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Nature Jul 2020Pneumonia resulting from infection is one of the leading causes of death worldwide. Pulmonary infection by the respiratory syncytial virus (RSV) is a large burden on...
Pneumonia resulting from infection is one of the leading causes of death worldwide. Pulmonary infection by the respiratory syncytial virus (RSV) is a large burden on human health, for which there are few therapeutic options. RSV targets ciliated epithelial cells in the airways, but how viruses such as RSV interact with receptors on these cells is not understood. Nucleolin is an entry coreceptor for RSV and also mediates the cellular entry of influenza, the parainfluenza virus, some enteroviruses and the bacterium that causes tularaemia. Here we show a mechanism of RSV entry into cells in which outside-in signalling, involving binding of the prefusion RSV-F glycoprotein with the insulin-like growth factor-1 receptor, triggers the activation of protein kinase C zeta (PKCζ). This cellular signalling cascade recruits nucleolin from the nuclei of cells to the plasma membrane, where it also binds to RSV-F on virions. We find that inhibiting PKCζ activation prevents the trafficking of nucleolin to RSV particles on airway organoid cultures, and reduces viral replication and pathology in RSV-infected mice. These findings reveal a mechanism of virus entry in which receptor engagement and signal transduction bring the coreceptor to viral particles at the cell surface, and could form the basis of new therapeutics to treat RSV infection.
Topics: Cell Line; Cell Nucleus; Enzyme Activation; Humans; Membrane Fusion; Phosphoproteins; Protein Binding; Protein Kinase C; RNA-Binding Proteins; Receptor, IGF Type 1; Receptors, Virus; Respiratory Syncytial Viruses; Viral Load; Virus Internalization; Nucleolin
PubMed: 32494007
DOI: 10.1038/s41586-020-2369-7 -
Human Vaccines & Immunotherapeutics May 2021Respiratory Syncytial Virus (RSV) causes lower respiratory tract infections that can be severe and sometimes fatal. The risk for severe RSV infection is highest in... (Randomized Controlled Trial)
Randomized Controlled Trial
A phase 1, randomized, placebo-controlled study to evaluate the safety and immunogenicity of an mRNA-based RSV prefusion F protein vaccine in healthy younger and older adults.
Respiratory Syncytial Virus (RSV) causes lower respiratory tract infections that can be severe and sometimes fatal. The risk for severe RSV infection is highest in infants and older adults. A safe and effective RSV vaccine for older adults represents a serious unmet medical need due to higher morbidity and mortality in this age group. In this randomized, partially double-blind, placebo-controlled, phase 1 dose-escalation study, we evaluated the safety, tolerability and immunogenicity of an investigational messenger ribonucleic acid (mRNA) vaccine encoding the RSV fusion protein (F) stabilized in the prefusion conformation. The study was conducted in healthy younger adults (ages ≥18 and ≤49 years) and healthy older adults (ages ≥60 and ≤79 years). Participants received mRNA-1777 (V171) or placebo as a single intramuscular dose. For each dose level, three sentinel participants were administered open-label mRNA-1777 (V171). Seventy-two younger adults were randomized and administered 25, 100, or 200 µg mRNA-1777 (V171) or placebo, and 107 older adults were randomized and administered 25, 100, 200 or 300 µg mRNA-1777 (V171) or placebo. Primary objectives were safety and tolerability and secondary objectives included humoral and cell-mediated immunogenicity. All dose levels of mRNA-1777 (V171) were generally well tolerated and no serious adverse events related to the vaccine were reported. Immunization with mRNA-1777 (V171) elicited a humoral immune response as measured by increases in RSV neutralizing antibody titers, serum antibody titers to RSV prefusion F protein, D25 competing antibody titers to RSV prefusion F protein, and cell-mediated immune responses to RSV-F peptides.
Topics: Aged; Antibodies, Neutralizing; Antibodies, Viral; Humans; Immunogenicity, Vaccine; Middle Aged; RNA, Messenger; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Syncytial Virus, Human; Viral Fusion Proteins
PubMed: 33121346
DOI: 10.1080/21645515.2020.1829899 -
Journal of Virology Apr 2022Respiratory syncytial virus (RSV) is a leading cause of pediatric acute respiratory infection worldwide. There are currently no approved vaccines or antivirals to combat...
Respiratory syncytial virus (RSV) is a leading cause of pediatric acute respiratory infection worldwide. There are currently no approved vaccines or antivirals to combat RSV disease. A few transformed cell lines and two historic strains have been extensively used to study RSV. Here, we reported a thorough molecular and cell biological characterization of HEp-2 and A549 cells infected with one of four strains of RSV representing both major subgroups as well as historic and more contemporary genotypes (RSV/A/Tracy [GA1], RSV/A/Ontario [ON], RSV/B/18537 [GB1], and RSV/B/Buenos Aires [BA]) via measurements of viral replication kinetics and viral gene expression, immunofluorescence-based imaging of gross cellular morphology and cell-associated RSV, and measurements of host response, including transcriptional changes and levels of secreted cytokines and growth factors. Infection with the respiratory syncytial virus (RSV) early in life is essentially guaranteed and can lead to severe disease. Most RSV studies have involved either of two historic RSV/A strains infecting one of two cell lines, HEp-2 or A549 cells. However, RSV contains ample variation within two evolving subgroups (A and B), and HEp-2 and A549 cell lines are genetically distinct. Here, we measured viral action and host response in both HEp-2 and A549 cells infected with four RSV strains from both subgroups and representing both historic and more contemporary strains. We discovered a subgroup-dependent difference in viral gene expression and found A549 cells were more potently antiviral and more sensitive, albeit subtly, to viral variation. Our findings revealed important differences between RSV subgroups and two widely used cell lines and provided baseline data for experiments with model systems better representative of natural RSV infection.
Topics: A549 Cells; Antiviral Agents; Cell Line; Host Microbial Interactions; Humans; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Severity of Illness Index; Species Specificity; Virus Replication
PubMed: 35285685
DOI: 10.1128/jvi.01904-21 -
Clinical Infectious Diseases : An... Jul 2022Respiratory syncytial virus (RSV), parainfluenza virus (PIV), and human metapneumovirus (hMPV) are increasingly associated with chronic lung allograft dysfunction (CLAD)... (Meta-Analysis)
Meta-Analysis
Respiratory Syncytial Virus, Human Metapneumovirus, and Parainfluenza Virus Infections in Lung Transplant Recipients: A Systematic Review of Outcomes and Treatment Strategies.
BACKGROUND
Respiratory syncytial virus (RSV), parainfluenza virus (PIV), and human metapneumovirus (hMPV) are increasingly associated with chronic lung allograft dysfunction (CLAD) in lung transplant recipients (LTR). This systematic review primarily aimed to assess outcomes of RSV/PIV/hMPV infections in LTR and secondarily to assess evidence regarding the efficacy of ribavirin.
METHODS
Relevant databases were queried and study outcomes extracted using a standardized method and summarized.
RESULTS
Nineteen retrospective and 12 prospective studies were included (total 1060 cases). Pooled 30-day mortality was low (0-3%), but CLAD progression 180-360 days postinfection was substantial (pooled incidences 19-24%) and probably associated with severe infection. Ribavirin trended toward effectiveness for CLAD prevention in exploratory meta-analysis (odds ratio [OR] 0.61, [0.27-1.18]), although results were highly variable between studies.
CONCLUSIONS
RSV/PIV/hMPV infection was followed by a high CLAD incidence. Treatment options, including ribavirin, are limited. There is an urgent need for high-quality studies to provide better treatment options for these infections.
Topics: Humans; Lung; Metapneumovirus; Parainfluenza Virus 1, Human; Parainfluenza Virus 2, Human; Paramyxoviridae Infections; Prospective Studies; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Respiratory Tract Infections; Retrospective Studies; Ribavirin; Transplant Recipients
PubMed: 35022697
DOI: 10.1093/cid/ciab969 -
Cell Jul 2023Respiratory syncytial virus (RSV) is the most common cause of serious respiratory infection in infants. Reinfections occur commonly, including in older adults. For six...
Respiratory syncytial virus (RSV) is the most common cause of serious respiratory infection in infants. Reinfections occur commonly, including in older adults. For six decades, effective vaccines remained elusive. Stabilization of the prefusion conformation of the RSV glycoprotein F was critical for development of effective vaccines to prevent RSV in older adults. To view this Bench to Bedside, open or download the PDF.
Topics: Humans; Aged; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Antibodies, Neutralizing; Antibodies, Viral; Respiratory Syncytial Virus, Human; Viral Fusion Proteins
PubMed: 37478816
DOI: 10.1016/j.cell.2023.05.048 -
The Journal of Infectious Diseases Nov 2023No overall estimate of respiratory syncytial virus (RSV)-associated hospitalizations in children aged under 5 years has been published for the European Union (EU). We...
BACKGROUND
No overall estimate of respiratory syncytial virus (RSV)-associated hospitalizations in children aged under 5 years has been published for the European Union (EU). We aimed to estimate the RSV hospitalization burden in children aged under 5 years in EU countries and Norway, by age group.
METHODS
We collated national RSV-associated hospitalization estimates calculated using linear regression models via the RESCEU project for Denmark, England, Finland, Norway, the Netherlands, and Scotland, 2006-2018. Additional estimates were obtained from a systematic review. Using multiple imputation and nearest neighbor matching methods, we estimated overall RSV-associated hospitalizations and rates in the EU.
RESULTS
Additional estimates for 2 countries (France and Spain) were found in the literature. In the EU, an average of 245 244 (95% confidence interval [CI], 224 688-265 799) yearly hospital admissions with a respiratory infection per year were associated with RSV in children aged under 5 years, with most cases occurring among children aged under 1 year (75%). Infants aged under 2 months represented the most affected group (71.6 per 1000 children; 95% CI, 66.6-76.6).
CONCLUSIONS
Our findings will help support decisions regarding prevention efforts and represent an important benchmark to understand changes in the RSV burden following the introduction of RSV immunization programs in Europe.
Topics: Child; Child, Preschool; Humans; Infant; European Union; Hospitalization; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Respiratory Tract Infections; Systematic Reviews as Topic
PubMed: 37246724
DOI: 10.1093/infdis/jiad188 -
The Journal of Infectious Diseases Nov 2023Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in adults that can result in hospitalizations. Estimating RSV-associated...
BACKGROUND
Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in adults that can result in hospitalizations. Estimating RSV-associated hospitalization is critical for planning RSV-related healthcare across Europe.
METHODS
We gathered RSV-associated hospitalization estimates from the RSV Consortium in Europe (RESCEU) for adults in Denmark, England, Finland, Norway, Netherlands, and Scotland from 2006 to 2017. We extrapolated these estimates to 28 European Union (EU) countries using nearest-neighbor matching, multiple imputations, and 2 sets of 10 indicators.
RESULTS
On average, 158 229 (95% confidence interval [CI], 140 865-175 592) RSV-associated hospitalizations occur annually among adults in the EU (≥18 years); 92% of these hospitalizations occur in adults ≥65 years. Among 75-84 years, the annual average is estimated at 74 519 (95% CI, 69 923-79 115) at a rate of 2.24 (95% CI, 2.10-2.38) per 1000. Among ≥85 years, the annual average is estimated at 37 904 (95% CI, 32 444-43 363) at a rate of 2.99 (95% CI, 2.56-3.42).
CONCLUSIONS
Our estimates of RSV-associated hospitalizations in adults are the first analysis integrating available data to provide the disease burden across the EU. Importantly, for a condition considered in the past to be primarily a disease of young children, the average annual hospitalization estimate in adults was lower but of a similar magnitude to the estimate in young children (0-4 years): 158 229 (95% CI, 140 865-175 592) versus 245 244 (95% CI, 224 688-265 799).
Topics: Child; Humans; Adult; Infant; Child, Preschool; Respiratory Syncytial Virus Infections; European Union; Respiratory Syncytial Virus, Human; Respiratory Tract Infections; Hospitalization
PubMed: 37246742
DOI: 10.1093/infdis/jiad189 -
Frontiers in Immunology 2022Respiratory tract infections are a leading cause of morbidity and mortality in newborns, infants, and young children. These early life infections present a formidable... (Review)
Review
Respiratory tract infections are a leading cause of morbidity and mortality in newborns, infants, and young children. These early life infections present a formidable immunologic challenge with a number of possibly conflicting goals: simultaneously eliminate the acute pathogen, preserve the primary gas-exchange function of the lung parenchyma in a developing lung, and limit long-term sequelae of both the infection and the inflammatory response. The latter has been most well studied in the context of childhood asthma, where multiple epidemiologic studies have linked early life viral infection with subsequent bronchospasm. This review will focus on the clinical relevance of respiratory syncytial virus (RSV), human metapneumovirus (HMPV), and rhinovirus (RV) and examine the protective and pathogenic host responses within the neonate.
Topics: Child; Child, Preschool; Humans; Immunity; Infant; Infant, Newborn; Metapneumovirus; Respiratory Syncytial Virus, Human; Respiratory Tract Infections; Viruses
PubMed: 35493465
DOI: 10.3389/fimmu.2022.863149 -
The Journal of Infectious Diseases Dec 2022Respiratory syncytial virus (RSV) is an important cause of disease in older adults. We evaluated the safety and immunogenicity of a stabilized RSV prefusion F subunit... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Respiratory syncytial virus (RSV) is an important cause of disease in older adults. We evaluated the safety and immunogenicity of a stabilized RSV prefusion F subunit (RSVpreF) vaccine candidate with/without adjuvant in adults aged 65-85 years.
METHODS
Primary cohort participants were equally randomized to 1 of 7 RSVpreF formulations: 60 µg with either Al(OH)3 or CpG/Al(OH)3, 120 µg with either Al(OH)3 or CpG/Al(OH)3, 240 µg with either Al(OH)3 or CpG/Al(OH)3, 240 µg unadjuvanted, or placebo, administered concomitantly with high-dose seasonal inactivated influenza vaccine (SIIV). Participants in the month 0,2 cohort were randomized to RSVpreF 240 µg with CpG/Al(OH)3 or placebo, administered at months 0 and 2.
RESULTS
All RSVpreF vaccine candidates elicited robust and persistent serum neutralizing responses when administered alone or with SIIV. There was no notable difference in neutralizing response between the formulations, including those containing CpG. In the month 0,2 cohort, there was no booster effect of dose 2. SIIV responses were similar or slightly lower with concomitant administration of RSVpreF. Most systemic and local reactions were mild and more frequent after RSVpreF than placebo.
CONCLUSIONS
RSVpreF formulations were well tolerated and elicited robust neutralizing responses in older adults; however, CpG/Al(OH)3 did not further enhance responses. Clinical Trials Registration. NCT03572062.
Topics: Humans; Aged; Respiratory Syncytial Virus Vaccines; Viral Fusion Proteins; Respiratory Syncytial Virus Infections; Antibodies, Neutralizing; Antibodies, Viral; Respiratory Syncytial Virus, Human; Adjuvants, Immunologic; Adjuvants, Pharmaceutic
PubMed: 35543281
DOI: 10.1093/infdis/jiac189 -
Nature Reviews. Microbiology Feb 2023This study reports that SARS-CoV-2 binds to cilia and reprogrammes microvilli to promote replication in the nasal airway.
This study reports that SARS-CoV-2 binds to cilia and reprogrammes microvilli to promote replication in the nasal airway.
Topics: Mucus; SARS-CoV-2; Cilia; Respiratory Syncytial Virus, Human
PubMed: 36513767
DOI: 10.1038/s41579-022-00842-6