Destruction of the architectural and subsequently the functional integrity of the lung following pulmonary viral infections is attributable to both the extent of pathogen replication and to host-generated inflammation. In addition, because antigenically distinct lung viruses are constantly emerging, there is a need to develop safe, broad spectrum immunoprophylactic strategies capable of both enhancing protective immune responses in the lung and limiting immune-mediated lung damage in response to pulmonary viral infection. Here we utilize a heat-shock protein cage nanoparticle (Hs-PCN) to significantly accelerate clearance of diverse respiratory viruses after primary infection and also modulate the host response resulting in less lung damage. Mice pretreated with Hs-PCN, independent of any specific viral antigens, were protected against both sub-lethal and lethal doses of two different influenza viruses; a mouse-adapted SARS-coronavirus, or mouse pneumovirus. The enhanced protection is associated with the ability of the Hs-PCN treatment to cause the development of inducible bronchus-associated lymphoid tissue (iBALT) in the lung and is also dependent on CD4+ T cell, B cell, MyD88 and type I IFN receptor-signalling, but not on the presence of CD8+ T cells. The efficacy of the Hs- PCN is augmented by the presence of an adjuvant and protection is effective against viruses but not lung bacteria. Protection appears to be the result of augmented innate as well as adaptive immunity. In addition, Hs- PCN-treated mice have a high constitutive production of IL-10 in their lungs and have a significantly attenuated lung IFN-γ, TNF-α and IL-6 response upon influenza infection. The Hs-PCNs are nearly completely cleared from the host within 24 hours and do not cause detectable toxicity to the lung. The iBALT that Hs-PCN induces is similar to the iBALT induced naturally with pulmonary virus infection including its transitory presence. Mice with Hs-PCN-induced iBALT have no adverse effects and displayed attenuated airway hyperreactivity and allergic inflammation in response to antigenic challenge in a mouse asthma model, suggesting that the presence of iBALT does not predispose mice to allergic disease. The Hs-PCN remains active after lyophilization, can be effectively delivered by aerosol exposure, and is easily engineered for tissue- or cellspecific targeting. Thus, we hypothesize that Hs-PCN treatment can be developed as a broad spectrum immunoprophylactic treatment that through iBALT formation augments both local innate and primary adaptive immune responses in the lungs against a broad spectrum of respiratory viruses. The following specific aims will address this hypothesis. 1. To determine how Hs-PCN treatment enhances the adaptive primary immune response making mice more resistant to primary pulmonary viral infection. 2. To determine how Hs-PCN treatment enhances innate immunity to respiratory viruses. 3. To determine how Hs-PCN causes induction of iBALT. 4. To optimize Hs-PCN efficacy with addition of adjuvants and to determine how adjuvants synergize with Hs-PCN to enhance resistance to respiratory viruses. 5. To further develop the immunoprophylactic product potential of Hs-PCN. Thus, PCN-induced protection represents a novel immunoprophylactic strategy in which treatment with one compound protects against a broad spectrum of lung viruses by augmenting both innate and primary adaptive immune responses resulting in less disease through not only enhanced viral clearance, but also modification of the host response making it less damaging.
Development of specific vaccines is costly and takes many years, making vaccine development to the many lung viruses that emerge every year impractical. We have developed a new immunoprophylactic strategy based on treatment with a protein cage nanoparticle that is effective against a broad range of viruses by inducing tissue in the lungs that enhances the immune response to any virus. We propose to determine how this strategy works and to optimize the effectiveness of these nanoparticles in protecting against viruses.
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