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PubMed2000

Mechanism of interference mediated by human parainfluenza virus type 3 infection.

Viral interference is characterized by the resistance of infected cells to infection by a challenge virus. Mechanisms of viral interference have not been characterized for human parainfluenza virus type 3 (HPF3), and the possible role of the neuraminidase (receptor-destroying) enzyme of the hemagglutinin-neuraminidase (HN) glycoprotein has not been assessed. To determine whether continual HN expression results in depletion of the viral receptors and thus prevents entry and cell fusion, we tested whether cells expressing wild-type HPF3 HN are resistant to viral infection. Stable expression of wild-type HN-green fluorescent protein (GFP) on cell membranes in different amounts allowed us to establish a correlation between the level of HN expression, the level of neuraminidase activity, and the level of protection from HPF3 infection. Cells with the highest levels of HN expression and neuraminidase activity on the cell surface were most resistant to infection by HPF3. To determine whether this resistance is attributable to the viral neuraminidase, we used a cloned variant HPF3 HN that has two amino acid alterations in HN leading to the loss of detectable neuraminidase activity. Cells expressing the neuraminidase-deficient variant HN-GFP were not protected from infection, despite expressing HN on their surface at levels even higher than the wild-type cell clones. Our results demonstrate that the HPF3 HN-mediated interference effect can be attributed to the presence of an active neuraminidase enzyme activity and provide the first definitive evidence that the mechanism for attachment interference by a paramyxovirus is attributable to the viral neuraminidase.

Cell Line↗
PubMed1994

Regions on the hemagglutinin-neuraminidase proteins of human parainfluenza virus type-1 and Sendai virus important for membrane fusion.

To study the contributions of the hemagglutinin-neuraminidase (HN) and the fusion (F) glycoproteins in virus-induced membrane fusion, the HN and F proteins of human parainfluenza virus type-1 (hPIV-1) and Sendai virus (SV) were expressed in HeLa T4+ cells using the vaccinia virus-T7 RNA polymerase transient expression system. Expression of F protein alone did not induce cell fusion. However, coexpression of homologous F and HN proteins resulted in extensive syncytium formation by hPIV-1 or SV glycoproteins, which supports the proposal that both the F and HN glycoproteins are necessary for membrane fusion. To investigate the function of HN in membrane fusion, we coexpressed heterologous combinations of the HN and F proteins of hPIV-1 and SV. No fusion was observed when SV HN and hPIV-1 F proteins were coexpressed. In contrast, the coexpression of hPIV-1 HN and SV F induced extensive cell fusion. These results suggest that specific interaction between HN and F is required to induce membrane fusion. To locate regions that are essential to the fusion promoting activity, chimeric HN proteins of SV and hPIV-1 were constructed. The chimeric proteins coexpressed with the SV or hPIV-1 F proteins indicated that some regions in the middle 62% of HN contribute to the fusion-promoting activity. To determine the role of the transmembrane region of HN on fusion-promoting activity, mutant HN proteins were expressed and their biological activities examined. Mutation of hPIV-1 HN at residue 55 from cysteine to tryptophan did not affect cell binding, neuraminidase activities, or homooligomer formation, but did result in the loss of cell fusion activity. The mutation of the same cysteine residue to glycine retained the fusion-promoting activity, suggesting that a sulfhydryl moiety is not specifically required at position 55, but the structure of the residue that occupies the position is important in fusion-promoting activity.

HN Protein↗
PubMed2005

Protection of dogs for 13 months against Bordetella bronchiseptica and canine parainfluenza virus with a modified live vaccine.

Twelve specific pathogen-free (spf) puppies were vaccinated intranasally with a bivalent, modified live vaccine against infectious tracheobronchitis (group 1) and six puppies of the same age and from the same source served as unvaccinated controls (group 2). Both groups were challenged with wild-type Bordetella bronchiseptica and canine parainfluenza virus by the aerosol route 56 weeks after group 1 had been vaccinated, and at the same time six 10-week-old spf puppies from the same source (group 3) were also challenged. Oronasal swabs were taken regularly before and after the challenge, for the isolation of bacteria and viruses, and the dogs were observed for clinical signs for three weeks after the challenge. The control dogs became culture-positive for B bronchiseptica and canine parainfluenza virus, but the isolation yields from the vaccinated group were significantly lower (P<0.05). The mean clinical scores of the vaccinated group were 61 per cent lower than the scores of group 2 (P=0.009), and 90 per cent lower than the scores of group 3 (P=0.001).

Animals↗
PubMed1987

Complete nucleotide sequence of the matrix protein mRNA and three intergenic junctions of human parainfluenza virus type 3.

The complete sequence of the gene encoding the matrix protein (M) of human parainfluenza virus type 3 (PIV-3) was determined from cDNA clones and from primer extension dideoxy sequencing of the viral genome. The M mRNA is 1150 nucleotides in length, exclusive of polyadenylate, and codes for a protein of 353 amino acids, having a calculated molecular weight of 39,480. The M protein of PIV-3 was found to have a high degree of sequence homology with that of a closely related paramyxovirus, Sendai virus, and to a lesser extent it contained sequence homology with two more distant paramyxoviruses, measles virus and canine distemper virus. We also determined the sequences of the intergenic junctions for the first four genes of PIV-3: NP, P, M, and F. Comparison of these sequences yielded a consensus mRNA start sequence of 5'-AGGANNAAAGA-3', an mRNA end sequence of 5'-UAAGAAAAA-3', and an intergenic sequence of 5'-CUU-3'. The end sequence of the M gene is unusual in that it contains an eight base insertion prior to the A5 tract found in the consensus sequence. This disruption appears to cause a high frequency of readthrough by the viral transcriptase at this junction.

Amino Acid Sequence↗
PubMed1990

Molecular cloning and sequence analysis of the fusion glycoprotein gene of human parainfluenza virus type 2.

A cDNA clone containing a 2.0-kb insert was identified as the human parainfluenza virus type 2 (PI2) fusion glycoprotein gene by hybridizing with a viral RNA probe and a synthetic oligonucleotide derived from a conserved sequence found in other paramyxovirus fusion protein genes. The complete nucleotide sequence of the glycoprotein gene was determined by the dideoxynucleotide sequencing procedure and found to contain a single, large open reading frame encoding a protein of 551 amino acids with a calculated molecular weight of 59,664. Comparison of the P12 fusion protein with those of other paramyxoviruses indicated similarities in overall length, N-terminal signal peptide sequence (amino acids 7 to 25), C-terminal membrane-spanning region (amino acids 486 to 513), and a highly conserved fusion sequence region at the N-terminus of the F1 subunit (amino acids 107 to 132).

Amino Acid Sequence↗
PubMed1997

Pediatric hospitalizations for croup (laryngotracheobronchitis): biennial increases associated with human parainfluenza virus 1 epidemics.

Croup is a common manifestation of respiratory tract infection in children, and human parainfluenza virus 1 (HPIV-1) is the agent most commonly associated with croup. In the United States, HPIV-1 produces a distinctive pattern of biennial epidemics of respiratory illness during the autumn months of odd-numbered years. National Hospital Discharge Survey data for croup hospitalizations among patients <15 years old between 1979 and 1993 were examined along with laboratory-based surveillance data on HPIV-1 activity in the United States. The mean annual number of croup hospitalizations was 41,000 (range, 27,000-62,000/year). Ninety-one percent of hospitalizations occurred among children <5 years of age. Minor peaks in croup hospitalizations occurred each year in February, and major peaks occurred in October of odd-numbered years, coincident with peak HPIV-1 activity. Each biennial epidemic of HPIV-1 was associated with 18,000 excess croup hospitalizations nationwide.

Adenovirus Infections, Human↗
PubMed1991

Fusion properties of cells persistently infected with human parainfluenza virus type 3: participation of hemagglutinin-neuraminidase in membrane fusion.

Cells persistently infected with human parainfluenza virus type 3 (HPF3) exhibit a novel phenotype. They are completely resistant to fusion with each other but readily fuse with uninfected cells. We demonstrate that the inability of these cells to fuse with each other is due to a lack of cell surface neuraminic acid. Neuraminic acid is the receptor for the HPF3 hemagglutinin-neuraminidase (HN) glycoprotein, the molecule responsible for binding of the virus to cell surfaces. Uninfected CV-1 cells were treated with neuraminidase and then tested for their ability to fuse with the persistently infected (pi) cells. Neuraminidase treatment totally abolished cell fusion. To extend this result, we used a cell line deficient in sialic acid and demonstrated that these cells, like the neuraminidase-treated CV-1 cells, were unable to fuse with pi cells. We then tested whether mimicking the agglutinating function of the HN molecule with lectins would result in cell fusion. We added a panel of five lectins to the neuraminic acid-deficient cells and showed that binding of these cells to the pi cells did not result in fusion; the lectins could not substitute for interaction of neuraminic acid with the HN molecule in promoting membrane fusion. These results provide compelling evidence that the HN molecule of HPF3 and its interaction with neuraminic acid participate in membrane fusion and that cell fusion is mediated by an interaction more complex than mere juxtaposition of the cell membranes.

Animals↗
PubMed2004

Prolonged outbreak of human parainfluenza virus 3 infection in a stem cell transplant outpatient department: insights from molecular epidemiologic analysis.

Human parainfluenza virus type 3 (hPIV3) infections cause considerable morbidity and mortality after stem cell transplantation, and inpatient nosocomial outbreaks are common. From September 1998 to July 1999, 93 stem cell transplantation recipients at our institution contracted hPIV3, of which 66 (71%) were being followed up in our outpatient department (OPD). The peak incidence was in September and October, when 39 cases were identified; thereafter, hPIV3 incidence decreased to approximately 5 cases per month. Nucleotide sequences (778 nucleotides from variable regions of the hemagglutinin-neuraminidase gene) from 46 patient and 8 community hPIV3 isolates were compared to determine epidemiologic relatedness. Sequence analysis of OPD isolates revealed that 18 of 19 isolates from September and October and 11 of 15 isolates from November 1998 to July 1999 were genetically similar. In contrast, 2 of 3 community isolates from September and October and 0 of 5 from November to July were linked to this cluster. Symptomatic surveillance and isolation were ineffective in terminating the outbreak, suggesting asymptomatic shedding among patients, staff, or visitors or viral persistence on environmental surfaces as possible explanations. The concept of nosocomial transmission should be expanded to include the OPD for immunosuppressed patients.

Cross Infection↗
PubMed2001

Polarity of human parainfluenza virus type 3 infection in polarized human lung epithelial A549 cells: role of microfilament and microtubule.

Human parainfluenza virus type 3 (HPIV-3) is an airborne pathogen that infects the epithelial cells of the respiratory tract. In the present study we investigated the interaction of HPIV-3 with the type II alveolar human lung polarized epithelial A549 cells. Although HPIV-3 entry and budding were bidirectional from both the apical and the basolateral domains, HPIV-3 exhibited preferential entry and release from the apical pole. While disruption of the cellular actin microfilament and microtubule by cytochalasin D and nocodazole, respectively, had no effect on virus entry, disruption of the microtubule but not the microfilament inhibited HPIV-3 release.

Actin Cytoskeleton↗
PubMed1987

Immediate persistent infection by human parainfluenza virus 3: unique fusion properties of the persistently infected cells.

We describe here a persistently infected cell system with unique properties. Cells infected with human parainfluenza virus type 3 (PF3) at high multiplicities of infection showed little or no cytopathic effects (cell fusion). Unlike other paramyxovirus persistent infections that require a long development time, the majority of the cells survived the initial infection and formed persistently infected cell cultures that were immediately available for study. In addition, unlike other paramyxovirus persistent infections, the PF3 system described here produced high levels of infectious virus and did not undergo periodic crises. Although cells persistently infected with PF3 contained large amounts of the cleaved, active form of the viral fusion protein, F1, the persistently infected cells did not fuse with each other. However, they did fuse with uninfected cells within minutes of cell-to-cell contact. Other persistent paramyxovirus infections do not have this property. Fusion occurred with all cells tested, including red blood cells, and was not dependent on protein synthesis. The unique fusion properties of these PF3 persistently infected cells make this an interesting system for the study of mechanisms of viral fusion and mechanisms of inhibition of viral fusion.

Animals↗
PubMed2005

A bovine parainfluenza virus type 3 vaccine is safe and immunogenic in early infancy.

BACKGROUND: A phase 2 trial was conducted to assess in young infants the safety, tolerability, infectivity, and immunogenicity of multiple doses of an intranasal vaccine using bovine parainfluenza virus type 3 (bPIV3). METHODS: One hundred ninety-two healthy 2-month-old infants were randomized 1 : 1 : 1 to receive 1x10(5) median tissue culture infective dose (TCID(50)) bPIV3 vaccine, 1x10(6) TCID(50) bPIV3 vaccine, or placebo at 2, 4, 6, and 12-15 months of age. Safety information was collected by use of diary sheets and telephone interviews. Nasal wash and serum specimens were collected for assessment of infectivity and immunogenicity. RESULTS: The safety profiles of both dosages of bPIV3 were similar to that of placebo, with the exception of fever with temperature of >/=38.1 degrees C after dose 2 only, occurring in 34% of the 1x10(5) TCID(50) group, 35% of the 1x10(6) TCID(50) group, and 12% of the placebo group (P<.01). No vaccine-related serious adverse events were reported. The cumulative vaccine infectivity (isolation of bPIV3 and/or bPIV3 seroconversion) after dose 3 was similar in the 2 vaccine groups (87% in the 1x10(5) TCID(50) group and 77% in the 1x10(6) TCID(50) group) (P=.46). Seroconversion rates after dose 3, assessed by means of hemagglutination inhibition assay, after adjustment for decrease in maternal antibody titers, were 67% in the 1x10(5) TCID(50) group, 57% in the 1x10(6) TCID(50) group, and 12% in the placebo group (P<.01). Isolation of bPIV3 was common after dose 1, dose 2, or dose 3, but only 1 of 51 participants in the vaccine groups had bPIV3 isolated after dose 4. CONCLUSIONS: Multiple doses of bPIV3 vaccine were well tolerated and immunogenic in young infants.

Administration, Intranasal↗
PubMed2005

Infection of ciliated cells by human parainfluenza virus type 3 in an in vitro model of human airway epithelium.

We constructed a human recombinant parainfluenza virus type 3 (rPIV3) that expresses enhanced green fluorescent protein (GFP) and used this virus, rgPIV3, to characterize PIV3 infection of an established in vitro model of human pseudostratified mucociliary airway epithelium (HAE). The apical surface of HAE was highly susceptible to rgPIV3 infection, whereas only occasional cells were infected when virus was applied to the basolateral surface. Infection involved exclusively ciliated epithelial cells. There was little evidence of virus-mediated cytopathology and no spread of the virus beyond the ciliated cell types. Infection of ciliated cells by rgPIV3 was sensitive to a neuraminidase specific for alpha2-6-linked sialic acid residues, but not to a neuraminidase that cleaves alpha2-3- and alpha2-8-linked sialic acid residues. This provided evidence that rgPIV3 utilizes alpha2-6-linked sialic acid residues for initiating infection, a specificity also described for human influenza viruses. The PIV3 fusion (F) glycoprotein was trafficked exclusively to the apical surface of ciliated cells, which also was the site of release of progeny virus. F glycoprotein localized predominately to the membranes of the cilial shafts, suggesting that progeny viruses may bud from cilia per se. The polarized trafficking of F glycoprotein to the apical surface also likely restricts its interaction with neighboring cells and could account for the observed lack of cell-cell fusion. HAE derived from cystic fibrosis patients was not more susceptible to rgPIV3 infection but did exhibit limited spread of virus due to impaired movement of lumenal secretions due to compromised function of the cilia.

Bronchi↗
PubMed2005

Immunohistochemical detection of antigens of distemper, adenovirus and parainfluenza viruses in domestic dogs with pneumonia.

The lungs of 35 dogs that died in Mexico from acute or subacute pneumonia were examined immunohistochemically for canine distemper virus (CDV), canine adenovirus (CAV) and canine parainfluenza virus (CpiV), to determine their frequency and occurrence and possible associations. CDV was identified in 27 (77%) cases, CAV in 20 (57%) and CpiV in 18 (51%). The most frequent dual association was that between CDV and CpiV (five cases; 14%). All three viruses, however, were identified in the same lung in 10 cases. Immunolabelling occurred in alveolar macrophages, monocytes, pneumocytes, epithelial cells and syncytial cells. It was concluded that immunohistochemistry is a useful diagnostic tool in canine respiratory disease to complement histopathological examination.

Adenoviridae Infections↗
PubMed1991

Brief report: parainfluenza virus type 3 infections: findings in Sydney and some observations on variations in seasonality world-wide.

Parainfluenza virus type 3 (Para 3) is an important childhood pathogen causing a significant amount of bronchiolitis and pneumonia in infants. Virus data were analysed over a twelve-year period (1978-1989), and a peak incidence of infection was observed in spring as in Houston, USA, unlike in the United Kingdom where summer epidemics appear to be the norm. The temperature ranges were analysed in the different study areas during Para 3 epidemics and similar ranges in temperature were noted which might provide an explanation for the apparently discordant findings in seasonality reported from different parts of the world.

Australia↗
PubMed1990

Sequence of the hemagglutinin-neuraminidase gene of human parainfluenza virus type 1.

The nucleotide sequence of the gene encoding the hemagglutinin-neuraminidase (HN) glycoprotein of human parainfluenza virus type 1 (PI1) was determined from cDNA clones derived from poly(A)+ RNA extracted from infected cells. A single open reading frame in the sequence was found to encode a putative protein of 575 amino acids with a calculated molecular weight of 63,960. The predicted amino acid sequence contains ten potential sites for N-linked glycosylation and one major hydrophobic region located 35 amino acids from the amino terminus, which appears to be the signal-anchor domain of HN. Comparison of the amino acid sequence with the HN glycoproteins of other paramyxoviruses indicated that the PI1 HN protein is most closely related to the Sendai virus (SV) HN protein.

Amino Acid Sequence↗
PubMed1997

Antigenic structure, function, and evolution of the hemagglutinin-neuraminidase protein of human parainfluenza virus type 1.

Twenty-two monoclonal antibodies directed to the hemagglutinin-neuraminidase protein of human parainfluenza virus type 1 (HPIV-1) were used in competition assays to create an antigenic map of neutralization sites. Eighty-seven clinical strains isolated over 35 years from multiple geographic regions were reacted in ELISA, hemagglutinin-inhibition, and microneutralization assays with these monoclonal antibodies. Together these assays revealed 21 epitopes on five nonoverlapping antigenic sites (I, III-VI) with a sixth (II) bridging site connecting sites I, III, and IV. Only 7 (33%) of these epitopes were conserved among all isolates. Previously described HPIV-1 genotypes were associated with the presence or absence of specific antigenic sites and evidence of probable immune selection within genotypes. Two sites were present on all isolates tested (III, V), and one (VI, genotype A) has not been found for 15 years. Forty hemagglutinin-neuraminidase nucleotide sequences were analyzed in terms of homology, structure, and evolution. These data may be useful in future epidemiologic, therapeutic, or vaccine-related work.

Antibodies, Monoclonal↗
PubMed1993

Rescue of synthetic analogs of genome RNA of human parainfluenza virus type 3.

A simple system that allows expression and packaging of a foreign gene by human parainfluenza virus type 3 (HPIV-3) has been described. First, a cDNA was constructed to encode an internally deleted version of HPIV-3 genome RNA. The viral genes were replaced with a negative sense copy of the bacterial chloramphenicol acetyl transferase (CAT) reporter gene. In vitro run-off transcription with T7 RNA polymerase synthesized an 870 nucleotide RNA that contained the antisense coding region of the CAT gene flanked by the transcription regulatory sequences and the 3' and 5' end extracistronic sequences of the HPIV-3 genome. When introduced into cells that are infected with HPIV-3, this RNA was amplified and the reporter gene was expressed, as measured by the CAT activity in the cell extract. Furthermore, the synthetic RNA was packaged into infectious virions. The addition of two extra nucleotides at the 5' end of the parental trailer region decreased the CAT activity by more than 90%, suggesting a requirement for the intact 5'-regulatory domain in the viral replicative cycle. Interestingly, the addition of one extra nucleotide to the 3' end totally abolished the CAT activity indicating that an exact 3' terminus is critical in this process.

Animals↗
PubMed1996

Rapid diagnosis of human parainfluenza virus type 1 infection by quantitative reverse transcription-PCR-enzyme hybridization assay.

The detection and quantitation of human parainfluenza virus type 1 (HPIV-1) RNA in nasal wash specimens from 49 children with lower respiratory infections were performed by a reverse transcription-PCR-enzyme hybridization assay (RT-PCR-EHA). The HPIV-1 RT-PCR-EHA was then used to test 40 samples from asymptomatic children. Primers and probes were designed from regions within the HPIV-1 hemagglutinin-neuraminidase gene which are highly conserved among all known genotypes. HPIV-1 was detected in all nine children who were culture positive. Other common respiratory viruses (HPIV-2, -3, and -4, mumps virus, respiratory syncytial virus, and influenza virus) were not detected by the HPIV-1 assay. Forty symptomatic children were negative by culture, and four of these were positive by RT-PCR-EHA. All of the samples from asymptomatic children were negative by culture and RT-PCR-EHA. RT-PCR-EHA was 100% sensitive (95% confidence interval, 0.66 to 1.00) and 95% specific (95% confidence interval, 0.88 to 0.99) compared with culture. The four false-positive results (relative to the results of culture) were in children with lower respiratory infections compatible with HPIV-1 infection and suggest that RT-PCR-EHA may be more sensitive than culture. Our data indicate that HPIV-1 may be underdiagnosed by routine culturing methods. RT-PCR-EHA has been demonstrated to be an easy, rapid, sensitive, and specific test for diagnosing HPIV-1 infection and provides a methodology for the rapid detection of closely related respiratory viruses.

Bacterial Proteins↗