Gene expression in epithelial cells in response to pneumovirus infection

Respiratory syncytial virus (RSV) and pneumonia virus of mice (PVM) are viruses of the family Paramyxoviridae, subfamily pneumovirus, which cause clinically important respiratory infections in humans and rodents, respectively. The respiratory epithelial target cells respond to viral infection with specific alterations in gene expression, including production of chemoattractant cytokines, adhesion molecules, elements that are related to the apoptosis response, and others that remain incompletely understood. Here we review our current understanding of these mucosal responses and discuss several genomic approaches, including differential display reverse transcription-polymerase chain reaction (PCR) and gene array strategies, that will permit us to unravel the nature of these responses in a more complete and systematic manner

Inflammatory responses to acute pneumovirus infection in neonatal mice

Background: The innate immune responses of neonates differ dramatically from those of adults. Here we examine the acute inflammatory responses of neonatal and weanling mice infected with pneumonia virus of mice (PVM), a rodent pathogen (family Paramyxoviridae, genus Pneumovirus) that replicates the sequelae of severe respiratory syncytial virus infection. Results: We demonstrate that virus replication proceeds indistinguishably in all age groups (inoculated at 1, 2, 3 and 4 weeks of age), although inflammatory responses vary in extent and character. Some of the biochemical mediators detected varied minimally with age at inoculation. Most of the mediators evaluated demonstrated elevated expression over baseline correlating directly with age at the time of virus inoculation. Among the latter group are CCL2, CCL3, and IFN-γ, all cytokines previously associated with PVM-induced inflammatory pathology in mature mice. Likewise, we detect neutrophil recruitment to lung tissue in all age groups, but recruitment is most pronounced among the older (3 - 4 week old) mice. Interestingly, all mice exhibit failure to thrive, lagging in expected weight gain for given age, including the youngest mice that present little overt evidence of inflammation. Conclusions: Our findings among the youngest mice may explain in part the phenomenon of atypical or minimally symptomatic respiratory infections in human neonates, which may be explored further with this infection model

A Case–Crossover Study of Wintertime Ambient Air Pollution and Infant Bronchiolitis

We examined the association of infant bronchiolitis with acute exposure to ambient air pollutants. DESIGN: We employed a time-stratified case–crossover method and based the exposure windows on a priori, biologically based hypotheses. PARTICIPANTS: We evaluated effects in 19,901 infants in the South Coast Air Basin of California in 1995–2000 with a hospital discharge record for bronchiolitis in the first year of life (International Classification of Diseases, 9th Revision, CM466.1). EVALUATIONS/MEASUREMENTS: Study subjects’ ZIP code was linked to ambient air pollution monitors to derive exposures. We estimated the risk of bronchiolitis hospitalization associated with increases in wintertime ambient air pollutants using conditional logistic regression. RESULTS: We observed no increased risk after acute exposure to particulate matter ≤ 2.5 μm in aerodynamic diameter (PM(2.5)), carbon monoxide, or nitrogen dioxide. PM(2.5) exposure models suggested a 26–41% increased risk in the most premature infants born at gestational ages between 25 and 29 weeks; however, these findings were based on very small numbers. CONCLUSIONS: We found little support for a link between acute increases in ambient air pollution and infant bronchiolitis except modestly increased risk for PM(2.5) exposure among infants born very prematurely. In these infants, the periods of viral acquisition and incubation concurred with the time of increased risk. RELEVANCE TO PROFESSIONAL PRACTICE: We present novel data for the infant period and the key respiratory disease of infancy, bronchiolitis. Incompletely explained trends in rising bronchiolitis hospitalization rates and increasing number of infants born prematurely underscore the importance of evaluating the impact of ambient air pollution in this age group in other populations and studies

The CC chemokine ligand 3 regulates CD11c+CD11b+CD8alpha- dendritic cell maturation and activation following viral infection of the central nervous system: implications for a role in T cell activation.

The role of CC chemokine ligand 3 (CCL3) in activation of dendritic cells (DCs) following mouse hepatitis virus (MHV) infection of the central nervous system (CNS) was examined. The results indicate that CCL3 participates in an effective host response to MHV infection by contributing to CD11c+CD11b+CD8alpha- DC maturation, activation, and migration to cervical lymph nodes (CLN). Diminished CD8alpha- DC activation correlated with reduced IFN-gamma expression by virus-specific T cells accompanied by increased IL-10 production suggesting that CCL3 contributes to an effective host response to viral infection by enhancing the T cell activation potential of DC

Efficient replication of pneumonia virus of mice (PVM) in a mouse macrophage cell line

Pneumonia virus of mice (PVM; family Paramyxoviridae, subfamily Pneumovirinae) is a natural respiratory pathogen of rodent species and an important new model for the study of severe viral bronchiolitis and pneumonia. However, despite high virus titers typically detected in infected mouse lung tissue in vivo, cell lines used routinely for virus propagation in vitro are not highly susceptible to PVM infection. We have evaluated several rodent and primate cell lines for susceptibility to PVM infection, and detected highest virus titers from infection of the mouse monocyte-macrophage RAW 264.7 cell line. Additionally, virus replication in RAW 264.7 cells induces the synthesis and secretion of proinflammatory cytokines relevant to respiratory virus disease, including tumor necrosis factor-α (TNF-α), interferon-β (IFN-β), macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β) and the functional homolog of human IL-8, mouse macrophage inflammatory peptide-2 (MIP-2). Identification and characterization of a rodent cell line that supports the replication of PVM and induces the synthesis of disease-related proinflammatory mediators will facilitate studies of molecular mechanisms of viral pathogenesis that will complement and expand on findings from mouse model systems

Early-life viral infection and allergen exposure interact to induce an asthmatic phenotype in mice

<p>Abstract</p> <p>Background</p> <p>Early-life respiratory viral infections, notably with respiratory syncytial virus (RSV), increase the risk of subsequent development of childhood asthma. The purpose of this study was to assess whether early-life infection with a species-specific model of RSV and subsequent allergen exposure predisposed to the development of features of asthma.</p> <p>Methods</p> <p>We employed a unique combination of animal models in which BALB/c mice were neonatally infected with pneumonia virus of mice (PVM, which replicates severe RSV disease in human infants) and following recovery, were intranasally sensitised with ovalbumin. Animals received low-level challenge with aerosolised antigen for 4 weeks to elicit changes of chronic asthma, followed by a single moderate-level challenge to induce an exacerbation of inflammation. We then assessed airway inflammation, epithelial changes characteristic of remodelling, airway hyperresponsiveness (AHR) and host immunological responses.</p> <p>Results</p> <p>Allergic airway inflammation, including recruitment of eosinophils, was prominent only in animals that had recovered from neonatal infection with PVM and then been sensitised and chronically challenged with antigen. Furthermore, only these mice exhibited an augmented Th2-biased immune response, including elevated serum levels of anti-ovalbumin IgE and IgG₁as well as increased relative expression of Th2-associated cytokines IL-4, IL-5 and IL-13. By comparison, development of AHR and mucous cell change were associated with recovery from PVM infection, regardless of subsequent allergen challenge. Increased expression of IL-25, which could contribute to induction of a Th2 response, was demonstrable in the lung following PVM infection. Signalling via the IL-4 receptor α chain was crucial to the development of allergic inflammation, mucous cell change and AHR, because all of these were absent in receptor-deficient mice. In contrast, changes of remodelling were evident in mice that received chronic allergen challenge, regardless of neonatal PVM infection, and were not dependent on signalling via the IL-4 receptor.</p> <p>Conclusion</p> <p>In this mouse model, interaction between early-life viral infection and allergen sensitisation/challenge is essential for development of the characteristic features of childhood asthma, including allergic inflammation and a Th2-biased immune response.</p

Transient asymptomatic white matter lesions following Epstein-Barr virus encephalitis

We present the case of a patient with Epstein-Barr virus (EBV) encephalitis who developed abnormal white matter lesions during the chronic phases of the infection. A 2-year-old-boy was admitted for a 2 day history of decreased activity with ataxic gait. The results of the physical examination were unremarkable except for generalized lethargy and enlarged tonsils with exudates. Brain magnetic resonance imaging (MRI) at admission showed multiple high signal intensities in both basal ganglia and thalami. The result of EBV polymerase chain reaction (PCR) of the cerebral spinal fluid was positive, and a serological test showed acute EBV infection. The patient was diagnosed with EBV encephalitis and recovered fully without any residual neurologic complications. Subsequently, follow-up MRI at 5 weeks revealed extensive periventricular white matter lesions. Since the patient remained clinically stable and asymptomatic during the follow-up period, no additional studies were performed and no additional treatments were provided. At the 1-year follow-up, cranial MRI showed complete disappearance of the abnormal high signal intensities previously seen in the white matter. The patient continued to remain healthy with no focal neurologic deficits on examination. This is the first case of asymptomatic self-limited white matter lesions seen in serial MRI studies in a Korean boy with EBV encephalitis

Reducing respiratory syncytial virus (RSV) hospitalization in a lower-income country by vaccinating mothers-to-be and their households

Respiratory syncytial virus is the leading cause of lower respiratory tract infection among infants. RSV is a priority for vaccine development. In this study, we investigate the potential effectiveness of a two-vaccine strategy aimed at mothers-to-be, thereby boosting maternally acquired antibodies of infants, and their household cohabitants, further cocooning infants against infection. We use a dynamic RSV transmission model which captures transmission both within households and communities, adapted to the changing demographics and RSV seasonality of a low-income country. Model parameters were inferred from past RSV hospitalisations, and forecasts made over a 10-year horizon. We find that a 50% reduction in RSV hospitalisations is possible if the maternal vaccine effectiveness can achieve 75 days of additional protection for newborns combined with a 75% coverage of their birth household co-inhabitants (∼7.5% population coverage)