Influenza virus represents a major worldwide health problem and influenza pandemics are amongst the deadliest disease events for humans and many animal species. Although it is known that the innate immune system represents the first line of defense against the virus, the mechanism by which it is activated in response to influenza virus remains to be elucidated. This project aims to study the interaction between the innate immune system, particularly the complement system, and influenza virus. Four specific objectives are proposed: 1) Examine the role of complement C3 and complement receptors Cr1/2 in the development of memory B cells. We will characterize the humoral response to influenza in knock-out C3-/- and Cr1/2-/- mice to evaluate the long-term production of anti-flu antibody (Ab). We will use different methods, including serological techniques, EliSpot and FACS analyses, to characterize the neutralizing Ab titers and reveal the frequency of Ab-producing cells. 2) Examine the role of natural IgM in host innate and adaptive responses to influenza. We will try to identify clones of natural IgM that neutralize the virus, by screening a panel of B-1 cell hybridomas for virus binding and neutralization. The identification of the antigenic epitope recognized by the natural IgM could provide a conserved target for vaccine development. 3) Describe the trafficking of flu-specific B cells in influenza-infected mice. We will study the interaction between fluorescently-labeled virus and immune cells in the lymph node of transgenic mice. We will use intravital microscopy that allows real-time analysis of cellular trafficking within live animals. 4) Study how the viral RNA polymerase affects host innate immune pathways. We will study the effect of the viral polymerase on host signal transduction and gene expression. We will use two-hybrid screening, siRNA and microarray technology, to identify innate immune genes the expression of which is affected by the viral polymerase.
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