4 research outputs found

    An Approach for a Synthetic CTL Vaccine Design against Zika Flavivirus Using Class I and Class II Epitopes Identified by Computer Modeling

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    The threat posed by severe congenital abnormalities related to Zika virus (ZKV) infection during pregnancy has turned development of a ZKV vaccine into an emergency. Recent work suggests that the cytotoxic T lymphocyte (CTL) response to infection is an important defense mechanism in response to ZKV. Here, we develop the rationale and strategy for a new approach to developing cytotoxic T lymphocyte (CTL) vaccines for ZKV flavivirus infection. The proposed approach is based on recent studies using a protein structure computer model for HIV epitope selection designed to select epitopes for CTL attack optimized for viruses that exhibit antigenic drift. Because naturally processed and presented human ZKV T cell epitopes have not yet been described, we identified predicted class I peptide sequences on ZKV matching previously identified DNV (Dengue) class I epitopes and by using a Major Histocompatibility Complex (MHC) binding prediction tool. A subset of those met the criteria for optimal CD8+ attack based on physical chemistry parameters determined by analysis of the ZKV protein structure encoded in open source Protein Data File (PDB) format files. We also identified candidate ZKV epitopes predicted to bind promiscuously to multiple HLA class II molecules that could provide help to the CTL responses. This work suggests that a CTL vaccine for ZKV may be possible even if ZKV exhibits significant antigenic drift. We have previously described a microsphere-based CTL vaccine platform capable of eliciting an immune response for class I epitopes in mice and are currently working toward in vivo testing of class I and class II epitope delivery directed against ZKV epitopes using the same microsphere-based vaccine.Flow Pharma, Inc.CNPq (Brazilian National Scientific Council)FAPESP (Sao Paulo State Research Foundation)Univ Sao Paulo, Sch Med, Lab Clin Immunol & Allergy LIM60, Sao Paulo, BrazilInst Invest Immunol III INCT, Sao Paulo, BrazilUniv Sao Paulo, Heart Inst Incor, Sch Med, Sao Paulo, BrazilFed Univ Sao Paulo UNIFESP EPM, Dept Microbiol Immunol & Parasitol, Sao Paulo, BrazilColumbia Univ, Dept Med, Sch Med, Endocrinol Div, New York, NY USAMorrow, AlexCiotlos, SerbanFlow Pharma Inc, Redwood City, CA 94063 USAMassachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USAUniv Fed Sao Paulo UNIFESP EPM, Dept Microbiol Immunol & Parasitol, Sao Paulo, BrazilFlow Pharma, Inc.CNPqFAPESP: 13/50302-3Web of Scienc

    Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types.

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    Cellular senescence is a driver of many age-related pathologies. There is an active search for pharmaceuticals termed senolytics that can mitigate or remove senescent cells in vivo by targeting genes that promote the survival of senescent cells. We utilized single-cell RNA sequencing to identify CRYAB as a robust senescence-induced gene and potential target for senolysis. Using chemical inhibitor screening for CRYAB disruption, we identified 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis, as a potent senolytic. We then validated 25HC as a senolytic in mouse and human cells in culture and in vivo in mouse skeletal muscle. Thus, 25HC represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver
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