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PubMed1996

Inhibitory effect of pulmonary surfactant on Sendai virus infection in rat lungs.

Intranasal infection of rats with active (infectious) Sendai virus enhances secretion of tryptase Clara, a Sendai virus-activating protease, into the bronchial lumen by Clara cells of the bronchial epitheliums, and inversely suppresses secretion of pulmonary surfactant, an inhibitor of the protease, into the lumen [Kido H et al. (1993) FEBS Lett 322: 115-119]. A trypsin-resistant mutant, TR-2, showed similar effects, although its replication was restricted to a single cycle in the lungs. In contrast, neither nonactive (noninfectious) wild-type virus possessing receptor-binding activity and lacking envelope fusion activity nor UV-inactivated virus retaining receptor binding and envelope fusion activities altered the mode of secretions. These results indicate that viral replication is required for producing a condition in the bronchial lumen for proteolytic activation of progeny virus, thereby infection is extended to a fatal pneumonia. On the other hand, intranasal administration of infected rats with pulmonary surfactant suppressed activation of progeny virus and pathological changes in the lungs, suggesting a therapeutic use of pulmonary surfactant for influenza pneumonia.

Animals↗
PubMed1996

Positive and negative host factors for Sendai virus transcription and their organ distribution in rat.

In vitro mRNA synthesis by Sendai virus is almost entirely dependent on the addition of cellular proteins (positive host factors), one of which could be tubulin. In this study, we investigated the distribution of host factors in various rat organs. Extracts from the brain, thymus, heart, lung, testis, ovary, and uterus all supported in vitro Sendai virus transcription, among which the highest activity was obtained with the brain extract. On the other hand, little or no activity was detected in the liver, spleen, and kidney extracts. An inverse correlation between the apparent host factor activity to stimulate mRNA synthesis and RNase activity that hydrolyzes Sendai virus mRNAs was found, except in the liver extract. However, when a transcription initiation complex was isolated and subjected to RNA chain elongation reaction, all of the extracts including those from liver, spleen and kidney, were active. Immunoblotting showed that tubulin molecules were integrated in these initiation complexes, supporting the notion that tubulin is involved in the initiation complex formation. We also identified a transcription inhibitory activity without any detectable RNase activity in the liver extract. This negative host factor seemed to act on RNA chain elongation. It is likely that Sendai virus transcription is regulated by both positive and negative regulatory factors.

Animals↗
PubMed1998

Determinants of pantropism of the F1-R mutant of Sendai virus: specific mutations involved are in the F and M genes.

Mutations in the fusion, F, protein of Sendai virus resulting in increased cleavability by ubiquitous host protease(s), and mutations in the matrix, M, protein resulting in bipolar budding, are both important determinants for the systemic infection in mice caused by the protease activating pantropic mutant, F1-R. Several mutants of Sendai virus (BY, BF, and KD-M) with phenotypes of bipolar budding and/or increased cleavability of F protein were isolated. Genomic RNA sequence analysis of the F and M genes of the mutants revealed that several deduced amino acids in the F and M proteins were different from those of F1-R, T-5 (a revertant of F1-R), and wild-type viruses. The BF and KD-M mutants that budded bipolarly and were also activated by ubiquitous proteases were examined for replication in tissue culture cells and in mice. All of the mutants exhibited multiple-step replication in MDCK, MDBK, and LLC-MK2 cells without trypsin, but formed plaques only in MDCK cells. One of the mutants, designated KD-52M, was similar to F1-R in that it formed plaques in all three cell lines without addition of exogenous protease. However, none of the mutants viruses, including KD-52M, caused a systemic infection in mice. The mutated M protein of F1-R enhances the disruption of microtubles. However, none of the mutants with a bipolar budding phenotype (BY, BF, and KD-M), disrupted the microtubules to the same extent as F1-R. All of these mutants had mutations in the M protein that were different from those found in F1-R. Taken together, these results suggest that mutations at Ser115 to Pro in the F protein and at Asp 128 to Gly and Ile210 to Thr in the M protein of F1-R are the mutations specifically required for the systemic infection caused by F1-R.

Amino Acid Sequence↗
PubMed1999

Replication-incompetent Sendai virus can suppress the antiviral action of type I interferon.

Altered baby hamster kidney (BHK-R) cells, which were established by serial passage of BHK cells in the presence of Sendai virus (SeV), allowed vesicular stomatitis virus (VSV) to replicate despite treatment with type I interferon (IFN). We have analyzed here mechanisms of the unresponsiveness to IFN. BHK-R cells cultured in the absence of SeV for 10 days under the conditions of no cell division (BHK-R10D) became sensitive to IFN. Studies on induction of unresponsiveness to IFN in BHK-R10D cells revealed that entry of SeV nucleocapsids into a cell was essential. Interestingly, even UV-inactivated SeV but not Newcastle disease virus was found to be able to confer resistance to IFN on HeLa or BHK cells as well as on BHK-R10D cells, suggesting that the IFN-resistance resulted from functions of SeV independent of replication of the viral genome but not from mutations of the cellular genome. Furthermore immunofluorescent experiments demonstrated that UV-inactivated SeV could rescue VSV replication from the antiviral action of IFN without expression of SeV antigens, confirming that the secondary transcription resulting in synthesis of large amounts of viral proteins was dispensable for the IFN-resistance. Thus we have revealed a unique strategy of SeV against the antiviral action of IFN.

Animals↗
PubMed2001

Attenuation of a field Sendai virus isolate through egg-passages is associated with an impediment of viral genome replication in mouse respiratory cells.

We investigated the mechanisms responsible for attenuation of mouse pathogenicity of Sendai virus (SeV) through passages in eggs. A highly virulent clone, E0, derived from the field SeV Hamamatsu strain, was successively passaged in hen's eggs. Analysis of the mouse lethal dose 50% (MLD50) of virus clones obtained from the viruses at egg-passages 1, 15, 30 and 50 demonstrated that attenuation of E0 by egg-passage occurred due to the gradual appearance of and replacement by virus variants possessing higher MLD50. Comparison of viral replication in the mouse lung and mouse pathogenicity with the representative SeV clones, E0, E15c12, E30c12 and E50c19, obtained from the respective egg-passages revealed that the low pathogenicity of the egg-passaged clones was due to poor multi-cycle viral replication in the lung. Furthermore, MLD50s of the SeV clones were found to be negatively correlated with the replication capability in primary mouse pulmonary epithelial (MPE) cells; the egg-passaged clones with more attenuated phenotypes showed lower replication capability in MPE cells. In the MPE cells infected with the SeV clones at m.o.i. 10, however, viral protein and mRNA syntheses of the egg-passaged clones were enhanced or comparable to those of the parental E0 clone at 1 day and 2 days post infection (p.i.) but decreased more rapidly thereafter. In contrast, viral genome synthesis of the egg-passaged clones in the cells at 2 days p.i. was several times lower than that of E0. These results strongly suggest that attenuation of a virulent field SeV strain by egg-passage occurs due to the appearance and selection of virus variants possessing poor propagation capacity in mouse respiratory epithelial cells, which is caused primarily by an impediment of viral genome replication.

Animals↗
PubMedDate not supplied

Toxicity and antiviral activity of LY253963 against respiratory syncytial and parainfluenza type 3 viruses in tissue culture and in cotton rats.

LY253963, the sodium salt of 1,3,4-thiadiazol-2-ylcyanamide, was evaluated in tissue culture and in cotton rats for toxicity and antiviral efficacy against respiratory syncytial (RSV) and parainfluenza type 3 (PIV3) viruses. The selective index (ratio of the median toxic dose: median efficacious dose) of LY253963 in HEp2 tissue culture cells was greater than 100 against both RSV and PIV3. When given intraperitoneally to cotton rats, the minimum protective dose of LY253963 against both of these viruses was between 1 and 3 mg/kg/day. In contrast, doses of LY253963 as high as 30 mg/kg/day, administered orally after experimental inoculation of virus, did not significantly reduce pulmonary virus titers in treated animals compared to control animals given placebo. No toxic effects were noted in cotton rats, even in those given 20 mg/kg/day for eight consecutive days.

Animals↗
PubMed1988

Current approaches to the development of vaccines effective against parainfluenza and respiratory syncytial viruses.

Vaccines against parainfluenza (PIV) and respiratory syncytial viruses (RSV) that are currently being developed include both live and subunit vaccines. Candidate live PIV vaccines that have been found to be attenuated and efficacious in rodents or primate models are (1) cold-adapted, temperature-sensitive mutants of PIV-type 3 that have been serially passaged at low temperature (20 degrees C) in simian kidney tissue culture; (2) protease-activation mutants (PIV-1-Sendai), which have mutations that decrease the cleavability of their F glycoprotein by host cell protease; (3) an animal virus, bovine PIV-3 virus, which is antigenically related to the human PIV-3 virus, and (4) vaccinia recombinant viruses bearing RSV or PIV-3 glycoproteins. Subunit RSV and PIV-3 viruses are being produced and evaluated as immunogens. A major concern with these vaccines is the possibility of disease potentiation following virus infection as occurred previously with formalin-inactivated measles and RSV vaccines. Studies indicate that PIV-3 and RSV glycoprotein vaccines are immunogenic and efficacious in animals but insufficient data exist to estimate their capacity to potentiate disease. However, since a cotton rat model is available to detect potentiated disease resulting from infection of cotton rats previously immunized with formalin-inactivated RSV vaccine, it is now possible to systematically evaluate new vaccines in experimental animals for disease potentiation before studies are initiated in humans. It is likely within the next several years that one or more of these PIV or RSV vaccines will be tested in humans for safety and immunogenicity.

Animals↗
PubMed1996

Effect of MDP-Lys(L18) as a mucosal immunoadjuvant on protection of mucosal infections by Sendai virus and rotavirus.

To examine the effect of MDP-Lys(L18), a derivative of muramyl dipeptide (MDP), as a mucosal immunoadjuvant, we investigated its activity to augment host resistance against mucosal infections by Sendai virus and rotavirus in mice. In an experimental infection model using suckling mice (10-day-old) inoculated perorally (p.o.) with 1.5 x 10(6) p.f.u. mouse-1 of rotavirus strain SA11, intrarectal (i.r.) as well as p.o. administration of MDP-Lys(L18) (50 micrograms mouse-1) prior to virus infection markedly reduced rotavirus-induced diarrhea. Furthermore, when MDP-Lys(L18) was administered p.o. (1 mg mouse-1), i.r. (300 micrograms mouse-1) or intranasally (i.n., 100 micrograms mouse-1) various days before Sendai virus infection (2.6 x 10(4) HAD mouse-1), all the mucosal administration of MDP-Lys(L18) significantly protected a lethal infection of Sendai virus, showing a dose-dependent manner. However, the efficacy of MDP-Lys(L18) to induce the prophylactic activity against the viruses somewhat varied according to the administration route and timing. In time course analysis of virus isolation in vivo, the mice administered with MDP-Lys(L18) exhibited a significant reduction of both viruses in the lungs for Sendai virus and in the bowels for rotavirus. These results suggest that MDP-Lys(L18) is a potent mucosal immunoadjuvant to enhance nonspecific host resistance against two mucosal infectious viruses, Sendai virus and rotavirus.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2001

Effects of paramyxoviral infection on airway epithelial cell Foxj1 expression, ciliogenesis, and mucociliary function.

To elucidate molecular mechanisms underlying the association between respiratory viral infection and predisposition to subsequent bacterial infection, we used in vivo and in vitro models and human samples to characterize respiratory virus-induced changes in airway epithelial cell morphology, gene expression, and mucociliary function. Mouse paramyxoviral bronchitis resulted in airway epithelial cell infection and a distinct pattern of epithelial cell morphology changes and altered expression of the differentiation markers beta-tubulin-IV, Clara cell secretory protein, and Foxj1. Furthermore, changes in gene expression were recapitulated using an in vitro epithelial cell culture system and progressed independent of the host inflammatory response. Restoration of mature airway epithelium occurred in a pattern similar to epithelial cell differentiation and ciliogenesis in embryonic lung development characterized by sequential proliferation of undifferentiated cells, basal body production, Foxj1 expression, and beta-tubulin-IV expression. The effects of virus-induced alterations in morphology and gene expression on epithelial cell function were illustrated by decreased airway mucociliary velocity and impaired bacterial clearance. Similar changes in epithelial cell Foxj1 expression were also observed in human paramyxoviral respiratory infection. Taken together, these model systems of paramyxoviral respiratory infection mimic human pathology and identify epithelial cell Foxj1 expression as an early marker of epithelial cell differentiation, recovery, and function.

Animals↗
PubMed1999

Cytotoxic interactions between bovine parainfluenza type 3 virus and bovine alveolar macrophages.

This paper describes an investigation of the cytotoxic activity of bovine alveolar macrophages for parainfluenza type 3 (PI-3) virus-infected target cells, using 51Cr release assays. Alveolar macrophages from uninfected calves were shown to be capable of killing PI-3 virus infected cells without the presence of antibody or complement (antibody-independent cell-mediated cytotoxicity). The level of killing was shown to vary from animal to animal with specific lysis values ranging from <5% to 70%. Presence of PI-3 virus antiserum was shown to inhibit, rather than enhance macrophage cytotoxicity in a dose-dependent manner, suggesting that bovine alveolar macrophages do not always exhibit antibody-dependent lysis in all cases. Following intranasal and intratracheal inoculation of calves with PI-3 virus, the level of cytotoxicity by macrophages lavaged from the lungs of the calves increased substantially, and by Day 5 post inoculation, levels of 95% to 98% specific lysis were recorded. After Day 5, the killing ability decreased rapidly to low levels. Cell-free lavage fluids, collected from PI-3 virus infected and control calves at various times throughout the experiment, were incubated with aliquots of an alveolar macrophage population from an uninfected donor calf, which initially showed a low level of killing, and were subsequently added to PI-3 virus infected target cells. The recorded levels of cytotoxicity, mirrored those which were seen with the initial macrophage effector cells from the infected and control animals, suggesting that macrophage cytotoxicity was largely controlled by extracellular factors.

Animals↗
PubMed1999

Seroprevalence to bovine virus diarrhoea virus and other viruses of the bovine respiratory complex in Venezuela (Apure State).

Six hundred and fifteen serum samples obtained from cows in five districts of Apure State, Venezuela, were tested by ELISA for antibodies to bovine virus diarrhoea virus (BVDV). The same samples were also ELISA-tested for antibodies to bovine herpesvirus type 1 (BHV-1) and bovine respiratory syncytial virus (BRSV). Additionally, the haemagglutination-inhibition (HI) test was used for detecting antibodies to parainfluenza virus type 3 (PIV-3). Overall, seroprevalence to BVDV was 36+/-7% (SE); seroprevalence varied by district (19-42%). BHV-1 seroprevalence was 67+/-4%; variation by district was similar to that of BVDV. However, the first 80 serum samples tested by BHV-1 ELISA all had a strong background reaction with the control antigen. Therefore, these sera were adsorbed to a homogenate of non-infected bovine kidney cell line (MDBK) and retested by ELISA. The non-specific reactivity was significantly reduced (p<0.001 by Wilcoxon's signed-rank test). Compared to the virus-neutralisation (VN) test, the adsorbed BHV-1 ELISA showed 94% agreement and gave a kappa value of 0.84, indicating that the adsorption did not interfere with test accuracy. Seroprevalence against BRSV was 85+/-3%, and showed differences across districts. Most of the cows (94+/-2%) were seropositive to PIV-3, and there were no significant differences among districts.

Animals↗
PubMed1999

Increased replication of Sendai virus in morphine-treated epithelial cells: evidence for the involvement of the intracellular levels of glutathione.

This paper shows that morphine increases Sendai virus replication in cultured epithelial cells. The effect was maximal when it was added before viral infection. Morphine also reduced the intracellular level of glutathione, namely, the oxidative and most abundant cell thiol. Altered intracellular redox status has recently been proposed as a factor influencing viral infection. Support for this view was provided by our data showing that inhibition of de novo glutathione synthesis, using L-buthionine sulfoximine, increased virus replication. These findings provide the first evidence that morphine increases the susceptibility to virus infection by altering the intracellular levels of glutathione.

Analgesics, Opioid↗
PubMed1997

Protective effect of mucosal administration of recombinant human macrophage colony-stimulating factor (rhM-CSF) on mucosal infection of Sendai virus in mice.

We investigated the protection confered by the mucosal administration of recombinant human macrophage colony-stimulating factor (rhM-CSF) against mucosal infection of Sendai virus in mice. In an experimental infection model using Sendai virus, an intranasal (i.n.) administration of rhM-CSF (20 micrograms per mouse) 2 days before injection induced significant protection against a lethal infection of this virus. Also, its antiviral activity was dependent upon the dose of rhM-CSF. However, a subcutaneous (s.c.) administration of rhM-CSF with an effective dose (20 micrograms per mouse) i.n. did not confer protection. In a time course analysis of virus growth in the lungs, mice given rhM-CSF. i.n. significantly inhibited the early period of infection, compared with the untreated mice. Moreover, the level of interferon-gamma (IFN-gamma) in lung wash fluids from the rhM-CSF-treated mice was higher than that of the untreated mice. These results suggested that the mucosal (i.n.), but not the systemic (s.c.) administration of rhM-CSF augments host resistance against mucosal infection with Sendai virus, and that its prophylactic activity is related to growth inhibition of the virus and enhanced IFN-gamma secretion in the lungs.

Animals↗
PubMedDate not supplied

The bovine parainfluenza virus type-3 (BPIV-3) hemagglutinin/neuraminidase glycoprotein expressed in baculovirus protects calves against experimental BPIV-3 challenge.

Despite the availability of numerous vaccine schedules, "shipping fever", an acute bronchopneumonia brought on in part by a complex of bovine respiratory viruses, remains a major source of economic loss in the beef and dairy industries. We are exploring new strategies of bovine vaccine design which we hope may provide more effective and more cost-efficient control of these pathogens. In this report, we examined the possible use of subunit vaccines, using as an example the hemagglutinin/neuraminidase (HN) protein of bovine parainfluenza virus type-3 (BPIV-3) expressed in the baculovirus expression system. We showed that the protein was expressed at high levels, and was modified to a similar, but not identical size as the native HN protein expressed from BPIV-3 infected bovine cells. We further demonstrated antigenicity and biological activity of the expressed HN protein. Finally, we vaccinated colostrum deprived sera-negative calves with the baculo HN recombinant protein and challenged with BPIV-3. Vaccination induced excellent serum neutralizing antibody responses, and surprisingly, good mucosal antibody responses, even though the vaccine was administered parenterally. The vaccinated animals were well protected against challenge.

Animals↗
PubMed1997

Intranasal Sendai virus vaccine protects African green monkeys from infection with human parainfluenza virus-type one.

Human parainfluenza virus-type I (hPIV-1) infections are a common cause of "group" and hospitalizations among young children. Here we address the possibility of using the xenotropic Sendai virus [a mouse parainfluenza virus (PIV)] as a vaccine for hPIV-1. Sendai virus was administered to six African green monkeys (Cercopithecus aethiops) by the intranasal (i.n.) route. A long lasting virus-specific antibody response was elicited, both in the serum and nasal cavity. Sendai virus caused no apparent clinical symptoms in the primates, but live virus was detected in the nasal cavity for several days after inoculation. No virus was detected after a second dose of Sendai virus was administered on day 126 after the initial priming. Animals were challenged with hPIV-1 i.n. on day 154. All six vaccinated animals were fully protected from infection while six of six control animals were infected with hPIV-1. The antibody responses induced by Sendai virus immunizations proved to be greater than those induced by hPIV-1. These results demonstrate that unmanipulated Sendai virus is an effective vaccine against hPIV-1 in a primate model and may constitute a practical vaccine for human use.

Administration, Intranasal↗
PubMed1999

DNA vaccination as a tool to identify subdominant CD8 T cell epitopes.

DNA vaccination is highly efficient at inducing CD8(+) T cell responses in animal models. Here we investigated whether DNA vaccine technology could be exploited to identify subdominant cytotoxic T lymphocytes (CTL) epitopes. Previous studies have shown that the Sendai virus HN protein does not induce a CD8(+) T cell response in C57BL/6 mice. Thus, we vaccinated C57BL/6 mice with a DNA vaccine encoding Sendai virus hemagglutinin neuraminidase (HN) protein. The data show that this strategy elicited a potent D(b)-restricted CD8(+) CTL response against at least one subdominant HN-derived epitope. These CTL were able to lyse Sendai virus-infected target cells, demonstrating that the epitope was appropriately processed and present at sufficient levels for T cell recognition. However, these cells did not confer protection against lethal challenge with Sendai virus. These data demonstrate the capacity of DNA vaccine to raise CTL responses to subdominant epitopes, but show that such responses may be limited in their efficacy against non-persistent viruses.

Animals↗