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Nasopharyngeal Lactobacillus is associated with a reduced risk of childhood wheezing illnesses following acute respiratory syncytial virus infection in infancy.
Rosas-Salazar C, Shilts MH, Tovchigrechko A, Schobel S, Chappell JD, Larkin EK, Gebretsadik T, Halpin RA, Nelson KE, Moore ML, Anderson LJ, Peebles RS, Das SR, Hartert TV
(2018) J Allergy Clin Immunol 142: 1447-1456.e9
MeSH Terms: Acute Disease, Child, Preschool, Cohort Studies, Female, Humans, Infant, Lactobacillus, Male, Microbiota, Nasopharynx, RNA, Ribosomal, 16S, Respiratory Sounds, Respiratory Syncytial Virus Infections, Risk
Show Abstract · Added March 14, 2018
BACKGROUND - Early life acute respiratory infection (ARI) with respiratory syncytial virus (RSV) has been strongly associated with the development of childhood wheezing illnesses, but the pathways underlying this association are poorly understood.
OBJECTIVE - To examine the role of the nasopharyngeal microbiome in the development of childhood wheezing illnesses following RSV ARI in infancy.
METHODS - We conducted a nested cohort study of 118 previously healthy, term infants with confirmed RSV ARI by RT-PCR. We used next-generation sequencing of the V4 region of the 16S ribosomal RNA gene to characterize the nasopharyngeal microbiome during RSV ARI. Our main outcome of interest was 2-year subsequent wheeze.
RESULTS - Of the 118 infants, 113 (95.8%) had 2-year outcome data. Of these, 46 (40.7%) had parental report of subsequent wheeze. There was no association between the overall taxonomic composition, diversity, and richness of the nasopharyngeal microbiome during RSV ARI with the development of subsequent wheeze. However, the nasopharyngeal detection and abundance of Lactobacillus was consistently higher in infants who did not develop this outcome. Lactobacillus also ranked first among the different genera in a model distinguishing infants with and without subsequent wheeze.
CONCLUSIONS - The nasopharyngeal detection and increased abundance of Lactobacillus during RSV ARI in infancy are associated with a reduced risk of childhood wheezing illnesses at age 2 years.
Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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14 MeSH Terms
Differences in the Nasopharyngeal Microbiome During Acute Respiratory Tract Infection With Human Rhinovirus and Respiratory Syncytial Virus in Infancy.
Rosas-Salazar C, Shilts MH, Tovchigrechko A, Schobel S, Chappell JD, Larkin EK, Shankar J, Yooseph S, Nelson KE, Halpin RA, Moore ML, Anderson LJ, Peebles RS, Das SR, Hartert TV
(2016) J Infect Dis 214: 1924-1928
MeSH Terms: Bacteria, DNA, Ribosomal, Female, Humans, Infant, Male, Microbiota, Nasopharynx, Picornaviridae Infections, Prospective Studies, RNA, Ribosomal, 16S, Respiratory Syncytial Virus Infections, Respiratory Tract Infections, Sequence Analysis, DNA
Show Abstract · Added March 14, 2018
Respiratory viruses alter the nasopharyngeal microbiome and may be associated with a distinct microbial signature. To test this hypothesis, we compared the nasopharyngeal microbiome of 135 previously healthy infants with acute respiratory infection due to human rhinovirus (HRV; n = 52) or respiratory syncytial virus (RSV; n = 83). The nasopharyngeal microbiome was assessed by sequencing the V4 region of the 16S ribosomal RNA. Respiratory viruses were identified by quantitative reverse-transcription polymerase chain reaction. We found significant differences in the overall taxonomic composition and abundance of certain bacterial genera between infants infected with HRV and those infected with RSV. Our results suggest that respiratory tract viral infections are associated with different nasopharyngeal microbial profiles.
© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.
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14 MeSH Terms
Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV.
Joyce MG, Zhang B, Ou L, Chen M, Chuang GY, Druz A, Kong WP, Lai YT, Rundlet EJ, Tsybovsky Y, Yang Y, Georgiev IS, Guttman M, Lees CR, Pancera M, Sastry M, Soto C, Stewart-Jones GBE, Thomas PV, Van Galen JG, Baxa U, Lee KK, Mascola JR, Graham BS, Kwong PD
(2016) Nat Struct Mol Biol 23: 811-820
MeSH Terms: Animals, Crystallography, X-Ray, Female, Glycoproteins, HEK293 Cells, Humans, Male, Mice, Inbred C57BL, Models, Molecular, Protein Engineering, Protein Stability, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, Vaccination, Viral Fusion Proteins, Viral Vaccines
Show Abstract · Added May 3, 2017
Structure-based design of vaccines, particularly the iterative optimization used so successfully in the structure-based design of drugs, has been a long-sought goal. We previously developed a first-generation vaccine antigen called DS-Cav1, comprising a prefusion-stabilized form of the fusion (F) glycoprotein, which elicits high-titer protective responses against respiratory syncytial virus (RSV) in mice and macaques. Here we report the improvement of DS-Cav1 through iterative cycles of structure-based design that significantly increased the titer of RSV-protective responses. The resultant second-generation 'DS2'-stabilized immunogens have their F subunits genetically linked, their fusion peptides deleted and their interprotomer movements stabilized by an additional disulfide bond. These DS2 immunogens are promising vaccine candidates with superior attributes, such as their lack of a requirement for furin cleavage and their increased antigenic stability against heat inactivation. The iterative structure-based improvement described here may have utility in the optimization of other vaccine antigens.
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Immunogenicity and efficacy of alphavirus-derived replicon vaccines for respiratory syncytial virus and human metapneumovirus in nonhuman primates.
Bates JT, Pickens JA, Schuster JE, Johnson M, Tollefson SJ, Williams JV, Davis NL, Johnston RE, Schultz-Darken N, Slaughter JC, Smith-House F, Crowe JE
(2016) Vaccine 34: 950-6
MeSH Terms: Alphavirus, Animals, Antibodies, Neutralizing, Antibodies, Viral, Bronchoalveolar Lavage Fluid, Chlorocebus aethiops, Encephalitis Virus, Venezuelan Equine, Immunoglobulin G, Metapneumovirus, Neutralization Tests, Nose, Paramyxoviridae Infections, Replicon, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus, Human, Viral Fusion Proteins, Viral Vaccines
Show Abstract · Added January 26, 2016
Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) are major causes of illness among children, the elderly, and the immunocompromised. No vaccine has been licensed for protection against either of these viruses. We tested the ability of two Venezuelan equine encephalitis virus-based viral replicon particle (VEE-VRP) vaccines that express the hRSV or hMPV fusion (F) protein to confer protection against hRSV or hMPV in African green monkeys. Animals immunized with VEE-VRP vaccines developed RSV or MPV F-specific antibodies and serum neutralizing activity. Compared to control animals, immunized animals were better able to control viral load in the respiratory mucosa following challenge and had lower levels of viral genome in nasopharyngeal and bronchoalveolar lavage fluids. The high level of immunogenicity and protective efficacy induced by these vaccine candidates in nonhuman primates suggest that they hold promise for further development.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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17 MeSH Terms
Incidence and Risk Factors for Respiratory Syncytial Virus and Human Metapneumovirus Infections among Children in the Remote Highlands of Peru.
Wu A, Budge PJ, Williams J, Griffin MR, Edwards KM, Johnson M, Zhu Y, Hartinger S, Verastegui H, Gil AI, Lanata CF, Grijalva CG
(2015) PLoS One 10: e0130233
MeSH Terms: Child, Child, Preschool, Female, Humans, Incidence, Infant, Infant, Newborn, Male, Metapneumovirus, Multivariate Analysis, Paramyxoviridae Infections, Peru, Poisson Distribution, Prospective Studies, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus, Human, Risk Factors, Rural Population
Show Abstract · Added July 27, 2018
INTRODUCTION - The disease burden and risk factors for respiratory syncytial virus (RSV) and human metapneumovirus (MPV) infections among children living in remote, rural areas remain unclear.
MATERIALS AND METHODS - We conducted a prospective, household-based cohort study of children aged <3 years living in remote rural highland communities in San Marcos, Cajamarca, Peru. Acute respiratory illnesses (ARI), including lower respiratory tract infection (LRTI), were monitored through weekly household visits from March 2009 through September 2011. Nasal swabs collected during ARI/LRTI were tested for RSV, MPV, and other respiratory viruses using real-time RT-PCR. Incidence rates and rate ratios were calculated using mixed effects Poisson regression.
RESULTS - Among 892 enrolled children, incidence rates of RSV and MPV ARI were 30 and 17 episodes per 100 child-years, respectively. The proportions of RSV and MPV ARI that presented as LRTI were 12.5% and 8.9%, respectively. Clinic visits for ARI and hospitalizations were significantly more frequent (all p values <0.05) among children with RSV (clinic 41% and hospital 5.3%) and MPV ARI (38% and 3.5%) when compared with other viral infections (23% and 0.7%) and infections without virus detected (24% and 0.6%). In multivariable analysis, risk factors for RSV detection included younger age (RR 1.02, 95% CI: 1.00-1.03), the presence of a smoker in the house (RR 1.63, 95% CI: 1.12-2.38), residing at higher altitudes (RR 1.93, 95% CI: 1.25-3.00 for 2nd compared to 1st quartile residents; RR 1.98, 95% CI: 1.26-3.13 for 3rd compared to 1st quartile residents). Having an unemployed household head was significantly associated with MPV risk (RR 2.11, 95% CI: 1.12-4.01).
CONCLUSION - In rural high altitude communities in Peru, childhood ARI due to RSV or MPV were common and associated with higher morbidity than ARI due to other viruses or with no viral detections. The risk factors identified in this study may be considered for interventional studies to control infections by these viruses among young children from developing countries.
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Challenges and opportunities in developing respiratory syncytial virus therapeutics.
Simões EA, DeVincenzo JP, Boeckh M, Bont L, Crowe JE, Griffiths P, Hayden FG, Hodinka RL, Smyth RL, Spencer K, Thirstrup S, Walsh EE, Whitley RJ
(2015) J Infect Dis 211 Suppl 1: S1-S20
MeSH Terms: Antiviral Agents, Clinical Trials as Topic, Drug Approval, Drug Discovery, Drug Therapy, Combination, Humans, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses
Show Abstract · Added January 26, 2016
Two meetings, one sponsored by the Wellcome Trust in 2012 and the other by the Global Virology Foundation in 2013, assembled academic, public health and pharmaceutical industry experts to assess the challenges and opportunities for developing antivirals for the treatment of respiratory syncytial virus (RSV) infections. The practicalities of clinical trials and establishing reliable outcome measures in different target groups were discussed in the context of the regulatory pathways that could accelerate the translation of promising compounds into licensed agents. RSV drug development is hampered by the perceptions of a relatively small and fragmented market that may discourage major pharmaceutical company investment. Conversely, the public health need is far too large for RSV to be designated an orphan or neglected disease. Recent advances in understanding RSV epidemiology, improved point-of-care diagnostics, and identification of candidate antiviral drugs argue that the major obstacles to drug development can and will be overcome. Further progress will depend on studies of disease pathogenesis and knowledge provided from controlled clinical trials of these new therapeutic agents. The use of combinations of inhibitors that have different mechanisms of action may be necessary to increase antiviral potency and reduce the risk of resistance emergence.
© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
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8 MeSH Terms
TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization.
Caballero MT, Serra ME, Acosta PL, Marzec J, Gibbons L, Salim M, Rodriguez A, Reynaldi A, Garcia A, Bado D, Buchholz UJ, Hijano DR, Coviello S, Newcomb D, Bellabarba M, Ferolla FM, Libster R, Berenstein A, Siniawaski S, Blumetti V, Echavarria M, Pinto L, Lawrence A, Ossorio MF, Grosman A, Mateu CG, Bayle C, Dericco A, Pellegrini M, Igarza I, Repetto HA, Grimaldi LA, Gudapati P, Polack NR, Althabe F, Shi M, Ferrero F, Bergel E, Stein RT, Peebles RS, Boothby M, Kleeberger SR, Polack FP
(2015) J Clin Invest 125: 571-82
MeSH Terms: Animals, Bronchiolitis, Viral, Disease Models, Animal, Environmental Exposure, Female, GATA3 Transcription Factor, Genotype, Humans, Infant, Infant, Newborn, Interferon-gamma, Interleukin-4, Lipopolysaccharides, Male, Mice, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, T-Box Domain Proteins, Th2 Cells, Toll-Like Receptor 4
Show Abstract · Added January 20, 2015
While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.
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20 MeSH Terms
Toward primary prevention of asthma. Reviewing the evidence for early-life respiratory viral infections as modifiable risk factors to prevent childhood asthma.
Feldman AS, He Y, Moore ML, Hershenson MB, Hartert TV
(2015) Am J Respir Crit Care Med 191: 34-44
MeSH Terms: Antibodies, Monoclonal, Humanized, Antiviral Agents, Asthma, Child, Preschool, Diet, Environmental Exposure, Epigenesis, Genetic, Genetic Predisposition to Disease, Humans, Infant, Microbiota, Palivizumab, Primary Prevention, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, Respiratory Tract Infections, Rhinovirus, Risk Factors, Severity of Illness Index, Tobacco Smoke Pollution
Show Abstract · Added January 20, 2015
A first step in primary disease prevention is identifying common, modifiable risk factors that contribute to a significant proportion of disease development. Infant respiratory viral infection and childhood asthma are the most common acute and chronic diseases of childhood, respectively. Common clinical features and links between these diseases have long been recognized, with early-life respiratory syncytial virus (RSV) and rhinovirus (RV) lower respiratory tract infections (LRTIs) being strongly associated with increased asthma risk. However, there has long been debate over the role of these respiratory viruses in asthma inception. In this article, we systematically review the evidence linking early-life RSV and RV LRTIs with asthma inception and whether they could therefore be targets for primary prevention efforts.
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Identification of residues in the human respiratory syncytial virus fusion protein that modulate fusion activity and pathogenesis.
Hotard AL, Lee S, Currier MG, Crowe JE, Sakamoto K, Newcomb DC, Peebles RS, Plemper RK, Moore ML
(2015) J Virol 89: 512-22
MeSH Terms: Animals, Cell Line, DNA Mutational Analysis, Disease Models, Animal, Female, Histocytochemistry, Humans, Lung, Mice, Inbred BALB C, Respiratory Syncytial Virus Infections, Respiratory Syncytial Virus, Human, Viral Fusion Proteins, Viral Load, Virus Internalization, Weight Loss
Show Abstract · Added January 20, 2015
UNLABELLED - Human respiratory syncytial virus (RSV) lower respiratory tract infection can result in inflammation and mucus plugging of airways. RSV strain A2-line19F induces relatively high viral load and mucus in mice. The line 19 fusion (F) protein harbors five unique residues compared to the non-mucus-inducing strains A2 and Long, at positions 79, 191, 357, 371, and 557. We hypothesized that differential fusion activity is a determinant of pathogenesis. In a cell-cell fusion assay, line 19 F was more fusogenic than Long F. We changed the residues unique to line 19 F to the corresponding residues in Long F and identified residues 79 and 191 together as responsible for high fusion activity. Surprisingly, mutation of residues 357 or 357 with 371 resulted in gain of fusion activity. Thus, we generated RSV F mutants with a range of defined fusion activity and engineered these into recombinant viruses. We found a clear, positive correlation between fusion activity and early viral load in mice; however, we did not detect a correlation between viral loads and levels of airway mucin expression. The F mutant with the highest fusion activity, A2-line19F-K357T/Y371N, induced high viral loads, severe lung histopathology, and weight loss but did not induce high levels of airway mucin expression. We defined residues 79/191 as critical for line 19 F fusion activity and 357/371 as playing a role in A2-line19F mucus induction. Defining the molecular basis of the role of RSV F in pathogenesis may aid vaccine and therapeutic strategies aimed at this protein.
IMPORTANCE - Human respiratory syncytial virus (RSV) is the most important lower respiratory tract pathogen of infants for which there is no vaccine. Elucidating mechanisms of RSV pathogenesis is important for rational vaccine and drug design. We defined specific amino acids in the fusion (F) protein of RSV strain line 19 critical for fusion activity and elucidated a correlation between fusion activity and viral load in mice. Further, we identified two distinct amino acids in F as contributing to the mucogenic phenotype of the A2-line19F virus. Taken together, these results illustrate a role for RSV F in virulence.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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Interferon response and respiratory virus control are preserved in bronchial epithelial cells in asthma.
Patel DA, You Y, Huang G, Byers DE, Kim HJ, Agapov E, Moore ML, Peebles RS, Castro M, Sumino K, Shifren A, Brody SL, Holtzman MJ
(2014) J Allergy Clin Immunol 134: 1402-1412.e7
MeSH Terms: Adult, Asthma, Bronchi, Cells, Cultured, Epithelial Cells, Female, Humans, Influenza A virus, Influenza, Human, Interferons, Male, RNA, Messenger, RNA, Viral, Respiratory Syncytial Virus Infections, Respiratory Syncytial Viruses, Young Adult
Show Abstract · Added January 20, 2015
BACKGROUND - Some investigators find a deficiency in IFN production from airway epithelial cells infected with human rhinovirus in asthma, but whether this abnormality occurs with other respiratory viruses is uncertain.
OBJECTIVE - To assess the effect of influenza A virus (IAV) and respiratory syncytial virus (RSV) infection on IFN production and viral level in human bronchial epithelial cells (hBECs) from subjects with and without asthma.
METHODS - Primary-culture hBECs from subjects with mild to severe asthma (n = 11) and controls without asthma (hBECs; n = 7) were infected with live or ultraviolet-inactivated IAV (WS/33 strain), RSV (Long strain), or RSV (A/2001/2-20 strain) with multiplicity of infection 0.01 to 1. Levels of virus along with IFN-β and IFN-λ and IFN-stimulated gene expression (tracked by 2'-5'-oligoadenylate synthetase 1 and myxovirus (influenza virus) resistance 1 mRNA) were determined up to 72 hours postinoculation.
RESULTS - After IAV infection, viral levels were increased 2-fold in hBECs from asthmatic subjects compared with nonasthmatic control subjects (P < .05) and this increase occurred in concert with increased IFN-λ1 levels and no significant difference in IFNB1, 2'-5'-oligoadenylate synthetase 1, or myxovirus (influenza virus) resistance 1mRNA levels. After RSV infections, viral levels were not significantly increased in hBECs from asthmatic versus nonasthmatic subjects and the only significant difference between groups was a decrease in IFN-λ levels (P < .05) that correlated with a decrease in viral titer. All these differences were found only at isolated time points and were not sustained throughout the 72-hour infection period.
CONCLUSIONS - The results indicate that IAV and RSV control and IFN response to these viruses in airway epithelial cells is remarkably similar between subjects with and without asthma.
Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms