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PubMed2004

Extensive mast cell degranulation in bovine respiratory syncytial virus-associated paroxystic respiratory distress syndrome.

Bovine respiratory syncytial virus (BRSV) infection is an important cause of outbreaks of respiratory disease among calves. This virus commonly induces mild to severe respiratory signs but, in a substantial proportion of cases, is also reported to be associated with paroxystic respiratory distress syndrome (PRDS). The pathogenesis of this 'malignant' clinical form has not been fully elucidated. The present study aimed at determining whether mast cell (MC) degranulation plays a role in the physiopathologic cascade leading to the PRDS. Paired serum samples were taken in herds during outbreaks of severe respiratory diseases (acute sera) and 3 weeks after (convalescent sera). Based on seroconversion to BRSV and clinical picture, 67 pairs of sera were selected from calves with a BRSV-associated PRDS for circulating MC tryptase determination. A MC metachromatic score was measured in post-mortem lungs from animals died from a BRSV-associated PRDS (principals) and compared with reference scores obtained from healthy lungs (controls). Levels of tryptase were significantly higher in acute sera (26.6 +/- 12.4 microg/l) compared to convalescent sera (8.4 +/- 7.8 microg/l; P<0.001). Metachromatic scores yielded significantly different results between controls and principals (P<0.01), demonstrating a significant disappearance of metachromatic granules from lung MCs in principals. Taken together, these data demonstrate the presence of an extensive MC degranulation in BRSV-associated PRDS.

Animals↗
PubMed2005

Immune mechanisms of pathogenetic synergy in concurrent bovine pulmonary infection with Haemophilus somnus and bovine respiratory syncytial virus.

Bovine respiratory syncytial virus (BRSV) and Haemophilus somnus are two bovine respiratory pathogens that cause disease singly or as part of a polymicrobial infection. BRSV infection is often associated with a predisposition towards production of a T helper type 2 (Th2) response and IgE production. In contrast, an IgG2 response to H. somnus has been shown to be most important for recovery. An experiment was performed to evaluate the hypothesis that infection with H. somnus on day 6 of experimental BRSV infection would result in disease enhancement and potentially an altered immune response when compared with single infection. Three groups of calves were either dually infected or singly infected with H. somnus or BRSV. Serum and bronchoalveolar lavage fluid (BALF) pathogen specific IgG1, IgG2, IgE, and IgA responses were evaluated by ELISA. TaqMan RT-PCR was used to examine cytokine gene expression by PBMC and BAL cells. Clinical signs were evaluated for 28 days after BRSV infection, followed by necropsy and histological examination of the lungs. In dually infected calves, disease was significantly more severe, H. somnus was isolated from the lungs at necropsy, and high IgE and IgG responses were detected to H. somnus antigens. Cytokine profiles on day 27 were elevated in dually infected calves, but did not reflect a skewed profile. These results contrasted with singly infected calves that were essentially normal by day 10 of infection and lacked both lung pathology and the presence of H. somnus in the lung at necropsy. The increase in IgE antibodies specific for antigens of H. somnus presents a possible mechanism for pathogenesis of the disease enhancement.

Animals↗
PubMed2004

Detection of Brazilian bovine respiratory syncytial virus strain by a reverse transcriptase-nested-polymerase chain reaction in experimentally infected calves.

A reverse transcriptase (RT)-nested-polymerase chain reaction (PCR) was standardised to detect bovine respiratory syncytial virus (BRSV), using a Brazilian isolate, in three experimentally infected calves. This followed initial tests in infected chicken embryo related (CER) cells. One animal had lesions, characterized by interstitial multifocal pneumonia, severe interstitial and subpleural emphysema, and lung consolidated areas. Lung and tracheal tissues collected 6 days after infection were analysed by RT-nested-PCR. Primers, specific for the BRSV G and F glycoproteins genes, yielded amplification fragments of 371 and 481 bp, respectively, from the RNA of the cell-propagated virus. Using RNA extracted from organs of infected calves, RT-nested-PCR amplified the fragment of the G gene in all tracheal samples, but in only two of three lung samples analysed. These results suggest that RT-nested-PCR could be a promising assay for diagnosis and epidemiological analysis of BRSV in Brazil.

Animals↗
PubMed2006

Effects of experimental inoculation of bovine respiratory syncytial virus in different inbred mice lineages: establishment of a murine model for BRSV infection.

Bovine respiratory syncytial virus (BRSV), a member of the subfamily Pneumovirinae, family Paramyxoviridae, is a major cause of respiratory disorders in young cattle. A number of studies were conducted to validate a reliable animal model for the infection, since BRSV inoculation on the natural host is costly and often unsuccessful. Unfortunately, after inoculation of BRSV in Balb/C mice, viral replication may be detected; however, evident pathological alterations are absent on the experimentally infected animals. In order to establish a mice model that could be used further for preliminary studies of pathological and immunological aspects of BRSV infection, three mice inbred lineages (Balb/C, A/J and C57BL6), possessing different genetic backgrounds, were tested about its susceptibility to the inoculation with BRSV. Animals were inoculated through the nasal and ocular routes and were observed after inoculation. At 7 days post-inoculation (dpi) animals were necropsied and virological (virus isolation and viral nucleic acid amplification) as well as histopathological examinations were performed. A/J and C57BL6 showed interstitial pneumonia, when compared to the Balb/C group. These findings shows that mice may constitute a suitable model for the study of BRSV infections, depending on the mice strain used for experimental inoculations.

Animals↗
PubMed2004

Respiratory syncytial virus escape mutant derived in vitro resists palivizumab prophylaxis in cotton rats.

Palivizumab (PZ) is the only monoclonal antibody in human use against an infectious disease. PZ is a humanized monoclonal antibody that recognizes the fusion protein of respiratory syncytial virus (RSV). PZ prophylaxis reduces the likelihood of hospitalization for young children at risk for severe RSV infections. The quasispecies nature of RNA viruses allows rapid emergence of viruses with a selective advantage. A PZ resistant virus was selected by passage of RSV in the presence of PZ in cell culture. The cell culture-derived virus was completely resistant to PZ prophylaxis in cotton rats. The increasing use of PZ, and in particular, the use of PZ in immunosuppressed patients, provide opportunities for resistant viruses to emerge. Whether such viruses will appear and be of clinical significance for humans is unknown. Preclinical studies in cotton rats predicted the efficacy of PZ in humans; these results suggest that if PZ resistant viruses arise in humans, PZ prophylaxis may be ineffective.

Animals↗
PubMed2005

Antigen-dependent proliferation and cytokine induction in respiratory syncytial virus-infected cotton rats reflect the presence of effector-memory T cells.

Respiratory syncytial virus (RSV) is a major cause of lower airway disease in infants and children. Immunity to RSV is not long lasting, resulting in re-occurring infections throughout life. Effective long-lived immunity results when central-memory T cells that proliferate vigorously and secrete IL-2 are present. In contrast, effector-memory T cells that mainly produce IFN-gamma, facilitate virus clearance but are not long lived. To identify the type of memory response induced after RSV-A (Long) infection, we characterized the kinetics of the antigen-specific immune response and identified the types of cytokines induced. RSV-specific lymphocytic proliferation following primary and secondary infection was similar, and in both cases responses waned within a short period of time. In addition, mRNA for IFN-gamma but not IL-2 was induced in RSV-specific CD4(+) T cells. This supports the idea that the presence of effector-memory rather than central-memory T cells contributes to the ineffectiveness of the immune response to RSV.

Animals↗
PubMed2005

Identification of an H-2D(b)-restricted CD8+ cytotoxic T lymphocyte epitope in the matrix protein of respiratory syncytial virus.

Cytotoxic T lymphocytes (CTL) play a significant role in the clearance of respiratory syncytial virus (RSV) infection in humans and mice. Identification of class I MHC-restricted CTL epitopes is critical in elucidating mechanisms of CTL responses against viral infections. However, only four H-2d-restricted epitopes have been reported in mice. Because of the diversity of transgenic and knockout mice available to study immune responses, new epitopes in additional strains of mice must be identified. We therefore attempted to discover novel CTL epitopes in C57Bl/6 mice. Our efforts revealed a new H-2D(b)-restricted CTL epitope from the RSV M protein, corresponding to aa 187-195 (NAITNAKII). Also, M187-195-specific CTLs were activated with kinetics similar to the immunodominant BALB/c epitope, M2 82-90. This is the first RSV-specific CTL epitope described in a strain of mice other than BALB/c. Furthermore, identification of this H-2b-restricted CTL epitope provides access to genetically modified H-2b mice for more detailed studies of CTL mechanisms in RSV infection.

Amino Acid Sequence↗
PubMed2006

Characterization of the CD8+ T cell responses directed against respiratory syncytial virus during primary and secondary infection in C57BL/6 mice.

The BALB/c mouse model for human respiratory syncytial virus infection has contributed significantly to our understanding of the relative role for CD4+ and CD8+ T cells to immune protection and pathogenic immune responses. To enable comparison of RSV-specific T cell responses in different mouse strains and allow dissection of immune mechanisms by using transgenic and knockout mice that are mostly available on a C57BL/6 background, we characterized the specificity, level and functional capabilities of CD8+ T cells during primary and secondary responses in lung parenchyma, airways and spleens of C57BL/6 mice. During the primary response, epitopes were recognized originating from the matrix, fusion, nucleo- and attachment proteins, whereas the secondary response focused predominantly on the matrix epitope. C57BL/6 mice are less permissive for hRSV infection than BALB/c mice, yet we found CD8+ T cell responses in the lungs and bronchoalveolar lavage, comparable to the responses described for BALB/c mice.

Amino Acid Sequence↗
PubMed2004

Cytokine pattern is solely influenced by priming vaccine but immunity and disease by both priming and boosting vaccines in mice challenged with respiratory syncytial virus.

Vaccine formulation can influence cytokine and disease patterns in mice following respiratory syncytial virus (RSV) challenge. The influence of different live and killed dual-vaccine combinations on subsequent immune responses was investigated. BALB/c mice received either killed followed by killed (KV/KV), killed followed by live (KV/LV), live followed by killed (LV/KV), or live followed by live (LV/LV) RSV vaccines intramuscularly. Mouse weight loss, viral replication, cytokine expression patterns, immunoglobulin isotype antibody profiles, neutralizing antibody responses, and cytotoxicity T lymphocyte (CTL) activities in lungs were compared on subsequent live RSV challenge. On challenge, mice vaccinated initially with KV and boosted with either KV or LV expressed significantly skewed ratios of IL-4 to IFN-gamma mRNA and IgG1 to IgG2a antibody, when compared to those vaccinated initially with LV. Low levels of RSV replication were detected in lungs of mice vaccinated with KV/KV, KV/LV, and LV/KV, but not in mice vaccinated with LV/LV. Mice vaccinated with KV/LV, LV/KV, or LV/LV had RSV-specific CTL activity in lungs six days after RSV challenge, while no CTL activity was detected in KV/KV-vaccinated mice. Mice vaccinated with KV/KV had the greatest weight loss, while LV/LV-vaccinated mice resulted in the least. Mice vaccinated with either KV/LV or LV/KV had intermediate weight loss after challenge. These data indicate that an original antigenic sin-like phenomenon was exhibited in cytokine and immunoglobulin isotype responses in mice after challenge. T helper (Th)-like immune responses were determined solely by the initial vaccination, while weight loss, viral replication, neutralizing antibody responses, and CTL activities were also influenced by boosted vaccinations.

Animals↗
PubMed2004

Molecular epidemiology of respiratory syncytial virus (RSV) of group A in Stockholm, Sweden, between 1965 and 2003.

The epidemiology of respiratory syncytial virus (RSV) group A was followed by nucleotide sequencing of the variable parts of the glycoprotein (G) gene. The amino acid sequences of an aminoterminal (A-terminal, amino acids 90-132) and carboxyterminal (C-terminal, amino acids 262-298) portion of the G protein in 47 virus strains, collected in Stockholm, between 1965 and 2004, were determined. In phylogenetic analysis jointly with previously described genotypes (GA1 to GA7 and SAA1), 33 virus strains (isolated between 1991 and 2004) belonged to genotype GA5, seven to GA2, three to genotype GA1 (isolated before 1991), one to genotype GA4 (isolated in 1982) and three to genotype GA7 (isolated in 1993 and 2001). Genotype GA5 was predominant in four epidemics, between 2000/2001 and 2003/2004. Little or no variation with time of the C-terminal amino acid sequence of the G protein was found when the virus strains were compared within their own genotype. Identical and nearly identical nucleotide sequences were found between strains isolated more than 10 (GA5) and 25 (GA2) years apart. The A-terminal part of they G protein of genotype GA2 was highly conserved. In contrast, the A-terminal part of the G protein of genotype GA5 exhibited a pronounced variation in its amino acid sequence over time.

Amino Acid Sequence↗
PubMed2005

Genetic stability determinants of temperature sensitive, live attenuated respiratory syncytial virus vaccine candidates.

An intranasally delivered, live attenuated, temperature sensitive (ts) respiratory syncytial virus vaccine candidate, rA2cp248/404/1,030DeltaSH, exhibits a low level of genetic instability in clinical studies, in contrast to the relatively high stability of two similar candidates, cpts248/404 and rA2cp248/404DeltaSH. The latter strains, containing two ts mutations (248ts and 404ts), are partially growth restricted at 37 degrees C, whereas, rA2cp248/404/1,030DeltaSH contains an additional ts mutation (1,030ts) that increases attenuation and partially restricts virus growth at 35 degrees C. Since the maximum human airway temperature is 35.5 degrees C, we investigated whether growth restriction at 35 degrees C contributes to genetic instability of rA2cp248/404/1,030DeltaSH in vitro. We conducted in vitro passage studies with the three strains at 32 degrees C (a fully permissive growth temperature) and 35 degrees C (restrictive for only rA2cp248/404/1,030DeltaSH). Instability of the ts phenotype was observed only in rA2cp248/404/1,030DeltaSH passaged at 35 degrees C, and corresponded with reversion at the 248ts or 1,030ts mutation sites, as observed in clinical studies. This study indicates that ts mutations that partially restrict replication at physiologic temperatures may contribute to genetic instability of viruses in vivo. In vitro passage studies performed at appropriate temperatures can be used to assess genetic stability and to prioritize ts vaccine candidates for clinical evaluation.

Administration, Intranasal↗
PubMed2006

Phylogenetic relationships of Brazilian bovine respiratory syncytial virus isolates and molecular homology modeling of attachment glycoprotein.

Bovine respiratory syncytial virus (BRSV) causes lower respiratory tract disease in young cattle. Recently, it was possible to determine the sequence of the G protein gene, which plays a role in the attachment of BRSV particles to the cells, from three distinct Brazilian isolates. The phylogenetic analysis conducted here using those sequences compared to other worldwide distributed isolates of BRSV allow us to allocate Brazilian strains within the subgroup B, which was no longer found in the world since the 1970s. One of the Brazilian strains has a major mutation between amino acid residues 173 and 178, within the central hydrophobic conserved region, exactly on the site of two of the four cysteine-noose forming cysteine residues. Homology modeling with the previously determined NMR structure of this protein domain was made to check whether these mutations altered the three-dimensional conformation of this immunodominant region. Possible consequences on the biological effects induced by such mutation on the G protein are discussed.

Amino Acid Sequence↗
PubMed1998

In-vitro studies on mechanisms of immunosuppression associated with bovine respiratory syncytial virus.

Bovine respiratory syncytial virus (BRSV) depressed the proliferative reactivity of normal ovine peripheral blood lymphocytes to phytohaemagglutinin (PHA). This BRSV-induced reduction in proliferative reactivity was not reversed or ameliorated by the addition of (1) indomethacin or flunixin meglumine, substances known to inhibit the production of prostaglandins, or (2) the cytokines, interleukin-1 (IL-1) and interleukin-2 (IL-2), or (3) rat growth factor. The results suggest that the suppression of ovine lymphocyte reactivity to PHA associated with BRSV was not caused by the release of cyclooxygenase products such as prostaglandins, or the production of inhibitors of IL-1 or IL-2.

Animals↗
PubMed1994

High-dose, short-duration ribavirin aerosol therapy compared with standard ribavirin therapy in children with suspected respiratory syncytial virus infection.

Children with suspected respiratory syncytial virus infection were examined prospectively in a randomized evaluation of standard ribavirin aerosol therapy (6 gm/300 ml water for 18 hours daily) compared with high-dose, short-duration ribavirin aerosol therapy (6 gm/100 ml water given for a period of 2 hours three times a day) by means of an oxygen hood (n = 20) or a ventilator (n = 12). Viral shedding was quantitated daily; clinical observations were recorded daily by 2 physicians aware and one unaware of treatment assignments. Study characteristics evaluated at entry were not significantly different in the high-dose and the standard-dose groups. Viral titers and clinical scores decreased similarly in both groups during the study; pulmonary function test results were also similar at discharge in children not receiving mechanical ventilation. Potential complications related to aerosol therapy were noted in three patients (one hood patient who was receiving standard therapy; two patients with an endotracheal tube in place who were receiving high-dose therapy); substantial crystallization was noted in the tubing of the patients undergoing intubation and receiving high-dose therapy. Environmental sampling revealed that ribavirin was nearly undetectable near patients supported by mechanical ventilation who were receiving either form of therapy, and was significantly decreased on a daily basis in patients without an endotracheal tube who were receiving high-dose therapy compared with those receiving standard therapy. The effects of high-dose, short-duration aerosol ribavirin therapy were similar to those of standard-dose therapy in our study patients and resulted in a decreased release of ribavirin into the room of patients receiving therapy by means of an oxygen hood.

Aerosols↗
PubMed1994

Complex atrial tachycardias and respiratory syncytial virus infections in infants.

Respiratory syncytial virus (RSV), a common cause of respiratory infections in children, has only rarely been associated with acquired heart disease. We reviewed hospital charts, rhythm strips, and electrocardiograms of 8 infants with abnormal supraventricular tachycardia (SVT), > 250 beats/min, associated with acute RSV infections. Cultures of nasopharyngeal specimens from six of eight infants grew RSV. Two infants with negative viral culture results had symptoms typical of an RSV infection during a documented RSV epidemic. Two infants had congenital heart defects. Seven of the eight infants had an ectopic atrial tachycardia, chaotic atrial tachycardia, or atrial flutter, and five of eight had episodes of nonsustained wide-complex SVT. One patient was initially treated with intravenously administered lidocaine for an incorrect diagnosis of ventricular tachycardia. SVT was unrelated to either beta-agonist therapy or hypoxic episodes. SVT did not recur after discharge in any infant with a structurally normal heart. Both patients with structural heart disease had recurrences of SVT. We conclude that RSV infections in infants may be associated with unusual atrial tachycardias and that the diagnosis may be complicated by episodes of nonsustained, wide-complex tachycardias. In patients with RSV and structurally normal hearts, chaotic and ectopic atrial tachycardias are self-limited and do not require prolonged drug therapy.

Atrial Flutter↗
PubMed1994

Treatment and prevention options for respiratory syncytial virus infections.

Although the therapeutic antiviral agents ribavirin and amantadine ameliorate illness caused by influenza A and respiratory syncytial virus (RSV) in children, these agents are used infrequently because they are not cost-effective. Research currently is directed toward defining the high-risk groups for which these antiviral drugs should be used. Treatment of severe respiratory infection with specific immune globulin, either alone or in combination with antiviral drugs, is another therapeutic approach. Prevention of viral respiratory diseases is preferable because some lung damage occurs before the beginning of treatment, and damage resulting from the immune response may continue even after the virus is inhibited. As natural history and animal studies suggest, passive immunization can be achieved for neonates through active immunization of the mother during pregnancy. However, this approach is limited by the half-life of the transferred antibodies and the lack of antibody in premature infants. Standard immune globulin does not contain sufficient RSV neutralizing antibody titer to fully protect against severe RSV illness. Passive immunization with RSV immune globulin in infants and children has been shown to prevent or attenuate RSV in high-risk groups. Active immunization against some respiratory viruses has been achieved by administration of inactive virus (or their subunits), recombinant viral antigens, and live attenuated virus. Large trials are under way to determine the safety and immunogenicity of these vaccines for children in whom young age and serious underlying illness are significant barriers to primary immune response. The current research environment is suitable for the development of an immunization strategy to prevent many of the significant respiratory infections in children.

Child↗
PubMed1994

Role of antibody and use of respiratory syncytial virus (RSV) immune globulin to prevent severe RSV disease in high-risk children.

Infants with cardiac disease or infants born prematurely with or without bronchopulmonary dysplasia are at increased risk of severe respiratory syncytial virus (RSV) disease. A recently developed RSV immune globulin (RSVIG) was studied in a 3-year multicenter trial to determine safety and efficacy in the prevention of severe RSV disease in children who are at high risk of severe RSV illness. Two hundred forty-nine children were studied; 102 had bronchopulmonary dysplasia, 87 had congenital heart disease, and 60 were born prematurely. RSVIG was given on a monthly basis to 81 children at a high dose of 750 mg/kg (15 ml/kg) and to 79 children at a low dose of 150 mg/kg (3 ml/kg). The 89 children in the control group did not receive RSVIG. There were 64 episodes of RSV infection: 19 in the high-dose group, 16 in the low-dose group, and 29 in the control group. High-dose recipients had significantly fewer RSV lower respiratory tract infections, hospitalizations, hospital days, intensive care unit days, and less use of ribavirin compared with control subjects. Only 19 adverse events were reported during the 580 infusions administered (3%). No death was attributed to RSV disease or RSVIG therapy. Treated children did not acquire exaggerated RSV illness in a subsequent year. Thus high-dose RSVIG reduced the incidence and severity of RSV lower respiratory tract infection. It is a safe and effective means of RSV prophylaxis in selected high-risk children.

Animals↗
PubMed1996

Respiratory syncytial virus-enriched globulin for the prevention of acute otitis media in high risk children.

Acute otitis media (AOM) has been associated with respiratory syncytial virus (RSV) infection; AOM develops in up to one third of children with RSV illness. A masked multicenter trial used an immune globulin enriched with RSV-neutralizing antibodies (RSVIG) to prevent RSV infection of the lower respiratory tract in 249 children with either bronchopulmonary dysplasia, congenital heart disease, or prematurity. To determine whether monthly RSVIG therapy might decrease the incidence of AOM, we retrospectively analyzed the records of 109 children in two of the centers. RSVIG was administered during RSV season of a high dose of 750 mg/kg monthly or a low dose of 150 mg/kg monthly; control children received no RSVIG. Children were examined for AOM by masked observers using pneumatic otoscopy. No difference in sex, race, underlying diagnosis, number of persons in the home, exposure to smoking, or atopy was found between groups studied. In recipients of high doses of RSVIG, significantly less AOM developed per season than in control children (mean episodes, 0.15 vs 0.78; p = 0.003), and fewer episodes of RSV-related AOM occurred (0 vs 5; p = 0.047). Low doses of RSVIG did not have a clinically significant impact. High doses of RSVIG appeared to have a significant impact on preventing AOM (both RSV- and non-RSV-related AOM) in these-high risk populations. This finding may have important implications in the development of improved preventive modalities for AOM.

Acute Disease↗