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A number of viruses have been proven to be primary respiratory pathogens of cattle. Viruses may play an important role in making cattle susceptible to secondary respiratory bacterial pathogens. Epidemiology, pathogenesis, laboratory diagnosis, and important properties in infectious bovine rhinotracheitis (IBR), parainfluenza-3 (PI-3), and bovine respiratory coronavirus (BRCV) are described in this article.
We have identified a virus-activated factor (VAF) that binds to a regulatory element shared by different virus-inducible genes. We provide evidence that VAF contains two members of the interferon regulatory factor (IRF) family of transcriptional activator proteins (IRF-3 and IRF-7), as well as the transcriptional coactivator proteins p300 and CBP. Remarkably, VAF, as well as recombinant IRF-3 and IRF-7 proteins, binds very weakly to the interferon-beta (IFN-beta) gene promoter in vitro. However, in virus-infected cells, both proteins are recruited to the endogenous IFN-beta promoter as part of a protein complex that includes ATF-2/c-Jun and NF-kappa B. These observations provide a unique example of the coordinate activation of multiple transcriptional activator proteins and their highly cooperative assembly into a transcriptional enhancer complex in vivo.
The epidemiological, clinical and virological features of 1220 children with acute bronchiolitis admitted to the Prince of Wales Hospital, Hong Kong, from 1985 to 1988 are reported. They accounted for 6.6% of total paediatric admissions and provided a case incidence of bronchiolitis requiring admission to hospital of approximately 21 per 1000 children 0-24 months of age. The clinical course and outcome was in general benign. The average hospital stay was 5 days and there were no deaths. Ten per cent of patients were repeatedly admitted to hospital with recurrent wheezing after discharge. Two infants developed bronchiolitis obliterans. Respiratory syncytial virus (RSV) was shown by direct immunofluorescence, virus culture and serology to be the commonest cause of acute bronchiolitis in Hong Kong. Other aetiological agents included parainfluenza and influenza viruses, adenoviruses, and Mycoplasma pneumoniae. In contrast to western countries, a seasonal variation of bronchiolitis was found with a peak incidence in the summer months. The significance of these observations is discussed.
Hens were immunized with partially purified Sendai virus that had been grown on chicken embryos. The titres of specific antibodies to Sendai virus varied from log2 13.0 to 15.5 during the 4 months after immunization and the immunoglobulin Y (IgY) concentration varied from 2 to 10 mg per ml of egg yolk. A method has been developed employing dextran blue to isolate IgY from the egg yolk. The dextran blue method was compared with two other methods (poly(ethylene glycol) and chloroform) in terms of yield, total protein content, IgY concentration, specific activity of IgY and SDS-PAGE analysis. The specific activity and the IgY content obtained by these three methods proved to be identical, in the range log2 12.9-14.1, and 4.6-12.8 mg/egg, respectively. However, the total protein content when purified by chloroform was 2-fold to 4-fold higher than that of the others. The analysis of IgY by SDS-PAGE demonstrated that IgY purified with dextran blue contained three major protein components with molecular weights of 34.7 kDa, 41 kDa and 66 kDa and one minor protein of 45 kDa. IgY that was extracted with chloroform contained two major proteins of 45.7 kDa and 75.2 kDa and that extracted with PEG-6000 contained only one major protein of 66 kDa. The IgY obtained by these latter methods also contained several minor proteins in the range 41-80 kDa.
The pig paramyxovirus of blue eye disease (PPBED) produces central nervous system (CNS) damage leading to death in piglets. However, when PPBED was injected into the muscle and came into contact with hind limb peripheral nerves and was transported to the CNS, it did not cause death and could be a mechanism by which to induce protection. This study analyses whether PPBED causes electrophysiological and morphological alterations in infected hind limb peripheral nerves. It also studies, whether PPBED induces the onset of haemagglutination inhibitory antibodies (HIA) when it is transported to the spinal cord after medial gastrocnemius (MG) intramuscular injection. PPBED was detected by an immunohistochemical method and nerve morphology was studied using electron microscopy. The physiological status of the nerve was evaluated with electrophysiological techniques. The electrical threshold of the infected MG nerve increased four- or five fold compared to that in the ipsilateral lateral gastrocnemius or in the MG nerve on the control side. The infected nerve fibres underwent myelin sheet disarrangement and their internal fibre diameter decreased. PPBED induced the onset of HIA.
UNLABELLED: Pig paramyxovirus of the blue eye disease (PPBED) is a novel member of the paramyxoviridac family which infects pigs. In neonatal pigs it causes neurological damage, whereas in adult pigs it affects the reproductive function. As PPBED damages the new-born pig central nervous system (CNS), it is important to study whether PPBED binds to the membrane proteins of all brain tissue, or selectively binds to neuronal tissue of the brain stem, olfactory bulb, hippocampus, cerebellum, frontal, temporal and parietal brain cortex. It is also important to establish whether it also infects neurones obtained from new-born, 60-day-old and adult pigs, and the role of carbohydrate residues in virus binding. The effect on virus binding of polyclonal antibodies against viral envelope proteins was also studied. Binding studies were performed using dot blot and virus overlay protein binding assays. PPBED was able to bind to membrane proteins from all brain regions, particularly to a protein band of approximately 116 kDa. Neuraminidase treatment of neuronal membrane proteins decreased virus binding; subsequent treatments with beta-galactosidase and manosidase did not increase virus binding inhibition. N-glycosidase F and trypsin also decreased virus binding, but not the O-glycanase. Antibodies against viral haemagglutinin-neuraminidase blocked virus binding more efficiently than antibodies against viral fusion protein. IN CONCLUSION: (1) PPBFD is able to bind to pig neurones of all brain regions studied and at all ages analysed; (2) a 116 kDa membrane protein containing sialic acid residues with an N-linked oligosaccharide chain was specifically recognized; (3) PPBED haemagglutinin-neuraminidase protein seems to play a central role in neural receptor recognition.
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A key rate-limiting step in the adaptive immune response at peripheral challenge sites is the transmission of antigen signals to T cells in regional lymph nodes. Recent evidence suggests that specialized dendritic cells (DC) fulfill this surveillance function in the resting state, but their relatively slow turnover in most peripheral tissues brings into question their effectiveness in signaling the arrival of highly pathogenic sources of antigen which require immediate mobilization of the full range of host defenses for maintenance of homeostasis. However, the present report demonstrates that recruitment of a wave of DC into the respiratory tract mucosa is a universal feature of the acute cellular response to local challenge with bacterial, viral, and soluble protein antigens. Consistent with this finding, we also demonstrate that freshly isolated respiratory mucosal DC respond in vitro to a variety of CC chemokines as well as complementary cleavage products and N-formyl-methionyl-leucine-phenylalanine. This suggests that rapid amplification of specific antigen surveillance at peripheral challenge sites is an integral feature of the innate immune response at mucosal surfaces, and serves as an "early warning system" to alert the adaptive immune system to incoming pathogens.
Human airway epithelial cells appear specially programmed for expression of immune response genes implicated in immunity and inflammation. To better determine how this epithelial system operates in vivo, we analyzed its behavior in mouse models that allow for in vitro versus in vivo comparison and genetic modification. Initial comparisons indicated that tumor necrosis factor alpha induction of epithelial intercellular adhesion molecule 1 required sequential induction of interleukin (IL)-12 (p70) and interferon gamma, and unexpectedly localized IL-12 production to airway epithelial cells. Epithelial IL-12 was also inducible during paramyxoviral bronchitis, but in this case, initial IL-12 p70 expression was followed by 75-fold greater expression of IL-12 p40 (as monomer and homodimer). Induction of IL-12 p40 was even further increased in IL-12 p35-deficient mice, and in this case, was associated with increased mortality and epithelial macrophage accumulation. The results placed epithelial cell overgeneration of IL-12 p40 as a key intermediate for virus-inducible inflammation and a candidate for epithelial immune response genes that are abnormally programmed in inflammatory disease. This possibility was further supported when we observed IL-12 p40 overexpression selectively in airway epithelial cells in subjects with asthma and concomitant increases in airway levels of IL-12 p40 (as homodimer) and airway macrophages. Taken together, these results suggest a novel role for epithelial-derived IL-12 p40 in modifying the level of airway inflammation during mucosal defense and disease.
A phase 2 clinical trial was conducted to evaluate the antibody responses to bovine parainfluenza virus type 3 (bPIV3) vaccination in young infants. Three groups were tested as follows: placebo (n=66) and 10(5) (n=64) or 10(6) (n=62) TCID(50) of bPIV3. The vaccine or placebo was administered intranasally at ages 2, 4, 6, and 12-15 months, and serum specimens were collected at ages 2, 6, 7, 12-15, and 13-16 months. Serum hemagglutination inhibition (HI) and IgA antibody titers against bPIV3 and human PIV3 (hPIV3) were measured. The results indicate that antibody responses to bPIV3 vaccination are more likely to be detected by the bPIV3 IgA and HI assays than by the hPIV3 IgA and HI assays, that bPIV3-induced antibody response can be differentiated from hPIV3-induced antibody response most reliably by comparing bPIV3 and hPIV3 HI titers, and that bPIV3 vaccine prevents vaccine recipients from developing antibody profiles of hPIV3 primary infection.
In concert with bacteria, respiratory viruses play a major role in the high rates of acute lower respiratory infection (ALRI) experienced in developing nations. Respiratory syncytial virus, parainfluenza and influenza viruses, and the adenoviruses are the predominant viral causes of ALRI in both developed and developing regions. In this review, the epidemiologic data from developing nations for these viral infections are summarized and the current status of viral vaccines for prevention of ALRI are described. Among the questions to be addressed before these vaccines are used in developing nations are (1) the age-specific rates of infection and disease, (2) the effect of high-dose early exposure to these viruses, and (3) the effect of malnutrition on the immunogenicity of the vaccines. Prospective family studies and other community-based approaches will be required in the acquisition of these data.
The Sendai virus (SeV) V protein is characterized by the unique cysteine-rich domain in its carboxy-terminal half which is fused to the amino-terminal half of the P protein, but its function has remained enigmatic. The V protein-directing mRNA is generated by a remarkable process known as mRNA editing involving the pseudotemplated addition of a single G residue at a specific septinucleotide locus in the P gene, whereas the unedited exact copy encodes the P protein. Here, we introduced two nucleotide changes in the septinucleotide motif (UUUUCCC to UUCUUCC) in a full-length SeV cDNA and were able to recover a virus from the cDNA, which was devoid of mRNA editing and hence unable to synthesize the V protein. Compared with the parental wild-type virus with regard to gene expression, replication and cytopathogenicity in various cell lines in vitro, the V(-) virus was found to be either potentiated or comparable but never attenuated. The V(-) virus, however, showed markedly attenuated in vivo replication capacity in and pathogenicity for mice. Thus, though categorized as a nonessential gene product, SeV V protein encodes a luxury function required for in vivo pathogenicity.
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Nitric oxide (NO), superoxide (O(2)(-)), and their reaction product peroxynitrite (ONOO(-)) are generated in excess during a host's response against viral infection, and contribute to viral pathogenesis by promoting oxidative stress and tissue injury. Here we demonstrate that NO and peroxynitrite greatly accelerates the mutation of Sendai virus (SeV), a nonsegmented negative-strand RNA virus, by using green fluorescent protein (GFP) inserted into and expressed by a recombinant SeV (GFP-SeV) as an indicator for mutation. GFP-SeV mutation frequencies were much higher in the wild-type mice than in those lacking inducible NO synthase, suggesting that mutation of the virus in vivo is NO dependent. High levels of NO and NO-mediated oxidative stress were induced by GFP-SeV infection in the lung of the wild-type mice, but not in the iNOS-deficient mice, as evidenced by electron spin resonance spectroscopy and immunohistochemical analysis for nitrotyrosine formation as well as histopathological examination. Furthermore, peroxynitrite, an NO-derived reactive nitrogen intermediate, enhanced viral mutation in vitro. These results indicate that the oxidative stress induced by NO produced during the natural course of viral infection increases mutation, expands the quasispecies spectrum, and facilitates evolution of RNA viruses.
The effects of endothelin-1 (ET-1) and sarafotoxin S6c (S6c) on cholinergic contractions elicited by electrical field stimulation (EFS) were examined in mouse tracheal preparations from healthy animals and from animals infected with parainfluenza-1 (P-1) virus. S6c (an ETB-selective agonist) and ET-1 caused marked ETA and/or ETB receptor-mediated potentiation of EFS-induced contraction in tracheal tissue from both groups. Despite the fact that such infection is known to markedly alter ET receptor density and function in mouse tracheal smooth muscle, no evidence for modulated neuronal ET receptor function was obtained. The reason for this differential sensitivity of smooth muscle and neuronal ET receptors to P-1 infection is unknown.
Overproduction and overexpression of endothelin-1 (ET-1) have been reported to contribute to the pathophysiology of pulmonary diseases, including pulmonary fibrosis, obliterative bronchiolitis, and primary pulmonary hypertension. To determine whether ET-1 contributes to the pathogenesis of pulmonary disease, we locally overexpressed ET-1 using an in vivo UV-inactivated hemagglutinating virus of Japan (HVJ) liposome-mediated gene transfer system. Plasmid DNA of ET-1 (pME18fc preproET-1) and high mobility group 1 (HMG1) protein were co-encapsulated in liposomes. Then the plasmid DNA and liposome complexes were introduced into the lung via the trachea in Wistar rats, using HVJ-mediated membrane fusion. Control animals received instillation of HVJ liposome with an empty cassette. Two weeks after in vivo transfection of the preproET-1 gene, hyperplastic connective tissue plaques were seen in the alveolar duct and small conducting airways, indicating histologically distinctive obliterative bronchiolitis. No histopathologic changes were seen in the control animals. These results suggested that local overexpression of ET-1 may play an important role in the pathogenesis of obliterative bronchiolitis.
OBJECTIVES: Acute laryngotracheitis is a disease in which mainly the subglottic area is infected, whereas adjacent parts of the larynx, especially the narrow glottic fold, remain unaffected. The reason for the difference between these two directly adjacent regions is unknown. Therefore, in the present study the influx of dendritic cells, neutrophils, T and B lymphocytes, natural killer cells, and macrophages into the mucosa of different laryngeal compartments was investigated after Sendai virus infection in the rat. The aims were to study both the influx of immunocompetent cells and the adhesion of the pathogen and to correlate them to the different reactions of the laryngeal areas during pseudocroup. METHODS: Acute laryngotracheitis was induced by intranasal application of Sendai virus in brown Norway rats. This virus is exclusively pneumotropic in rodents and belongs to the parainfluenza virus type 1, the main pathogen of acute laryngotracheitis in children. The numbers of dendritic cells, neutrophils, T and B lymphocytes, natural killer cells, and macrophages were determined in the supraglottic, glottic, subglottic, and tracheal mucosa on days 2, 5, 7, and 14 after virus application. Furthermore, the nucleoprotein of the virus and major histocompatibility complex (MHC) Class II expression were detected immunohistologically on the laryngeal epithelium. RESULTS: All cell subsets entered the laryngeal mucosa during inflammation. The highest influx was detected among dendritic cells subglottically. This was accompanied by a strong virus adhesion and MHC Class II expression on the subglottic epithelium. In contrast, only a few immunocompetent cells entered the adjacent glottic mucosa, and on the glottic epithelium staining for virus nucleoprotein and MHC Class II expression was weak. CONCLUSIONS: The inflammatory response of the laryngeal mucosa shows great regional differences in this animal model during experimental viral infection. The response was characterized by a strong subglottic and a weak glottic reaction. A possible reason for this difference might be region-specific viral adhesion on the epithelium of the laryngeal areas, as well as differences in MHC Class II expression. Thus, these data agree with the clinical observation during acute laryngotracheitis and may explain why the subglottic part of the larynx is affected preferentially during pseudocroup. The molecular mechanisms mediating the different reactions await clarification.