

When your body encounters intruders like viruses, bacteria, fungi, or parasites, this invasion triggers a complex and amazing process called the immune response. Activation of the body’s immune system is necessary to fight off these intruders, but it must also distinguish them from the body’s own healthy tissues. The goal of the immune response is to keep the body healthy. The earliest responses that occur to protect the body from invading organisms is called the innate immune response. In this article, we explain the components of the innate immune system and how this system helps to keep the body safe from dangerous invaders.

scholarly journals Ursodeoxycholic acid (UDCA) mitigates the host inflammatory response during Clostridioides difficile infection by altering gut bile acids which attenuates NF-κB signaling via bile acid activated receptors

2020 ◽  
Author(s):  
Jenessa A. Winston ◽  
Alissa J. Rivera ◽  
Jingwei Cai ◽  
Rajani Thanissery ◽  
Stephanie A. Montgomery ◽  
...  
Keyword(s):  
Immune Response ◽  
Bile Acid ◽  
Inflammatory Response ◽  
Ursodeoxycholic Acid ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Farnesoid X Receptor ◽  
Clostridioides Difficile

AbstractClostridioides difficile infection (CDI) is associated with increasing morbidity and mortality posing an urgent threat to public health. Recurrence of CDI after successful treatment with antibiotics is high, thus necessitating discovery of novel therapeutics against this enteric pathogen. Administration of the secondary bile acid ursodeoxycholic acid (UDCA, ursodiol) inhibits the life cycle of various strains of C. difficile in vitro, suggesting the FDA approved formulation of UDCA, known as ursodiol, may be able to restore colonization resistance against C. difficile in vivo. However, the mechanism(s) by which ursodiol is able to restore colonization resistance against C. difficile remains unknown. Here, we confirmed that ursodiol inhibits C. difficile R20291 spore germination and outgrowth, growth, and toxin activity in a dose dependent manner in vitro. In a murine model of CDI, exogenous administration of ursodiol resulted in significant alterations in the bile acid metabolome with little to no changes in gut microbial community structure. Ursodiol pretreatment resulted in attenuation of CDI pathogenesis early in the course of disease, which coincided with alterations in the cecal and colonic inflammatory transcriptome, bile acid activated receptors nuclear farnesoid X receptor (FXR), and transmembrane G protein-coupled membrane receptor 5 (TGR5), which are able to modulate the innate immune response through signaling pathways such as NF-κB. Although ursodiol pretreatment did not result in a consistent decrease in the C. difficile life cycle in vivo, it was able to attenuate an overly robust inflammatory response that is detrimental to the host during CDI. Ursodiol remains a viable non-antibiotic treatment and/or prevention strategy against CDI. Likewise, modulation of the host innate immune response via bile acid activated receptors, FXR and TGR5, represents a new potential treatment strategy for patients with CDI.ImportanceThe clinical utility of ursodiol for prevention of recurrent CDI is currently in Phase 4 clinical trials. However, the mechanism by which ursodiol exerts its impacts on C. difficile pathogenesis is poorly understood. Herein, we demonstrated that ursodiol pretreatment attenuates CDI pathogenesis early in the course of disease in mice, which coincides with alterations in the cecal and colonic inflammatory transcriptome, bile acid activated receptors nuclear farnesoid X receptor (FXR), and transmembrane G protein-coupled membrane receptor 5 (TGR5), which are able to modulate the innate immune response through signaling pathways such as NF-κB. Ursodiol attenuated an overly robust inflammatory response that is detrimental to the host during CDI, and thus remains a viable non-antibiotic treatment and/or prevention strategy against CDI. Likewise, modulation of the host innate immune response via bile acid activated receptors, FXR and TGR5, represents a new potential treatment strategy for patients with CDI.AbbreviationsαMCA – α-Muricholic acid; βMCA –β-Muricholic acid; ωMCA –ω-Muricholic acid; CA – Cholic acid; CDCA – Chenodeoxycholic acid; DCA – Deoxycholic acid; GCDCA – Glycochenodeoxycholic acid; GDCA – Glycodeoxycholic acid; GLCA – Glycolithocholic acid; GUDCA – Glycoursodeoxycholic acid; HCA – Hyodeoxycholic acid; iDCA – Isodeoxycholic acid; iLCA – Isolithocholic acid; LCA – Lithocholic acid; TCA – Taurocholic acid; TCDCA – Taurochenodeoxycholic acid; TDCA – Taurodeoxycholic acid; THCA – Taurohyodeoxycholic acid; TUDCA – Tauroursodeoxycholic acid; TβMCA– Tauro-β-muricholic acid; TωMCA –Tauro ω-muricholic acid; UDCA Ursodeoxycholic acid.

Sign in / Sign up

Export Citation Format

Share Document