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At least 937 records · Page 52Linked to original sources
PubMed2004

Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 gene.

Respiratory syncytial virus (RSV) infection is one of the major causes of respiratory tract infection for which no vaccine or antiviral treatment is available. The RSV NS1 protein seems to antagonize the host interferon (IFN) response; however, its mechanism is unknown. Here, we used a plasmid-borne small interfering RNA targeting the NS1 gene (siNS1) to examine the role of NS1 in modulating RSV infection. RSV replication was reduced in A549 cells, but not IFN-deficient Vero cells, transfected with siNS1. siNS1 induced upregulated expression of IFN-beta and IFN-inducible genes in A549 cells. siNS1-transfected human dendritic cells, upon RSV infection, produced elevated type-1 IFN and induced differentiation of naive CD4+ T cells to T helper type 1 (TH1) cells. Mice treated intranasally with siNS1 nanoparticles before or after infection with RSV showed substantially decreased virus titers in the lung and decreased inflammation and airway reactivity compared to controls. Thus, siNS1 nanoparticles may provide an effective inhibition of RSV infection in humans.

Antiviral Agents↗
PubMed2022

Species-specific transcriptomic changes upon respiratory syncytial virus infection in cotton rats.

The cotton rat (Sigmodon) is the gold standard pre-clinical small animal model for respiratory viral pathogens, especially for respiratory syncytial virus (RSV). However, without a reference genome or a published transcriptome, studies requiring gene expression analysis in cotton rats are severely limited. The aims of this study were to generate a comprehensive transcriptome from multiple tissues of two species of cotton rats that are commonly used as animal models (Sigmodon fulviventer and Sigmodon hispidus), and to compare and contrast gene expression changes and immune responses to RSV infection between the two species. Transcriptomes were assembled from lung, spleen, kidney, heart, and intestines for each species with a contig N50 > 1600. Annotation of contigs generated nearly 120,000 gene annotations for each species. The transcriptomes of S. fulviventer and S. hispidus were then used to assess immune response to RSV infection. We identified 238 unique genes that are significantly differentially expressed, including several genes implicated in RSV infection (e.g., Mx2, I27L2, LY6E, Viperin, Keratin 6A, ISG15, CXCL10, CXCL11, IRF9) as well as novel genes that have not previously described in RSV research (LG3BP, SYWC, ABEC1, IIGP1, CREB1). This study presents two comprehensive transcriptome references as resources for future gene expression analysis studies in the cotton rat model, as well as provides gene sequences for mechanistic characterization of molecular pathways. Overall, our results provide generalizable insights into the effect of host genetics on host-virus interactions, as well as identify new host therapeutic targets for RSV treatment and prevention.

Animals↗
PubMed1999

Effectiveness of RSVIG prophylaxis and therapy of respiratory syncytial virus in an immunosuppressed animal model.

Respiratory syncytial virus (RSV) has emerged as a leading cause of pneumonia, with high mortality, in bone marrow transplant (BMT) recipients, as well as in other profoundly immunocompromised patients, such as myelosuppressed adults with leukemia. We tested the efficacy of immunoglobulin with high anti-RSV neutralizing antibody levels (RSVIG) for prophylaxis and therapy of RSV infection in cotton rats undergoing prolonged immunosuppression with cyclophosphamide. These animals experience persistent infection, a model which is similar to the disease seen in post-BMT humans. Both prophylaxis and therapy reduced pulmonary viral replication over 500-fold to nearly undetectable levels. In animals receiving continual immunosuppression, the use of multiple therapeutic doses of RSVIG was able to prevent rebound viral replication, though virus was not completely eliminated.

Animals↗
PubMed2000

Respiratory syncytial virus immune globulin treatment of lower respiratory tract infection in pediatric patients undergoing bone marrow transplantation - a compassionate use experience.

Respiratory syncytial virus (RSV) pneumonia in BMT recipients carries a mortality rate of approximately 50-70% despite ribavirin (Virazole) treatment. In both immunocompetent and immunocompromised animal models, RSV neutralizing antibodies rapidly reduce pulmonary virus load after a single dose. RSV-IGIV (RespiGam) is an IgG immune globulin with high concentrations of RSV neutralizing antibody (>19 200 MU/ml). From June 1991 to February 1996, a compassionate-use protocol using RSV-IGIV for treatment of RSV infections was conducted. Eleven children at multiple centers, mean age 3.3 years (4 months to 9 years), were undergoing BMT and met the protocol criteria. They received a single 1500 mg/kg dose of RSV-IGIV infused over 12 h at a median of 5 days (1-37 days) after RSV symptom onset. Ten of these patients received prior or concurrent aerosolized ribavirin. Serum RSV neutralizing titers were measured in five patients and showed a 3- to 30-fold increase 24 h after RSV-IGIV infusion. Adverse events were mild. One of 11 (9.1%) patients died from their RSV illness (91% RSV survival). In comparison to previously published reports, RSV-IGIV treatment of RSV pneumonia in BMT patients may increase survival above that in such patients treated with ribavirin alone. Bone Marrow Transplantation (2000) 25, 161-165.

Administration, Inhalation↗
PubMed2002

Palivizumab is highly effective in suppressing respiratory syncytial virus in an immunosuppressed animal model.

Respiratory syncytial virus (RSV) is widely recognized as a leading cause of pneumonia, with substantial mortality, in bone marrow transplant recipients. We tested the efficacy of a systemic monoclonal antibody (MAB) preparation possessing a high titer of anti-RSV neutralizing antibody, palivizumab (Synagis) for prophylaxis and therapy of RSV infection in cytoxan (CY) immunosuppressed cotton rats, a model in which the efficacy of a polyclonal anti-RSV product (Respigam) has been demonstrated. Both prophylaxis and therapy with this MAB were highly effective in reducing pulmonary viral replication. However, multiple sequential therapeutic doses of MAB were necessary to control rebound viral replication in continually suppressed animals.

Animals↗
PubMed2007

Respiratory syncytial virus nephropathy in rats.

The pathogenesis of minimal change nephrotic syndrome (MCNS) remains unclear. Respiratory tract viruses could contribute to MCNS, and respiratory syncytial virus (RSV) is the most common one. In this study, we planned to investigate the effects of RSV on the proteinuria and glomerular structure of rats and to explore the role of RSV in the pathogenesis of MCNS. Rats were inoculated with 6 x 10(2), 10(4), and 10(6) PFU (plaque-forming units) RSV and killed on days 4, 8, 14, 28, and 60 postinoculation (RSV(4), RSV(8), RSV(14), RSV(28), and RSV(60)). The proteinuria and serum parameters were measured; renal histology was observed by light microscopy and electron microscopy; immune complex deposits were detected by immunofluorescence microscopy; and RSV RNA and RSV titer were determined by in situ hybridization and plaque assay, respectively. After inoculation, the proteinuria increased, especially in 6 x 10(6) PFU RSV(14),(28). The serum albumin of 6 x 10(6) PFU RSV(14),(28) and different-titer RSV(60) decreased. Slight hypercellularity in minority glomeruli and swelling in partial tubular epithelial cells were observed in RSV(4),(8), whereas a relief of the above changes and no abnormalities were detected in RSV(14) and RSV(28),(60), respectively, under a light microscope. Extensive foot process effacement was observed in 6 x 10(6) PFU RSV(14),(28),(60) under an electron microscope. No immune complex deposits were detected in the renal tissues. RSV RNA signal and RSV titer of renal tissues, depending on the dose of inoculum, reached their climax on day 8 postinoculation. Our study reports for the first time that RSV can lead to nephropathy in rats on days 14-60 postinoculation, especially in 6 x 10(6) PFU RSV-inoculated rats, which may be a new exploration of the pathogenesis of MCNS.

Animals↗
PubMed2001

Mammalian cell production of a respiratory syncytial virus (RSV) candidate vaccine recovered using a product-specific affinity column.

The recombinant production of a respiratory syncytial virus (RSV) candidate vaccine BBG2Na in baby hamster kidney cells (BHK-21 cells) was investigated. BBG2Na consists of a serum-albumin-binding region (BB) fused to a 101-amino-acid fragment of the RSV G-protein. Semliki Forest virus-based expression vectors encoding both intracellular and secreted forms of BBG2Na were constructed and found to be functional. Affinity recovery of BBG2Na employing human serum albumin columns was found to be inefficient due to the abundance of BSA in the applied samples. Instead, a strategy using a tailor-made affinity ligand based on a combinatorially engineered Staphylococcus aureus protein A domain, showing specific binding to the G-protein part of the product, was evaluated. In conclusion, a strategy for production and successful recovery of BBG2Na in mammalian cells was created, through the development of a product-specific affinity column.

Animals↗
PubMed2003

Respiratory syncytial virus augments production of fibroblast growth factor basic in vitro: implications for a possible mechanism of prolonged wheezing after infection.

Respiratory syncytial virus (RSV) has been linked to the development of clinical asthma. Cellular mechanisms of this observation are not yet clearly elucidated. In chronic asthma, production of growth factors and remodeling are associated with prolonged wheezing. It was hypothesized that cells infected with RSV may produce excessive levels of fibroblast growth factor basic (FGFb), and epidermal growth factor (EGF). Airway epithelial cells were incubated with either: (i) virus, (ii) inactivated virus, or (iii) media only. The levels of FGFb and EGF were measured in the cellular supernatant fluid. The study demonstrated that by 24 h after RSV inoculation, or exposure to RSV-killed virus, cells are stimulated to produce significantly more FGFb, compared with non-infected/non-exposed control cells. FGFb is an important factor in remodeling and fibroblast activation in the airway. Using treatment with actinomycin D and cylcohexamide the effect of inhibiting translation or transcription in the infected cells, on FGFb production was demonstrated. There were no alterations in EGF production detectable. Based on the findings, the mechanism of FGFb secretion after RSV inoculation, appears to be regulated at the levels of both transcription and translation. The increased FGFb release potentially could contribute to fibroblast activation and remodeling in the airway, and thus provide another possible mechanism for prolonged wheezing after infection.

Bronchi↗
PubMed2002

Influence of respiratory syncytial virus infection on cytokine and inflammatory responses in allergic mice.

BACKGROUND: Th2 lymphocyte responses are associated with inflammation and disease during allergic responses. Exposure to particular environmental factors during the expression of allergy could result in more pronounced Th2-like immune responses and more severe disease. One factor might be a respiratory virus infection. OBJECTIVE: The aim of our study was to investigate the influence of respiratory syncytial virus (RSV) infection on the expression of ovalbumin (OVA)-induced allergy in BALB/c mice. METHODS: We determined OVA-specific IgE in serum, cytokine profiles and histopathological lesions in lungs of OVA-allergic mice after RSV infection. RESULTS: OVA sensitization and challenge induced OVA-specific IgE in serum, Th2 cytokine mRNA expression, and mononuclear and eosinophilic inflammation in the lungs. RSV inoculation during the challenge period enhanced OVA-induced IL-4 and IL-5 mRNA expression in lung tissue. RSV further enhanced the OVA-induced hypertrophy of mucous cells and eosinophilic infiltration in lung tissue. Surprisingly, RSV infection decreased Th2 cytokine secretion and eosinophilic influx in bronchoalveolar lavage of OVA-allergic mice. Because inactivated RSV did not influence these responses, replication of RSV appeared essential for the modification of OVA-induced Th2 cytokine expression. RSV did not change OVA-specific IgE levels in serum. Furthermore, the RSV-induced IL-12 mRNA expression in lung tissue of OVA-allergic mice was diminished, but IFN-gamma mRNA expression was not affected. CONCLUSION: RSV infection enhanced particular OVA-induced Th2 cytokine mRNA responses and pulmonary lesions in allergic mice and thus aggravated allergic respiratory disease.

Animals↗
PubMed2003

Interferon-gamma levels in nasopharyngeal secretions of infants with respiratory syncytial virus and other respiratory viral infections.

Respiratory syncytial virus (RSV) infection, one of the most common causes of hospitalization of children in developed countries, has been implicated as a cause of asthma. We aimed to characterize the cytokine profile in nasopharyngeal aspirates (NPAs) taken from infants during upper respiratory tract infection to investigate whether RSV induced a unique immune response as compared with other viruses. Additionally, we sought to determine whether this profile was influenced by the infants' atopic status. A prospective birth cohort of babies at high risk of atopy was recruited. Ratios of a T-helper 1 (Th1) cytokine, interferon gamma (IFN-gamma) and a T-helper 2 (Th2)-like cytokine, interleukin-10 (IL-10), in NPAs were determined during episodes of respiratory tract infections in the first year. The viral aetiology of the respiratory tract infections was determined using polymerase chain reaction (PCR), culture and immunofluorescence. Atopic status was ascertained at 1 year of age using skin prick tests. Participants were recruited antenatally and subsequently followed in the community. Sixty babies with one or both parents atopic were enrolled into the study. IFN-gamma : IL-10 ratios in NPAs during upper respiratory tract infections and their correlation with viral aetiology and atopic status were the main outcome measures. The mean IFN-gamma : IL-10 ratio was significantly lower (due to lower IFN-gamma) during RSV infections than during infections with other viruses (P = 0.035). The cytokine ratio, however, did not differ between infants with or without wheeze during URTIs (P = 0.44), or between infants who were atopic or non-atopic (P = 0.49). This study suggests that RSV is associated with lower IFN-gamma production in young babies, regardless of their atopic status, compared to upper respiratory tract infections where either another virus is detected or where no viral identification is made.

Follow-Up Studies↗
PubMed2003

Influenza- and respiratory syncytial virus-associated morbidity and mortality in the nursing home population.

OBJECTIVES: To estimate winter viral-related morbidity and mortality in Tennessee nursing home residents during 4 consecutive years. DESIGN: A retrospective cohort study. SETTING: Three hundred eighty-one Tennessee nursing homes. PARTICIPANTS: Nursing home residents. MEASUREMENTS: Viral surveillance data were used to define three seasons: influenza (influenza and respiratory syncytial virus (RSV) cocirculating), RSV (RSV alone circulating), and non winter-viral (neither virus circulating). Adjusted seasonal differences in rates of cardiopulmonary hospitalizations, antibiotic prescriptions, and deaths during these three seasons were calculated to estimate annual hospitalizations, courses of antibiotics, and deaths attributable to influenza and RSV from 1995 to 1999. RESULTS: Nursing home residents had 81,885 person-years of follow-up. In the 63% of residents with comorbid conditions that increase influenza morbidity, influenza infection contributed to an estimated average of 28 hospitalizations, 147 courses of antibiotics, and 15 deaths per 1,000 persons annually. Similarly, RSV accounted for an annual average of 15 hospitalizations, 76 courses of antibiotics, and 17 deaths per 1,000 persons. Influenza and RSV accounted for 7% of cardiopulmonary hospitalizations and 9% of total deaths in high-risk residents during the 4 study years. Absolute morbidity and mortality were lower in residents without identified comorbid conditions but accounted for 15% of hospitalizations and 14% of deaths. These estimates depend on the assumption that morbidity and mortality from other respiratory viruses were distributed evenly between the three defined seasons. CONCLUSION: Influenza and RSV substantially increased hospitalization rates, antibiotic use, and deaths in elderly nursing home residents each winter. These data should encourage persistent efforts toward disease prevention, and thoughtful study of vaccine development and delivery, diagnostic tools, and methods of prophylaxis and therapy.

Aged↗
PubMed1996

Primary cytotoxic T-cell responses to bovine respiratory syncytial virus in calves.

Bovine respiratory syncytial virus (RSV) is a major cause of respiratory disease in young calves. Recent studies in calves, in which different T-cell subsets were depleted, have shown that CD8+ T cells play a central role in recovery from RSV infection. The present study demonstrates that RSV-specific, major histocompatibility complex-restricted cytotoxic T cells appear in the peripheral blood of gnotobiotic calves 7-10 days after infection with bovine RSV and were also detected in the lungs 10 days after infection. The cytotoxic T lymphocytes (CTL) recognized antigenically distinct strains of bovine RSV. There was no correlation between either the level of CTL activity in the lung or the development of CTL in the peripheral blood and the extent of pneumonic consolidation. The demonstration of CD8+ CTL in the lungs at a time when bovine RSV has been cleared confirms the importance of these cells in recovery from infection.

Animals↗
PubMed1996

Definition of cotton rat immunoglobulins: sigmodon species differ in expression of IgG isotypes and production of respiratory syncytial virus antibody.

The cotton rat (Sigmodon species) is the preferred animal model for experiments with a number of human pathogens, especially the respiratory viruses. The cotton rat is classified in the family Cricetidae (with hamsters and gerbils) and is a distant cousin of the common laboratory rat (Rattus) classified in the family Muridae (with the common laboratory mouse, Mus). Antibody reagents that are specific for cotton rat immunoglobulins have not been described. To enhance the usefulness of this model, four immunoglobulins in Sigmodon serum were characterized (IgG1, IgG2, IgA, IgM) and antisera specific for each immunoglobulin were made. Sera from three different species of Sigmodon were examined, S. hispidus (SH), S. arizoni (SA) and S. fulviventer (SF). Although IgA and IgM appeared similar in all three species, the IgG were expressed differently because normal serum levels of IgG2 were deficient in SH when compared with SA and SF and to other rodents. Similarly, IgG2 antibody response to purified protein antigen was deficient in SH although the IgG1 antibody response was superior to that in SF and SA. The three cotton rat species were infected with respiratory syncytial virus, and the kinetics of the antibody response was measured. Neutralizing antibody developed faster and to a higher titre in SH than in SA and SF. The enhanced immunoresponsiveness in SH may compensate for the IgG2 deficiency in SH and these changes appear to be relatively recent events in the evolution of this most populous species of Sigmodon.

Animals↗
PubMed1999

Phenotypic analysis of local cellular responses in calves infected with bovine respiratory syncytial virus.

Changes in lymphocyte subsets in the trachea, pulmonary tissue, bronchoalveolar lavage (BAL), peripheral blood and bronchial lymph node (BLN) of gnotobiotic calves infected with bovine respiratory syncytial virus (BRSV) were analysed by flow cytometry. Following BRSV infection, virus titres in the nasopharynx reached a peak between days 5 and 7 and infection was resolving from day 10. Although calves did not develop signs of clinical respiratory disease, there was evidence of gross pneumonia and histological changes typical of BRSV bronchiolitis, which were most extensive from day 710 of infection. Following BRSV infection there was a recruitment of CD8+ T cells into the trachea and lung, which peaked on day 10 after infection. Thus, there were approximately equal numbers of CD8+ and CD4+ T cells in the lung and trachea of uninfected calves, whereas by day 10 of infection, CD8+ cells outnumbered CD4+ cells by 3:1 in the lungs and 6:1 in the trachea of the infected calves. Although the increase in CD4+ T cells into the lungs was less marked than that of CD8+ T cells, changes in expression of CD45R, CD45RO, L-selectin and interleukin-2 receptors all suggested that CD4+ T cells were activated during BRSV infection. Changes in gamma delta T cells were not observed in BRSV-infected calves. There was a marked increase in B cells in the BLN after infection and BLN CD4+ T cells changed from the majority expressing L-selectin and CD45R in uninfected calves to a predominance of L-selectin- CD45R- CD45RO+ phenotype, 10 days after infection. In conclusion, CD8+ T cells constitute the major lymphocyte subpopulation in the respiratory tract of calves recovering from BRSV infection.

Animals↗
PubMed2001

Suppressive effect of locally produced interleukin-10 on respiratory syncytial virus infection.

Interleukin (IL)-10 is known to be a multifunctional cytokine. This study was designed to evaluate the role of IL-10 during respiratory syncytial virus (RSV) infection using a C57BL/6 transgenic (TG) mouse model in which the expression of murine IL-10 cDNA was regulated by a human salivary amylase promoter (IL-10 TG mice). These mice expressed a large amount of IL-10 in the nasal mucosa and in salivary glands. Viral replication in the respiratory tract after intranasal infection with RSV was suppressed significantly in IL-10 TG mice compared to non-transgenic controls. This suppression was IL-10 specific, because it was prevented by treating mice with neutralizing anti-IL-10 antibodies. We also found that IL-10-stimulated T cells displayed cytotoxic activity against infected murine nasal epithelial cells. Previous data indicated that IL-10 induces Fas ligand (L) expression on mouse T cells. Taken together, these data suggest that Fas/Fas L mediated cytotoxicity is involved in the suppression of RSV replication observed in IL-10 TG mice after intranasal infection.

Animals↗
PubMed2003

Respiratory syncytial virus decreases the capacity of myeloid dendritic cells to induce interferon-gamma in naïve T cells.

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants under 6 months of age. Since an RSV infection does not necessarily prevent a reinfection, we asked whether RSV might subvert an effective immune response by interfering with the function of dendritic cells (DCs). Immature DCs cultured from cord blood stem cells and infected with RSV reduced the rate of interferon-gamma (IFN-gamma) production in co-cultured autologous naïve T cells stimulated with the superantigen TSST-1. Maturation of DCs in response to poly(IC) but not to CD40 ligand did overcome the inhibitory effect of RSV. Further experiments demonstrated that induction of apoptosis, a selective increase in CD86 expression and lack of release of pro-inflammatory cytokines were associated with inhibition of IFN-gamma generation. In addition, RSV replication seemed to be essential for modulation of IFN-gamma production because a virus preparation inactivated by UV irradiation had no effect. Hence, one reason for multiple reinfections by RSV might be the subversion of antiviral immune responses by interference of RSV with DC function.

Antigens, CD↗
PubMed2002

Severe respiratory syncytial virus infection in early life is associated with increased type 2 cytokine production in Gambian children.

BACKGROUND: Severe respiratory syncytial virus (RSV) infection in early childhood has been associated with subsequent wheezing and atopy. The aim of this study was to test if severe RSV infection in early life was associated with an increase in type 2 cytokine production and atopy in Gambian children 5 years later. METHODS: A cohort of children with severe RSV infection during the first year of life ('cases', n = 66) and without ('controls', n = 122) was followed-up at 5 years of age. Immediate hypersensitivity to common allergens, airway reactivity, serum IgE concentration and the production of IFN-gamma, IL-5 and IL-13 by lymphocytes activated in vitro with RSV F-G or control antigens was determined. RESULTS: After adjustment for confounders, cases produced significantly higher concentrations of IL-13 in response to RSV F-G and of IL-5 and IL-13 in response to tuberculin. Cases were more likely to have presented with a wheezy lower respiratory tract infection in the first 3 years of life (adjusted odds ratio = 9.9; 95% CI 1.6-61.0), but not thereafter. Cases and controls had similar skin response to allergens, airway reactivity and serum IgE concentrations. CONCLUSION: Severe RSV infection in early life is associated with a higher production of type 2 cytokines in Gambian children at 5 years of age. However this does not appear to result in increased risk of atopy or clinical allergy at that age.

Bronchial Hyperreactivity↗
PubMed2000

High mortality rate associated with bovine respiratory syncytial virus (BRSV) infection in Belgian white blue calves previously vaccinated with an inactivated BRSV vaccine.

In a group of 60 Belgian White Blue calves less than 8 months old still housed in barns, a bovine respiratory syncytial virus (BRSV) outbreak was revealed on the basis of a direct diagnosis (immunofluorescence and virus isolation) performed on the lungs of dead animals, and the kinetics of BRSV neutralizing antibodies. Clinical signs, macroscopical and microscopical pulmonary lesions were also compatible with a BRSV infection. This outbreak is peculiar because the 35 oldest calves (204 +/- 29 days old) had been vaccinated 3-4 months before with an inactivated BRSV vaccine and 30% of these animals had died of respiratory distress. While they experienced a mild respiratory symptomatology, no death was recorded among the 25 youngest calves (69 +/- 29 days old) which had been left unvaccinated. Another peculiarity was found at the histological level where a massive infiltration of eosinophils was demonstrated in the pulmonary tissues of the dead animals. Together these data parallel the dramatic story described 30 years ago in children previously vaccinated with a formalin-inactivated human RSV (HRSV) vaccine upon a natural HRSV challenge. This illustrates that an immunopathological phenomenon also takes place after BRSV vaccination in cattle.

Animals↗