Despite decades of study, the immunobiology of paramyxoviruses such as RSV and parainfluenza remains poorly understood and a subject of intense controversy. This gap in knowledge has hampered the development of safe and effective vaccines and antiviral strategies. DCs are the most efficient antigen presenting cells (APCs) in inducing CTL responses to viruses. Interference with DC function, is a mechanism evolved by viruses to disrupt host defenses and survive immunological responses. The overall aim of this application is to define the in vitro interactions of human parainfluenza virus with dendritic cells (DCs). HPF3 infection can promote DC maturation while paradoxically interfering with their proper antigen presenting functions. Recent data suggest that the viral surface glycoproteins, the Hemagglutinin-Neuraminidase (HN) and the fusion protein (F), may mediate these effects. Our overall hypothesis is that interactions with DCs encountered shortly after infection of the respiratory mucosa are key determinants of HPF3 immunity and pathogenesis. Disruption of DC functions and impairment of cellular responses mediated by HN and F may contribute to the failure to establish long lasting protective immunity. Our first goal is to define the effects of the viral glycoproteins on differentiation and maturation of human DCs in vitro. We will dissect the specific contributions of HN and F and will determine whether particular functions of HN differentially affect this process. We will analyze how HPF3 infection -and exposure to the viral glycoproteins- influences migration and differentiation of monocytes into DCs in a tissue culture model of cell transmigration through endothelium. This model allows us to study how viral pathogens regulate DCs in a tissue setting, resembling more closely the natural conditions found in the mucosa of the human respiratory tract. Our second goal is to analyze HN and F immunoregulatory roles on the interaction of DCs with T cells in vitro. We will establish whether in vitro, HN and/or F account for the impairment of the stimulatory properties observed in HPF3 infected DCs by a direct cell contact-dependent mechanism. In addition, we will determine whether infection induces DCs to polarize T lymphocytes towards the expression of Th2 or Th1 type cytokines and whether HN and F are key determinants of this polarization. The definition of the viral glycoprotein(s) and their functions associated to the modulation of DCs will contribute to the ongoing effort for vaccine development through the generation of safer and more effective recombinant forms of HPF3. The identification of the viral domains important for HPF3-mediated immunoregulation will provide the target for novel antiviral pharmacologic strategies.
| Tan, Maria C; Battini, Lorenzo; Tuyama, Ana C et al. (2007) Characterization of human metapneumovirus infection of myeloid dendritic cells. Virology 357:1-9 |
