Regulation of Immunity to Respiratory Syncytial Virus by Dendritic Cells, Toll-Like Receptors, and Notch

The activation and maintenance of pulmonary viral disease is regulated at multiple levels and determined by the early innate response to the pathogenic stimuli. Subsequent activation events that rely directly and indirectly on the virus itself can alter the development and severity of the ensuing immunopathologic responses. In the present review we outline several interconnected mechanisms that rely on the early recognition of viral nucleic acid for the most appropriate anti-viral immune responses, including TLRs and Notch activation in DCs and T cells. Deviation or persistence of the immune response to respiratory viruses may impact significantly on the severity of the responses. While these mechanisms are likely similar in most respiratory viral infections, this review will focus on findings with respiratory syncytial virus (RSV) infections.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63262/1/vim.2007.0110.pd

The Balance between Plasmacytoid DC versus Conventional DC Determines Pulmonary Immunity to Virus Infections

Background: Respiratory syncytial virus (RSV) infects nearly all infants by age 2 and is a leading cause of broncialitis. RSV may employ several mechanisms to induce immune dysregulation, including dentritic cell (DC) modulation during the immune response to RSV. Methods and Findings: Expansion of cDC and pDC by Flt3L treatment promoted an anti-viral response with reduced pathophysiology characterized by decreased airway hyperreactivity, reduced Th2 cytokines, increased Th1 cytokines, and a reduction in airway inflammation and mucus overexpression. These protective aspects of DC expansion could be completely reversed by depleting pDCs during the RSV infections. Expansion of DCs by Flt3L treatment enhanced in CD8+ T cell responses, which was reversed by depletion of pDC. Conclusions: These results indicate that a balance between cDC and pDC in the lung and its lymph nodes is crucial for the outcome of a pulmonary infection. Increased pDC numbers induced by Flt3L treatment have a protective impact on the nature of the overall immune environment

A Novel Inactivated Intranasal Respiratory Syncytial Virus Vaccine Promotes Viral Clearance without Th2 Associated Vaccine-Enhanced Disease

Respiratory syncytial virus (RSV) is a leading cause of bronchiolitis and pneumonia in young children worldwide, and no vaccine is currently available. Inactivated RSV vaccines tested in the 1960's led to vaccine-enhanced disease upon viral challenge, which has undermined RSV vaccine development. RSV infection is increasingly being recognized as an important pathogen in the elderly, as well as other individuals with compromised pulmonary immunity. A safe and effective inactivated RSV vaccine would be of tremendous therapeutic benefit to many of these populations.In these preclinical studies, a mouse model was utilized to assess the efficacy of a novel, nanoemulsion-adjuvanted, inactivated mucosal RSV vaccine. Our results demonstrate that NE-RSV immunization induced durable, RSV-specific humoral responses, both systemically and in the lungs. Vaccinated mice exhibited increased protection against subsequent live viral challenge, which was associated with an enhanced Th1/Th17 response. In these studies, NE-RSV vaccinated mice displayed no evidence of Th2 mediated immunopotentiation, as has been previously described for other inactivated RSV vaccines.These studies indicate that nanoemulsion-based inactivated RSV vaccination can augment viral-specific immunity, decrease mucus production and increase viral clearance, without evidence of Th2 immune mediated pathology

B Cell Antigen Presentation Promotes Th2 Responses and Immunopathology during Chronic Allergic Lung Disease

Background: The role of B cells in allergic asthma remains undefined. One mechanism by which B cells clearly contribute to allergic disease is via the production of specific immunoglobulin, and especially IgE. Cognate interactions with specific T cells result in T cell help for B cells, resulting in differentiation and immunoglobulin secretion. Proximal to (and required for) T cell-dependent immunoglobulin production, however, is antigen presentation by B cells. While interaction with T cells clearly has implications for B cell function and differentiation, this study investigated the role that B cells have in shaping the T cell response during chronic allergic lung disease. Methodology/Principal Findings: In these studies, we used a clinically relevant mouse model of chronic allergic lung disease to study the role of B cells and B cell antigen presentation in this disease. In these studies we present several novel findings: 1) Lung B cells from chronically allergen challenged mice up-regulated MHC II and costimulatory molecules CD40, CD80 and CD86. 2) Using in vitro studies, B cells from the lungs of allergen challenged mice could present antigen to T cells, as assessed by T cell proliferation and the preferential production of Th2 cytokines. 3) Following chronic allergen challenge, the levels of Th2 cytokines IL-4 and IL-5 in the lungs and airways were significantly attenuated in B cell 2/2 mice, relative to controls. 4) B cell driven Th2 responses and mucus hyper secretion in the lungs were dependent upon MHC II expression by B cells. Conclusions/Significance: Collectively, these results provide evidence for antigen presentation as a novel mechanism b

Respiratory virus-induced TLR7 activation controls IL-17-associated increased mucus via IL-23 regulation

The response to respiratory syncytial virus (RSV), negative strand ssRNA virus, depends upon the ability to recognize specific pathogen-associated targets. In the current study, the role of TLR7 that recognizes ssRNA was examined. Using TLR7(-/-) mice, we found that the response to RSV infection in the lung was more pathogenic as assessed by significant increases in inflammation and mucus production. Although there appeared to be no effect of TLR7 deficiency on type I IFN, the pathology was associated with an alteration in T cell responses with increases in mucogenic cytokines IL-4, IL-13, and IL-17. Examination of dendritic cells from TLR7(-/-) animals indicated a preferential activation of IL-23 (a Th17-promoting cytokine) and a decrease in IL-12 production. Neutralization of IL-17 in the TLR7(-/-) mice resulted in a significant decrease in the mucogenic response in the lungs of the RSV-infected mice. Thus, without TLR7-mediated responses, an altered immune environment ensued with a significant effect on airway epithelial cell remodeling and goblet cell hyper/metaplasia, leading to increased mucus production

Role of B cell expression of MHC II in allergic disease.

<p>(A) Lung cytokines and (B) mucus-associated gene expression in the lungs of µMT/I-A^b−/− mice and µMT/WT mice. Mice with MHC II deficient (µMT/I-A^b−/− mice) or normal (µMT/WT ) B cells were generated using mixed bone marrow chimeras, and chronically challenged with allergen. The levels of cytokines in the lungs were determined from lung homogenate samples via Bioplex multiplex assay. The expression of mucus associated genes was assessed by real-time PCR using whole lung RNA. Bars represent the mean ±SEM of 4 mice per group. * = p<0.05 Similar results were obtained in two independent experiments.</p