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We report the isolation of parainfluenza virus type 3 from the CSF of a 19-year-old man with Guillain-Barré syndrome. Although parainfluenza viruses are usually associated with respiratory tract illnesses, some strains show a neurotropism not previously appreciated. Thus, parainfluenza viruses may be responsible for a portion of cases of Guillain-Barré syndrome.
To better understand the recovery process of infants with lower respiratory tract disease due to respiratory syncytial virus, the production of interferon by 129 children (ages 10 days to 24 months) with RSV infection was compared to that of 20 children with influenza (ages 1 to 36 months), and 37 children with parainfluenza virus infection (ages 4 to 66 months). Interferon assays of 285 nasal washes from children with RSV revealed that interferon production occurred in only 5 (4%) of the children. Significantly more children infected with infleunza virus, 55% (P less than 0.001), and parainfluenza virus, 30% (P less than 0.001), produced interferon. In addition, the quantity of interferon produced by children with RSV (geometric mean titer = 2) was significantly less than that of children with influenza (GMT = 26.8, P less than 0.001) and parainfluenza virus (GMT = 23.5, P less than 0.001). In the children infected with RSV, in constrast to those with influenza, interferon detection was not associated with diminished shedding of virus.
Cell fusion by human parainfluenza virus (HPIV) type 2 or type 3 requires the coexpression of both the fusion (F) and haemagglutinin-neuraminidase (HN) glycoproteins from the same virus type, indicating that promotion of fusion requires a type-specific interaction between F and HN. In this report we have further investigated the interaction of the ectodomains of the F and HN glycoproteins from HPIV2 and HPIV3. We constructed mutants of the HPIV2 F and HPIV3 F proteins (F'-KDEL) lacking a transmembrane anchor and a cytoplasmic tail, and containing a C-terminal signal for retention in the endoplasmic reticulum (ER). The P12 and P13 F'-KDEL proteins were both found to be retained intracellularly, and neither could induce cell fusion when co-expressed with homotypic HN proteins. Qualitative and quantitative cell-fusion assays also showed that both the P12 F'-KDEL and P13 F'-KDEL proteins have inhibitory effects on P12 F- and HN-induced cell fusion. However, the F-KDEL mutants were found to inhibit cell fusion by two distinct mechanisms. An interaction between P12 F'-KDEL and P12 HN results in intracellular retention of HN, and a block in its transport to the cell surface. In contrast, P13 F'-KDEL was found to suppress the steady-state intracellular expression levels of HPIV2 HN. These results support the conclusion that fusion involves an interaction between the HN and F proteins, and suggest that an association between F and HN may occur in the ER.
Natural macromolecular polycations (protamine, histones H1, H2A, H2B and H3) caused the clustering of influenza and parainfluenza viruses into aggregates heterogeneous in size, as well as a decrease in their hemagglutinating capacity. Polycation-induced virus alterations consisted in surface pyknosis and an increase most efficient as regards the interaction with viruses.
A cyclic pattern of virus production was observed when human parainfluenza virus 3 (HPIV3) was serially passaged nine times in LLC-MK2 cells. Viruses produced from serial passages 8 and 9 interfered with the replication of standard HPIV3. Three subgenomic RNA species (DI-1, DI-2, and DI-3) and virus genomic RNA were detected in the progeny virions produced from cells mixedly infected with standard virus and virus from either serial passages 5 or 8. Northern blot analysis with probes representing all six HPIV3 structural protein genes revealed that DI-1 and DI-2 RNAs contain sequences from the 5' end of the standard virus genome. DI-1 RNA contains L, HN, and F specific sequences, while DI-2 RNA contains only L and HN sequences. DI-3 RNA did not hybridize with any of the probes used. The possibility that DI-3 RNA contains sequences from the 5' end of the standard virus genome is discussed. These results demonstrate that 5' defective interfering particles are generated during serial passage of HPIV3.
Two hemagglutinating and hemadsorbant agents-serologically identified as parainfluenza viruses type 3-were isolated from the cerebrospinal fluid of a 10-month-old infant with meningoencephalitis and from the urethral secretion of a male patient with nonbacterial urethritis. Parainfluenza virus antigens types 1, 2, and 3 were detected by indirect immunofluorescence reactions in cells exfoliated in the vagina of women with genital neoplasia or common gynecopathies.
The genome of human parainfluenza virus type 3 (PIV3) is a single negative-sense RNA strand (vRNA) that is 15,463 nucleotides in length. A cDNA was constructed to encode an 898-nucleotide, internally deleted version of PIV3 vRNA, PIV3-CAT vRNA, in which the viral genes were replaced with the bacterial chloramphenicol acetyltransferase (CAT) reporter gene. The CAT gene was flanked in turn by sequences representing (i) nontranslated sequences of the first and last genes in the PIV3 genome, (ii) PIV3 gene-start and gene-end sequences, which are presumed to be transcription signals, and (iii) 3' extracistronic (leader) and 5' extracistronic (trailer) terminal regions of PIV3 vRNA. A second cDNA was constructed to encode the exact complement of PIV3-CAT vRNA; this positive-sense RNA, PIV3-CAT vcRNA, would correspond to the predicted replicative intermediate of PIV3-CAT vRNA. When synthesized in vitro by runoff transcription with T7 RNA polymerase and transfected separately into PIV3-infected cells, both PIV3-CAT vRNA and vcRNA were rescued with similar efficiencies; that is, they were expressed to yield CAT and were packaged into particles that could be used to infect fresh cells. Rescue of PIV3-CAT vRNA was strictly dependent on complementation by PIV3; PIV3 could not be replaced by respiratory syncytial virus or, unexpectedly, by a bovine strain of PIV3. Passage was blocked by prior incubation with neutralizing monoclonal antibodies specific to the PIV3 attachment protein. Also, during nine serial passages, the expression of CAT by PIV3-CAT vRNA increased more than 3,000-fold. These results indicated that the 3'-terminal 111 nucleotides and the 5'-terminal 115 nucleotides of PIV3 vRNA, which are present in PIV3-CAT vRNA, contained all of the cis-acting RNA sequences required for replication, gene expression, and transmission.
Envelope glycoproteins of human parainfluenza virus type 3 (PIV-3) were selectively solubilized with n-octyl beta-D-glucopyranoside and reconstituted into lipid vesicles by dialysis of the detergent. The efficacy of the glycoprotein preparation as a subunit vaccine when administered to hamsters intranasally or subcutaneously was compared. Animals receiving four intranasal immunizations with 5 micrograms of the glycoprotein preparation were completely resistant to challenge infection. Only partial protection, however, was observed in animals immunized subcutaneously with the same dose of antigen. The local glycoprotein-specific IgA response was significantly higher in intranasally immunized animals and was implicated in resistance to challenge infection.
The nucleotide sequence of the "P/V gene" of parainfluenza virus type 2 is presented. To determine the nature of any nontemplated additions of nucleotides that may arise during the synthesis of mRNA from this gene the polymerase chain reaction was used to amplify specific sequences of both genomic RNA and mRNA. These results demonstrated that the V protein is encoded by the genome while insertion of two nontemplated G residues are required to synthesize P mRNA. The predicted P protein has 44% identical amino acid homology with that of simian virus 5 and 37% with mumps virus; 25% of the amino acids is conserved between all three viruses.
Acute disseminated encephalomyelitis associated with the parainfluenza virus has rarely been reported in childhood. A 2.5-year-old girl with acute disseminated encephalomyelitis, who developed bilateral symmetrical lesions in the basal ganglion, thalamus, corpus callosum, cerebral subcortical white matter, and cerebellar medulla on brain magnetic resonance imaging is described. Serological confirmation of parainfluenza virus infection was made 2 weeks following the onset of neurological symptoms. Four months later, the patient had a full recovery. At present, 3 years later, no relapse has been reported and she is leading a normal life. Our case is of interest because of its rarity, the striking brain magnetic resonance imaging, and the good neurological outcome.
Members of the Paramyxovirinae subfamily of the Paramyxoviridae family of viruses have the unusual requirement that the nucleotide length of the viral genome must be an even multiple of six in order for efficient RNA replication, and hence virus replication, to occur. Human parainfluenza virus type 2 (HPIV2) is the only member of the genus that has been reported to have a genome length that is not an even multiple of six, and it has also been recovered from a full-length antigenomic-sense cDNA that did not conform to the "rule of six." To reexamine the issue of nucleotide length in natural isolates of HPIV2, a complete consensus genomic sequence was determined for three HPIV2 strains: Greer, Vanderbilt/1994 (V94), and Vanderbilt/1998. Each of these strains was found to have a genome length of 15,654 nucleotides (nt), thus conforming in each case to the rule of six. To directly examine the requirement that the genomic length of HPIV2 be an even multiple of six, we constructed six full-length antigenomic HPIV2/V94 cDNAs that deviated from a polyhexameric length by 0 to 5 nt. Recombinant HPIV2s were readily recovered from all of the cDNAs, including those that did not conform to the rule of six. One recombinant HPIV2 isolate was completely sequenced for each of the nonpolyhexameric antigenomic cDNAs. These were found to contain small nucleotide insertions or deletions that conferred polyhexameric length to the recovered genome. Interestingly, almost all of the length corrections occurred within the hemagglutinin-neuraminidase and large polymerase genes or the intervening intergenic region and thus were proximal to the insert that caused the deviation from the rule of six. These results demonstrate, in the context of complete infectious virus, that HPIV2 has a strong and seemingly absolute requirement for a polyhexameric genome.
Recombinant human parainfluenza virus type 3 (PIV3) was used as a vector to express the major protective antigen of measles virus, the hemagglutinin (HA) glycoprotein, in order to create a bivalent PIV3-measles virus that can be administered intranasally. The measles virus HA open reading frame (ORF) was inserted as an additional transcriptional unit into the N-P, P-M, or HA-neuraminidase (HN)-L gene junction of wild-type PIV3 or into the N-P or P-M gene junction of an attenuated derivative of PIV3, termed rcp45L. The recombinant PIV3 (rPIV3) viruses bearing the HA inserts replicated more slowly in vitro than their parental viruses but reached comparable peak titers of >/=10(7.5) 50% tissue culture infective doses per ml. Each of the wild-type or cold-passaged 45L (cp45L) PIV3(HA) chimeric viruses replicated 5- to 10-fold less well than its respective parent virus in the upper respiratory tract of hamsters. Thus, insertion of the approximately 2-kb ORF itself conferred attenuation, and this attenuation was additive to that conferred by the cp45L mutations. The attenuated cp45L PIV3(HA) recombinants induced a high level of resistance to replication of PIV3 challenge virus in hamsters and induced very high levels of measles virus neutralizing antibodies (>1:8,000) that are well in excess of those known to be protective in humans. rPIV3s expressing the HA gene in the N-P or P-M junction induced about 400-fold more measles virus-neutralizing antibody than did the rPIV3 with the HA gene in the HN-L junction, indicating that the N-P or P-M junction appears to be the preferred insertion site. Previous studies indicated that the PIV3 cp45 virus, a more attenuated version of rcp45L, replicates efficiently in the respiratory tract of monkeys and is immunogenic and protective even when administered in the presence of very high titers of passively transferred PIV3 antibodies (A. P. Durbin, C. J. Cho, W. R. Elkins, L. S. Wyatt, B. Moss, and B. R. Murphy, J. Infect. Dis. 179:1345-1351, 1999). This suggests that this intranasally administered PIV3(HA) chimeric virus can be used to immunize infants with maternally acquired measles virus antibodies in whom the current parenterally administered live measles virus vaccine is ineffective.
The matrix (M) protein plays an essential role in the assembly and budding of some enveloped RNA viruses. We expressed the human parainfluenza virus type 1 (hPIV-1) M and/or NP genes into 293T cells using the mammalian expression vector pCAGGS. Biochemical and electron microscopic analyses of transfected cells showed that the M protein alone can induce the budding of virus-like particles (vesicles) from the plasma membrane and that the NP protein can assemble into intracellular nucleocapsid-like (NC-like) structures. Furthermore, the coexpression of both the M and NP genes resulted in the production of vesicles enclosing NC-like structures, suggesting that the hPIV-1 M protein has the intrinsic ability to induce membrane vesiculation and to incorporate NC-like structures into these budding vesicles.
In order to determine the natural history of parainfluenza virus infection in early life, we followed prospectively 130 infants and children from birth or a few months of age for evidence of infection with PV. Using rapid diagnostic techniques, standard tissue culture infectivity, and serologic techniques we were able to document primary PV infection in 92% of these infants, and repeated infection with heterotypic or homotypic PV strains in 49% by 30 months of age. Increasing patient age had no significant effect in reducing the incidence of lower respiratory tract illness as a result of PV infection. Infection with one PV serotype provided no protection against LRTI at the time of subsequent infection with a heterotypic PV strain. In contrast, primary PV infection provided a brief period of immunity to LRTI upon homotypic reinfection. Secretory IgA responses to PV were determined by immunofluorescent techniques. Antibody response to PV strains causing primary infection and heterotypic repeated infection were transient and of low magnitude. Homotypic reinfection resulted in significantly enhanced production of secretory antibody to PV. At least in early life, repeated exposures to PV appear to be essential for maintaining immunity to severe forms of illness caused by PV infection.
The ability to recover human parainfluenza virus types 1 and 2 (HPIV-1, 2) from infected individuals has been highly variable. During the autumn of 1991, 158 nasal wash specimens collected from children with lower respiratory symptoms were split and cultured independently at two laboratories using different tissue culture techniques. Immunofluorescent antibody (IFA) and hemadsorption (HAd) assays were compared for their speed and efficiency in viral detection. 45 isolates [HPIV-1 (17) and HPIV-2 (28)] were recovered by one laboratory and only one (HPIV-2) by the other. IFA was the most sensitive assay detecting 87% of HPIV-1 and 70% of HPIV-2 by the fourth day of culture. HAd assay detected 87% of HPIV-1 isolates by the time they were positive by IFA, but only 35% of the HPIV-2 isolates. Significant methodologic differences between laboratories were then compared simultaneously for effect on virus recovery from culture positive frozen clinical specimens. Recovery of 100% of the isolates was achieved. Factors that contributed to differences in recovery of HPIV-1 and 2 were: (1) primary African green monkey (AGMK) cells were inferior to cynomolgus monkey kidney or LLC-MK2 cells, (2) addition of trypsin to culture medium for AGMK and LLC-MK2 cells enhanced recovery, (3) use of IFA was essential for rapid detection of HPIV-2, and (4) use of microtiter plate culture without specimen dilution enhanced virus recovery. A survey of clinical virology laboratories demonstrated considerable variability in the use of these techniques for routine respiratory virus culture.
The pathogenesis of parainfluenza 1 (Sendai) virus infection was compared among 25-day-old BN, F344, and LEW rats to identify a sensitive as well as a resistant inbred rat strain to Sendai virus-induced lung injury during early life. At 7 days after inoculation, BN rats had 65-fold higher (P less than .001) pulmonary viral titers and threefold higher (P less than .002) numbers of neutrophils in bronchoalveolar lavage fluid than did F344 rats. At 14 days after inoculation, when most virus-induced inflammation had been resolved, BN rats had a threefold greater (P less than .01) incidence of bronchioles with aggregates of lymphocytes and macrophages than did F344 rats. Control BN rats had higher numbers of bronchiolar eosinophils than did F344 or LEW rats. Although viral inoculation resulted in increased numbers of bronchiolar mast cells in all three strains at 14 days, bronchiolar mast cell density was greater (P less than .005) in virus-inoculated BN and LEW rats than in F344 rats. We conclude that BN rats are high responders and F344 rats are low responders to Sendai virus-induced bronchiolitis, pneumonia, and airway mastocytosis. These strain differences may be useful in elucidating important pathogenetic mechanisms in virus-induced airway injury and mastocytosis.
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