Innate immune signals modulate antiviral and polyreactive antibody responses during severe respiratory syncytial virus infection.

Antiviral antibody production during respiratory syncytial virus (RSV) infection in infants is poorly understood. To characterize local B lymphocyte responses, lung tissue and secretions from infants with RSV bronchiolitis were analyzed for innate B cell-stimulating factors and antiviral antibodies. In lung tissues of infants with fatal RSV bronchiolitis, CD20(+) lymphocytes and IgM-positive, IgG-positive, and IgA-positive plasma cells were prominent but CD4(+) T lymphocytes were not. Type I interferon-induced proteins and B cell tropic factors, including B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL), were colocalized in infected epithelium. In nasopharyngeal secretions from infants who survived RSV infection, class-switched antiviral and antinucleosomal antibodies were detected at presentation and correlated with BAFF and APRIL levels. Expression of APRIL and antiviral antibodies of IgA and IgM but not IgG isotype predicted better oxygen saturation. We conclude that B lymphocyte-stimulating factors derived from infected epithelium are primary determinants of the mucosal antibody response in infant RSV bronchiolitis.

Severe human lower respiratory tract illness caused by respiratory syncytial virus and influenza virus is characterized by the absence of pulmonary cytotoxic lymphocyte responses.

BACKGROUND: Respiratory syncytial virus (RSV) and influenza virus are common causes of infantile lower respiratory tract infection (LRTI). It is widely believed that both viral replication and inappropriately enhanced immune responses contribute to disease severity. In infants, RSV LRTI is known to be more severe than influenza virus LRTI. METHODS: We compared cytokines and chemokines in secretions of infants surviving various forms of respiratory illness caused by RSV or influenza viruses, to determine which mediators were associated with more-severe illness. We analyzed lung tissue from infants with fatal cases of RSV and influenza virus LRTI to determine the types of inflammatory cells present. Autopsy tissues were studied for the lymphotoxin granzyme and the apoptosis marker caspase 3. RESULTS: Quantities of lymphocyte-derived cytokines were minimal in secretions from infants with RSV infection. Concentrations of most cytokines were greater in influenza virus, rather than RSV, infection. Lung tissues from infants with fatal RSV and influenza virus LRTI demonstrated an extensive presence of viral antigen and a near absence of CD8-positive lymphocytes and natural killer cells, with marked expression of markers of apoptosis. CONCLUSIONS: Severe infantile RSV and influenza virus LRTI is characterized by inadequate (rather than excessive) adaptive immune responses, robust viral replication, and apoptotic crisis.

A comparison of epidemiologic and immunologic features of bronchiolitis caused by influenza virus and respiratory syncytial virus.

We studied epidemiologic and immunologic factors in infants with bronchiolitis caused by influenza virus. The proportion of these infants who were male and who had an immediate family member with a history of asthma was similar to that of a control group of infants with respiratory syncytial virus (RSV) bronchiolitis. In subjects with influenza virus infection, concentrations of the beta chemokine macrophage inflammatory protein-1alpha (MIP-1alpha), but not other beta chemokines, in nasopharyngeal secretions (NPS) were greater among infants with more severe, hypoxic bronchiolitis than in subjects with mild, nonhypoxic bronchiolitis, or upper respiratory tract infection alone. Quantities of MIP-1alpha were also correlated with lower values of oxygen saturation. These findings point out epidemiologic and immunologic similarities between bronchiolitis caused by influenza and RSV, and suggest that host factors are more important than the nature of the infecting virus in the development of severe forms of bronchiolitis caused by influenza and RSV.

Production of interferon gamma in respiratory syncytial virus infection of humans is not associated with interleukins 12 and 18.

In order to understand early events in the immune response to respiratory syncytial virus (RSV) infection, we studied the presence of various chemokines and cytokines in respiratory secretions of human infants with RSV infection. Interferon gamma (IFNgamma) was present in 30/39 (76.9%) subjects tested, but the IFNgamma-inducing cytokines interleukin (IL)12 and IL18 were detectable in 6/40 (15%) and 11/38 (28.9%) subjects, respectively. Quantities of IL12 and IL18 did not correlate with those of IFNgamma. IL18, but neither IFNgamma nor IL12 was found in significantly greater concentrations in subjects with mild, nonhypoxic forms of bronchiolitis than in those with upper respiratory illness alone or hypoxic bronchiolitis. The findings suggest that IFNgamma may be induced independently of the activities of IL12 and IL18 during RSV infection. Immune responses characterized by relatively greater release of IL18 may be associated with milder forms of bronchiolitis.

Zileuton reduces respiratory illness and lung inflammation, during respiratory syncytial virus infection, in mice.

To determine the role of leukotrienes in a mouse model of respiratory syncytial virus (RSV) infection, we correlated the quantity of leukotrienes in lung lavage fluids of infected mice with respiratory rates and measures of outflow obstruction and then determined the effects of the leukotriene inhibitor zileuton on clinical features and lung function. Concentrations of leukotrienes were correlated with both increasing respiratory rates and the degree of prolongation of expiratory time. Administration of zileuton 1 day before infection and through day 5 after infection markedly reversed airway constriction, reduced numbers of inflammatory cells in the lung, and prevented the weight loss associated with infection. Leukotrienes appear to contribute substantially to the pathogenesis of RSV-related disease.