scholarly journals Identification of Respiratory Syncytial Virus Nonstructural Protein 2 Residues Essential for Exploitation of the Host Ubiquitin System and Inhibition of Innate Immune Responses

2016 ◽  
Vol 90 (14) ◽  
pp. 6453-6463 ◽  
Author(s):  
Jillian N. Whelan ◽  
Kim C. Tran ◽  
Damian B. van Rossum ◽  
Michael N. Teng
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Innate Immune System ◽  
Reverse Genetics ◽  
Nonstructural Protein ◽  
Innate Immune ◽  
Effective Vaccine ◽  
Nonstructural Protein 2 ◽  
Ubiquitin System ◽  
Syncytial Virus

ABSTRACTRespiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in young children worldwide. The RSV nonstructural protein 2 (NS2) is a multifunctional protein that primarily acts to antagonize the innate immune system by targeting STAT2 for proteasomal degradation. We investigated the structural determinants of NS2 important for interaction with the host ubiquitin system to degrade STAT2 during infection. We found that NS2 expression enhances ubiquitination of host proteins. Bioinformatics analysis provided a platform for identification of specific residues that limit NS2-induced ubiquitination. Combinations of multiple mutations displayed an additive effect on reducing NS2-induced ubiquitination. Using a reverse genetics system, we generated recombinant RSV (rRSV) containing NS2 ubiquitin mutations, which maintained their effect on ubiquitin expression during infection. Interestingly, STAT2 degradation activity was ablated in the NS2 ubiquitin mutant rRSV. In addition, NS2 ubiquitin mutations decreased rRSV replication, indicating a correlation between NS2's ubiquitin function and antagonism of innate immune signaling to enhance viral replication. Our approach of targeting NS2 residues required for NS2 inhibition of immune responses provides a mechanism for attenuating RSV for vaccine development.IMPORTANCERSV has been circulating globally for more than 60 years, causing severe respiratory disease in pediatric, elderly, and immunocompromised populations. Production of a safe, effective vaccine against RSV is a public health priority. The NS2 protein is an effective target for prevention and treatment of RSV due to its antagonistic activity against the innate immune system. However, NS2-deleted RSV vaccine candidates rendered RSV overattenuated or poorly immunogenic. Alternatively, we can modify essential NS2 structural features to marginally limit viral growth while maintaining immune responses, providing the necessary balance between antigenicity and safety required for an effective vaccine. We coupled bioinformatics analysis with reverse genetics to introduce mutations into RSV's negative-sense genome. In this way we constructed rRSV NS2 ubiquitin mutants that limited NS2's ability to antagonize the innate immune system, thereby attenuating rRSV growth and increasing innate immune responses.

scholarly journals Innate immunity and the pneumococcus

Microbiology ◽  
2006 ◽  
Vol 152 (2) ◽  
pp. 285-293 ◽  
Author(s):  
Gavin K. Paterson ◽  
Tim J. Mitchell
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Streptococcus Pneumoniae ◽  
Immune Responses ◽  
Innate Immune System ◽  
Innate Immune ◽  
First Line ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Made In

The innate immune system provides a non-specific first line of defence against microbes and is crucial both in the development and effector stages of subsequent adaptive immune responses. Consistent with its importance, study of the innate immune system is a broad and fast-moving field. Here we provide an overview of the recent key advances made in this area with relation to the important pathogen Streptococcus pneumoniae (the pneumococcus).

scholarly journals Phenoloxidase activity and haemolymph cytology in honeybees challenged with a virus suspension (deformed wings virus DWV) or phosphate buffered suspension (PBS)

2019 ◽  
Vol 49 (2) ◽  
Author(s):  
Francesca Millanta ◽  
Simona Sagona ◽  
Maurizio Mazzei ◽  
Mario Forzan ◽  
Alessandro Poli ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Responses ◽  
Innate Immune System ◽  
Innate Immune ◽  
Additional Stress ◽  
Varroa Mite ◽  
Virus Suspension ◽  
Phenoloxidase Activity ◽  
Cell Immunity

ABSTRACT: The innate immune system of honeybees mainly consists in antimicrobial peptides, cellular immunity and melanisation. In order to investigate the immune response of honeybees to immune stressors, three stress degrees were tested. Newly emerged bees naturally DWV-infected were collected from a Varroa mite-free apiary and divided into three experimental groups: naturally DWV infected bees, PBS injected bees, and artificially DWV super infected bees. Phenoloxidase activity and haemolymph cellular subtype count were investigated. Phenoloxidase activity was highest (P<0.05) in DWV-superinfected bees, and the haemocyte population differed within the three observed groups. Although, immune responses following DWV infection have still not been completely clarified, this investigation sheds light on the relation between cell immunity and the phenoloxidase activity of DWV-naturally infected honeybees exposed to additional stress such as injury and viral superinfection.

Severe respiratory syncytial virus disease in preterm infants: a case of innate immaturity

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-216291
Author(s):  
Jeremy Anderson ◽  
Lien Anh Ha Do ◽  
Danielle Wurzel ◽  
Zheng Quan Toh ◽  
Kim Mulholland ◽  
...  
Keyword(s):  
Immune System ◽  
Respiratory Syncytial Virus ◽  
Preterm Infants ◽  
Innate Immune System ◽  
Virus Disease ◽  
Innate Immune ◽  
Term Infants ◽  
Viral Pathogen ◽  
Immune Biomarkers ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) is the most common viral pathogen associated with acute lower respiratory tract infection (LRTI) in children under 5 years of age. Severe RSV disease is associated with the development of chronic respiratory complications such as recurrent wheezing and asthma. A common risk factor for developing severe RSV disease is premature gestation and this is largely due to an immature innate immune system. This increases susceptibility to RSV since the innate immune system is less able to protect against pathogens at a time when adaptive immunity has not fully developed. This review focuses on comparing different aspects of innate immunity between preterm and term infants to better understand why preterm infants are more susceptible to severe RSV disease. Identifying early life innate immune biomarkers associated with the development of severe RSV disease, and understanding how these compare between preterm and term infants, remains a critically important question that would aid the development of interventions to reduce the burden of disease in this vulnerable population.

The innate immune system

2020 ◽  
pp. 307-314
Author(s):  
Paul Bowness
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Innate Immune System ◽  
Cell Types ◽  
Innate Immune ◽  
Microbial Pathogens ◽  
Innate Immune Responses ◽  
Adaptive Immune ◽  
System P ◽  
Different Cell Types

The innate immune system comprises evolutionarily ancient mechanisms that mediate first-line responses against microbial pathogens, and are also important in priming and execution of adaptive immune responses, and in defence against tumours. These responses, which recognize microbial non-self, damaged self, and absent self, are characterized by rapidity of action and they involve various different cell types, cell-associated receptors, and soluble factors. Previously thought to lack plasticity or memory, certain innate immune responses have recently been shown to be capable of ‘learning’ or ‘training’. Most cells of the innate immune system are derived from the myeloid precursors in the bone marrow. These include monocytes and their derivatives—macrophages and dendritic cells, blood granulocytes (neutrophils, basophils, and eosinophils), and tissue mast cells.

scholarly journals Tweaking Innate Immunity: The Promise of Innate Immunologicals as Anti-Infectives

2006 ◽  
Vol 17 (5) ◽  
pp. 307-314 ◽  
Author(s):  
Kenneth L Rosenthal
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Immune Responses ◽  
Innate Immune System ◽  
Immune Defense ◽  
Innate Immune ◽  
Parasitic Infections ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Adaptive Immune

New and exciting insights into the importance of the innate immune system are revolutionizing our understanding of immune defense against infections, pathogenesis, and the treatment and prevention of infectious diseases. The innate immune system uses multiple families of germline-encoded pattern recognition receptors (PRRs) to detect infection and trigger a variety of antimicrobial defense mechanisms. PRRs are evolutionarily highly conserved and serve to detect infection by recognizing pathogen-associated molecular patterns that are unique to microorganisms and essential for their survival. Toll-like receptors (TLRs) are transmembrane signalling receptors that activate gene expression programs that result in the production of proinflammatory cytokines and chemokines, type I interferons and antimicrobial factors. Furthermore, TLR activation facilitates and guides activation of adaptive immune responses through the activation of dendritic cells. TLRs are localized on the cell surface and in endosomal/lysosomal compartments, where they detect bacterial and viral infections. In contrast, nucleotide-binding oligomerization domain proteins and RNA helicases are located in the cell cytoplasm, where they serve as intracellular PRRs to detect cytoplasmic infections, particularly viruses. Due to their ability to enhance innate immune responses, novel strategies to use ligands, synthetic agonists or antagonists of PRRs (also known as 'innate immunologicals') can be used as stand-alone agents to provide immediate protection or treatment against bacterial, viral or parasitic infections. Furthermore, the newly appreciated importance of innate immunity in initiating and shaping adaptive immune responses is contributing to our understanding of vaccine adjuvants and promises to lead to improved next-generation vaccines.

scholarly journals Structural aspects of molecular recognition in the immune system. Part II: Pattern recognition receptors (IUPAC Technical Report)

2014 ◽  
Vol 86 (10) ◽  
pp. 1483-1538 ◽  
Author(s):  
John A. Robinson ◽  
Kerstin Moehle
Keyword(s):  
Pattern Recognition ◽  
Immune System ◽  
Immune Responses ◽  
Signaling Pathways ◽  
Innate Immune System ◽  
Pattern Recognition Receptors ◽  
Innate Immune ◽  
Helicase Domain ◽  
Downstream Signaling ◽  
Adaptive Immune

Abstract The vertebrate immune system uses pattern recognition receptors (PRRs) to detect a large variety of molecular signatures (pathogen-associated molecular patterns, PAMPs) from a broad range of different invading pathogens. The PAMPs range in size from relatively small molecules, to others of intermediate size such as bacterial lipopolysaccharide, lipopeptides, and oligosaccharides, to macromolecules such as viral DNA, RNA, and pathogen-derived proteins such as flagellin. Underlying this functional diversity of PRRs is a surprisingly small number of structurally distinct protein folds that include leucine-rich repeats in Toll-like receptors (TLRs) and NOD-like receptors (NLRs), the DExH box helicase domain in RIG-like receptors (RLRs), and C-type lectin domains (CTLDs) in the C-type lectins. Following PAMP recognition by the PRRs, downstream signaling pathways activate the innate immune system to respond to invading pathogenic organisms. The resulting stimulatory response is also vital for a balanced adaptive immune response to the pathogen, mediated by circulating antibodies and/or cytotoxic T cells. However, an aberrant stimulation of the innate immune system can also lead to excessive inflammatory and toxic stress responses. Exciting opportunities are now arising for the design of small synthetic molecules that bind to PRRs and influence downstream signaling pathways. Such molecules can be useful tools to modulate immune responses, for example, as adjuvants to stimulate adaptive immune responses to a vaccine, or as therapeutic agents to dampen aberrant immune responses, such as inflammation. The design of agonists or antagonists of PRRs can now benefit from a surge in knowledge of the 3D structures of PRRs, many in complexes with their natural ligands. This review article describes recent progress in structural studies of PRRs (TLRs, NLRs, CTLs, and RLRs), which is required for an understanding of how they specifically recognize structurally diverse “foreign” PAMPs amongst a background of other “self” molecules, sometimes closely related in structure, that are present in the human body.

scholarly journals lncRNAs Regulate Innate Immune Responses and Their Roles in Macrophage Polarization

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Zhen Wang ◽  
Ying Zheng
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Innate Immune System ◽  
Macrophage Polarization ◽  
Noncoding Rnas ◽  
Innate Immune ◽  
Microbial Pathogens ◽  
Innate Immune Responses ◽  
First Line ◽  
New Class

The innate immune system is the first line of defense against microbial pathogens. The activated innate immune system plays important roles in eliciting antimicrobial defenses. Despite the benefits of innate immune responses, excessive inflammation will cause host damage. Thus, tight regulation of these processes is required for the maintenance of immune homeostasis. Recently, a new class of long noncoding RNAs (lncRNAs) has emerged as important regulators in many physiological and pathological processes. Dysregulated lncRNAs have been found to be associated with excessive or uncontrolled inflammation. In this brief review, we summarize the roles of functional lncRNAs in regulating innate immune responses. We also discuss the roles of lncRNAs in macrophage polarization, an important molecular event in the innate immune responses.

scholarly journals Innate Immune Responses to Influenza Virus Infections in the Upper Respiratory Tract

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2090
Author(s):  
Edin J. Mifsud ◽  
Miku Kuba ◽  
Ian G. Barr
Keyword(s):  
Influenza Virus ◽  
Immune System ◽  
Epithelial Cells ◽  
Immune Responses ◽  
Respiratory Tract ◽  
Innate Immune System ◽  
Innate Immune ◽  
Upper Respiratory Tract ◽  
Adaptive Immune ◽  
Upper Respiratory

The innate immune system is the host’s first line of immune defence against any invading pathogen. To establish an infection in a human host the influenza virus must replicate in epithelial cells of the upper respiratory tract. However, there are several innate immune mechanisms in place to stop the virus from reaching epithelial cells. In addition to limiting viral replication and dissemination, the innate immune system also activates the adaptive immune system leading to viral clearance, enabling the respiratory system to return to normal homeostasis. However, an overzealous innate immune system or adaptive immune response can be associated with immunopathology and aid secondary bacterial infections of the lower respiratory tract leading to pneumonia. In this review, we discuss the mechanisms utilised by the innate immune system to limit influenza virus replication and the damage caused by influenza viruses on the respiratory tissues and how these very same protective immune responses can cause immunopathology.

scholarly journals Molecular and Structural Basis of DNA Sensors in Antiviral Innate Immunity

2020 ◽  
Vol 11 ◽  
Author(s):  
Ayesha Zahid ◽  
Hazrat Ismail ◽  
Bofeng Li ◽  
Tengchuan Jin
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Innate Immune System ◽  
Rna Polymerase Iii ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Structural Basis ◽  
Type I ◽  
Dna Sensors ◽  
Dna Sensing

DNA viruses are a source of great morbidity and mortality throughout the world by causing many diseases; thus, we need substantial knowledge regarding viral pathogenesis and the host’s antiviral immune responses to devise better preventive and therapeutic strategies. The innate immune system utilizes numerous germ-line encoded receptors called pattern-recognition receptors (PRRs) to detect various pathogen-associated molecular patterns (PAMPs) such as viral nucleic acids, ultimately resulting in antiviral immune responses in the form of proinflammatory cytokines and type I interferons. The immune-stimulatory role of DNA is known for a long time; however, DNA sensing ability of the innate immune system was unraveled only recently. At present, multiple DNA sensors have been proposed, and most of them use STING as a key adaptor protein to exert antiviral immune responses. In this review, we aim to provide molecular and structural underpinnings on endosomal DNA sensor Toll-like receptor 9 (TLR9) and multiple cytosolic DNA sensors including cyclic GMP-AMP synthase (cGAS), interferon-gamma inducible 16 (IFI16), absent in melanoma 2 (AIM2), and DNA-dependent activator of IRFs (DAI) to provide new insights on their signaling mechanisms and physiological relevance. We have also addressed less well-understood DNA sensors such as DEAD-box helicase DDX41, RNA polymerase III (RNA pol III), DNA-dependent protein kinase (DNA-PK), and meiotic recombination 11 homolog A (MRE11). By comprehensive understanding of molecular and structural aspects of DNA-sensing antiviral innate immune signaling pathways, potential new targets for viral and autoimmune diseases can be identified.

Sign in / Sign up

Export Citation Format

Share Document