Grant: Project Grant

Viral infection imposes substantial threatens to public health. Vaccination provides an effective approach for protection because it may induce high affinity antibodies to neutralize virus infection. However, current vaccination strategies have several limitations, including 1) antibody responses induced by vaccines sometimes are short lived; 2) frequent mutations in viruses often help viruses to escape antibody protection; 3) current vaccinations cannot provide effective protection against different subtype or variant viruses. In these regards, there is an urgent need to develop a strategy that may induce to broadly neutralizing antibodies (bnAb) for an endured pan-viral protection. Recently, we found that ablation of transcription factor EB (TFEB) in B lymphocytes (termed the Tfeb-/- mutation) enabled mice to develop much prolonged, high titers of high affinity antibody responses relative to wild-type controls. We showed that TFEB controls the development of memory B cells (MBCs), a small group of lymphocytes that may develop into antibody producing cells. Using influenza viruses as a model, we showed that after immunization with one subtype of viral antigen Tfeb-/- mice produce not only higher amounts of antibodies against this subtype but also other subtype virus. This finding thus supports to test our hypothesis that targeting TFEB can be a general strategy to enhance pan-vaccination. Here, by combining the expertise of Gu Lab in immunology and Wu Lab in structure-based drug design and medicinal chemistry, we will determine whether targeting TFEB can enhance vaccination efficacy against infection of various subtype viruses. We will also elucidate molecular mechanisms by which TFEB regulates MBCs and develop a novel chemical TFEB inhibitor to enhance pan-vaccination in human. This project will bring new insights into our understanding of immune responses following vaccination and identify a novel chemical agent to enhance vaccination.