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Journal of Immunology (Baltimore, Md. :... Jan 2010Lower respiratory tract infection by the human pneumovirus respiratory syncytial virus is a frequent cause of acute lung injury in children. Severe pneumovirus disease...
Lower respiratory tract infection by the human pneumovirus respiratory syncytial virus is a frequent cause of acute lung injury in children. Severe pneumovirus disease in humans is associated with activation of the granzyme pathway by effector lymphocytes, which may promote pathology by exaggerating proapoptotic caspase activity and proinflammatory activity. The main goal of this study was to determine whether granzymes contribute to the development of acute lung injury in pneumovirus-infected mice. Granzyme-expressing mice and granzyme A- and B-cluster single- and double-knockout mice were inoculated with the rodent pneumovirus pneumonia virus of mice strain J3666, and were studied for markers of lung inflammation and injury. Expression of granzyme A and B is detected in effector lymphocytes in mouse lungs in response to pneumovirus infection. Mice deficient for granzyme A and the granzyme B cluster have unchanged virus titers in the lungs but show a significantly delayed clinical response to fatal pneumovirus infection, a feature that is associated with delayed neutrophil recruitment, diminished activation of caspase-3, and reduced lung permeability. We conclude that granzyme A- and B-cluster deficiency delays the acute progression of pneumovirus disease by reducing alveolar injury.
Topics: Acute Lung Injury; Animals; Caspase 3; Cytotoxins; Disease Progression; Granzymes; Mice; Mice, Knockout; Neutrophil Infiltration; Pneumovirus; Pneumovirus Infections; Respiratory Tract Infections
PubMed: 20018616
DOI: 10.4049/jimmunol.0903029 -
BioMed Research International 2015Respiratory syncytial virus is a worldwide pathogen agent responsible for frequent respiratory tract infections that may become severe and potentially lethal in high... (Review)
Review
Respiratory syncytial virus is a worldwide pathogen agent responsible for frequent respiratory tract infections that may become severe and potentially lethal in high risk infants and adults. Several studies have been performed to investigate the immune response that determines the clinical course of the infection. In the present paper, we review the literature on viral, environmental, and host factors influencing virus response; the mechanisms of the immune response; and the action of nonimmunological factors. These mechanisms have often been studied in animal models and in the present review we also summarize the main findings obtained from animal models as well as the limits of each of these models. Understanding the lung response involved in the pathogenesis of these respiratory infections could be useful in improving the preventive strategies against respiratory syncytial virus.
Topics: Humans; Immunity, Innate; Lung; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Respiratory Tract Infections
PubMed: 26064963
DOI: 10.1155/2015/875723 -
Expert Review of Proteomics May 2021: Respiratory syncytial virus (RSV) is a major human pathogen associated with long term morbidity. RSV replication occurs primarily in the epithelium, producing a...
: Respiratory syncytial virus (RSV) is a major human pathogen associated with long term morbidity. RSV replication occurs primarily in the epithelium, producing a complex cellular response associated with acute inflammation and long-lived changes in pulmonary function and allergic disease. Proteomics approaches provide important insights into post-transcriptional regulatory processes including alterations in cellular complexes regulating the coordinated innate response and epigenome.: Peer-reviewed proteomics studies of host responses to RSV infections and proteomics techniques were analyzed. Methodologies identified include 1)." bottom-up" discovery proteomics, 2). Organellar proteomics by LC-gel fractionation; 3). Dynamic changes in protein interaction networks by LC-MS; and 4). selective reaction monitoring MS. We introduce recent developments in single-cell proteomics, top-down mass spectrometry, and photo-cleavable surfactant chemistries that will have impact on understanding how RSV induces extracellular matrix (ECM) composition and airway remodeling.: RSV replication induces global changes in the cellular proteome, dynamic shifts in nuclear proteins, and remodeling of epigenetic regulatory complexes linked to the innate response. Pathways discovered by proteomics technologies have led to deeper mechanistic understanding of the roles of heat shock proteins, redox response, transcriptional elongation complex remodeling and ECM secretion remodeling in host responses to RSV infections and pathological sequelae.
Topics: Chromatography, Liquid; Humans; Proteome; Proteomics; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human
PubMed: 34018899
DOI: 10.1080/14789450.2021.1931130 -
Vaccine Jan 2017Extraordinary progress in the structure and immunobiology of the human respiratory syncytial virus glycoproteins has been accomplished during the last few years.... (Review)
Review
Extraordinary progress in the structure and immunobiology of the human respiratory syncytial virus glycoproteins has been accomplished during the last few years. Determination of the fusion (F) glycoprotein structure folded in either the prefusion or the postfusion conformation was an inspiring breakthrough not only to understand the structural changes associated with the membrane fusion process but additionally to appreciate the antigenic intricacies of the F protein. Furthermore, these developments have opened new avenues for structure-based designs of promising hRSV vaccine candidates. Finally, recent advances in our knowledge of the attachment (G) glycoprotein and its interaction with cell-surface receptors have revitalized interest in this molecule as a vaccine, as well as its role in hRSV immunobiology.
Topics: Antigens, Viral; Glycoproteins; Humans; Protein Conformation; Respiratory Syncytial Virus Vaccines; Respiratory Syncytial Virus, Human; Virus Internalization
PubMed: 27692522
DOI: 10.1016/j.vaccine.2016.09.045 -
Biochemical Pharmacology Mar 2017The development of antiviral strategies to prevent or treat respiratory syncytial virus (RSV) infections is of great importance, especially considering the fact that RSV... (Review)
Review
The development of antiviral strategies to prevent or treat respiratory syncytial virus (RSV) infections is of great importance, especially considering the fact that RSV is one of the most important causes of pediatric respiratory infections. However, despite intense efforts, there is no antiviral or vaccine approved for the prevention or treatment of RSV infections. Several inhibitors, targeting different RSV proteins have been discovered over the past decade. We here review the most important chemical series as well as recent developments in understanding which viral proteins and/or host cell factors are good targets for inhibition of viral replication. In addition, we highlight the current in vitro and in vivo model systems of the disease. A number of molecules are currently in (advanced) preclinical or clinical development. Significant breakthroughs in the field may be expected in the upcoming years.
Topics: Animals; Antiviral Agents; Disease Models, Animal; Genetic Variation; Genome, Viral; Humans; Receptors, Virus; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Viral Proteins; Virus Internalization; Virus Replication
PubMed: 27659812
DOI: 10.1016/j.bcp.2016.09.014 -
The EMBO Journal Feb 2022Human respiratory syncytial virus (RSV) causes severe respiratory illness in children and the elderly. Here, using cryogenic electron microscopy and tomography combined...
Human respiratory syncytial virus (RSV) causes severe respiratory illness in children and the elderly. Here, using cryogenic electron microscopy and tomography combined with computational image analysis and three-dimensional reconstruction, we show that there is extensive helical ordering of the envelope-associated proteins and glycoproteins of RSV filamentous virions. We calculated a 16 Å resolution sub-tomogram average of the matrix protein (M) layer that forms an endoskeleton below the viral envelope. These data define a helical lattice of M-dimers, showing how M is oriented relative to the viral envelope. Glycoproteins that stud the viral envelope were also found to be helically ordered, a property that was coordinated by the M-layer. Furthermore, envelope glycoproteins clustered in pairs, a feature that may have implications for the conformation of fusion (F) glycoprotein epitopes that are the principal target for vaccine and monoclonal antibody development. We also report the presence, in authentic virus infections, of N-RNA rings packaged within RSV virions. These data provide molecular insight into the organisation of the virion and the mechanism of its assembly.
Topics: A549 Cells; Animals; Chlorocebus aethiops; Glycoproteins; Humans; Protein Conformation, alpha-Helical; Respiratory Syncytial Virus, Human; Vero Cells; Viral Envelope; Viral Matrix Proteins
PubMed: 34935163
DOI: 10.15252/embj.2021109728 -
Viruses May 2021Over two years (2012-2014), 719 nasopharyngeal samples were collected from 6-week- to 12-month-old infants presenting at the emergency department with moderate to severe... (Randomized Controlled Trial)
Randomized Controlled Trial
Over two years (2012-2014), 719 nasopharyngeal samples were collected from 6-week- to 12-month-old infants presenting at the emergency department with moderate to severe acute bronchiolitis. Viral testing was performed, and we found that 98% of samples were positive, including 90% for respiratory syncytial virus, 34% for human rhino virus, and 55% for viral co-detections, with a predominance of RSV/HRV co-infections (30%). Interestingly, we found that the risk of being infected by HRV is higher in the absence of RSV, suggesting interferences or exclusion mechanisms between these two viruses. Conversely, coronavirus infection had no impact on the likelihood of co-infection involving HRV and RSV. Bronchiolitis is the leading cause of hospitalizations in infants before 12 months of age, and many questions about its role in later chronic respiratory diseases (asthma and chronic obstructive pulmonary disease) exist. The role of virus detection and the burden of viral codetections need to be further explored, in order to understand the physiopathology of chronic respiratory diseases, a major public health issue.
Topics: Bronchiolitis, Viral; Coinfection; Emergency Service, Hospital; France; Humans; Infant; Multiplex Polymerase Chain Reaction; Nasopharynx; Respiratory Syncytial Virus, Human; Viruses
PubMed: 34073414
DOI: 10.3390/v13060990 -
FEMS Microbiology Reviews Sep 2006Respiratory syncytial virus is the major respiratory pathogen of infants and children worldwide, with no effective treatment or vaccine available. Steady progress has... (Review)
Review
Respiratory syncytial virus is the major respiratory pathogen of infants and children worldwide, with no effective treatment or vaccine available. Steady progress has been made in understanding the respiratory syncytial virus life cycle and the consequences of infection, but many areas of respiratory syncytial virus biology remain poorly understood, including the role of subcellular localisation of respiratory syncytial virus gene products such as the matrix protein in the infected host cell. The matrix protein plays a central role in viral assembly and, intriguingly, has been observed to traffic into and out of the nucleus at specific times during the respiratory syncytial virus infectious cycle. Further, the matrix protein has been shown to be able to inhibit transcription, which may be a key to respiratory syncytial virus pathogenesis. This review will focus on the role of the matrix protein in respiratory syncytial virus infection and what is known of its nucleocytoplasmic trafficking, the understanding of which may lead to new therapeutic approaches to combat respiratory syncytial virus, and/or vaccine development.
Topics: Animals; Humans; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Viral Matrix Proteins; Virus Assembly; Virus Replication
PubMed: 16911040
DOI: 10.1111/j.1574-6976.2006.00025.x -
Clinical Infectious Diseases : An... May 2018
Topics: Female; HIV; Humans; Longitudinal Studies; Postpartum Period; Pregnancy; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human
PubMed: 29253107
DOI: 10.1093/cid/cix1091 -
International Journal of Molecular... Feb 2021phosphoproteins (P) are essential co-factors of the viral polymerase by serving as a linchpin between the catalytic subunit and the ribonucleoprotein template. They... (Review)
Review
phosphoproteins (P) are essential co-factors of the viral polymerase by serving as a linchpin between the catalytic subunit and the ribonucleoprotein template. They have highly diverged, but their overall architecture is conserved. They are multidomain proteins, which all possess an oligomerization domain that separates - and -terminal domains. Large intrinsically disordered regions constitute their hallmark. Here, we exemplify their structural features and interaction potential, based on the P proteins. These P proteins are rather small, and their oligomerization domain is the only part with a defined 3D structure, owing to a quaternary arrangement. All other parts are either flexible or form short-lived secondary structure elements that transiently associate with the rest of the protein. P proteins interact with several viral and cellular proteins that are essential for viral transcription and replication. The combination of intrinsic disorder and tetrameric organization enables them to structurally adapt to different partners and to act as adaptor-like platforms to bring the latter close in space. Transient structures are stabilized in complex with protein partners. This class of proteins gives an insight into the structural versatility of non-globular intrinsically disordered protein domains.
Topics: Amino Acid Sequence; Animals; Binding Sites; Gene Expression Regulation, Viral; Humans; Intrinsically Disordered Proteins; Models, Molecular; Mononegavirales; Phosphoproteins; Pneumovirus; Protein Binding; Protein Conformation; Protein Folding; Protein Interaction Domains and Motifs; Respiratory Syncytial Virus, Human; Structure-Activity Relationship; Viral Proteins
PubMed: 33546457
DOI: 10.3390/ijms22041537