Biology subjects

Nanjunadappa, R. H.

Publications and source records attributed to Nanjunadappa, R. H..

3 recordsLinked to original sources

bioRxiv2024

Advancing Tolerogenic Immunotherapy: A Multi-Epitope Vaccine Design Targeting the CYP2D6 Autoantigen in Autoimmune Hepatitis Through Immuno-Informatics

Juvenile autoimmune hepatitis (JAIH) is a rare autoimmune disorder affecting children, characterized by the immune systems misguided attack on liver cells, primarily targeting the CYP2D6 autoantigen. This repeated attack leads to hepatic inflammation, fibrosis, and eventual liver failure. Current therapeutic strategies predominantly rely on immunosuppressive agents or whole B cell depletion antibodies, which render patients susceptible to infections and cancers. Hence, there is an urgent need for antigen-specific therapies to mitigate the severity of autoimmune hepatitis. Tolerogenic antigens represent a promising avenue in immunotherapy, capable of dampening autoimmunity. Here, we present a novel computationally designed multi-epitope tolerogenic vaccine tailored to target CYP2D6, aimed at inducing tolerogenic dendritic cells (DCs) and halting autoimmune progression in JAIH patients. To validate our approach, we have developed a similar vaccine for testing in mouse models of JAIH. The selected tolerogenic epitopes exhibit antigenicity without allergenicity or toxicity, and specifically induce IL-10 production (restricted to CD4+ T cell epitopes). In our vaccine design, tolerogenic poly-epitopes are linked with Toll-like receptor (TLR)-4-agonist, the 50S ribosomal unit, and IL-10, effectively programming DCs towards a tolerogenic state. Molecular docking and dynamic simulations have confirmed strong binding affinities and stable complexes between the vaccine structures, TLR4 and IL-10 receptor alpha (IL-10RA), indicating their potential for in vivo DC interaction and programming. Consequently, this innovative vaccine approach demands further exploration through wet lab experiments to assess its tolerogenicity, safety, and efficacy, thereby laying the groundwork for potential application in clinical settings.

immunology↗

bioRxiv2024

Unleashing the Immune Arsenal: Development of Broad-spectrum Multiepitope Bluetongue Vaccine Targeting Conserved T Cell Epitopes of Structural Proteins

Bluetongue (BT) is a severe arboviral disease affecting sheep, cows, and other wild ruminants, caused by the Bluetongue virus (BTV). The virus has evolved into over 32 serotypes, rendering existing vaccines less effective. While the structural proteins of this virus represent promising targets for vaccine development, they unfortunately exhibit high amino acid polymorphism and are laden with numerous inhibitory epitopes. Structural proteins such as VP1 and VP7 are highly conserved and may contain epitopes capable of triggering cross-reactive cell-mediated immunity (CMI). In this study, we identified highly conserved MHC-I and -II-restricted T cell epitopes within VP1, VP5, and VP7 BTV proteins and developed an effective in silico-immuno-informatics-based broad-spectrum BT multiepitope vaccine for bovine and laboratory mouse systems. The conserved epitopes utilized in the vaccines are highly antigenic, non-allergenic, non-toxic, and capable of inducing IFN-{gamma} (only CD4+ T cell epitopes). Both mouse and bovine vaccines were tethered with Toll-like receptor (TLR)-4-agonist adjuvants, beta-defensin 2, and the 50s ribosomal unit to stimulate innate immunity for CMI development. Protein-protein docking analysis revealed strong binding affinities, while extensive 100-nanosecond molecular dynamics simulations indicated stable complexes between the vaccine structures and TLR4. Vaccination simulation studies demonstrated their ability to trigger proinflammatory responses. Therefore, these novel vaccine designs necessitate further exploration through wet lab experiments to evaluate their immunogenicity, safety, and effectiveness for practical deployment in livestock.

immunology↗

bioRxiv2023

Immuno-informatics Study Identifies Conserved T Cell Epitopes in Non-structural Proteins of Bluetongue Virus Serotypes: Formulation of Computationally Optimized Next-Generation Broad-spectrum Multiepitope Vaccine

Bluetongue (BT) is a significant arboviral disease affecting sheep, cattle, goats, and wild ruminants, posing serious economic challenges to livestock industry. Control efforts have been hampered by the existence of over 32 distinct BT virus (BTV) serotypes and the absence of broad-spectrum vaccines. Some key non-structural proteins of BTV, including NS1, NS2, and NS3, exhibit notable amino acid sequence conservation. Our findings reveal that mouse MHC class I (MHC-I) CD8+ T cell epitopes are highly conserved in NS1 and NS3, while MHC-II epitopes are prevalent in all the three non-structural NS 1-3 proteins. Similarly, both class I and II Bovine Leukocyte antigen-restricted CD8+ and CD4+ T cell epitopes are conserved within NS1, NS2, and NS3 proteins. To construct in silico broad-spectrum vaccine, we subsequently screened these conserved epitopes based on antigenicity, allergenicity, toxicity, and solubility. Modeling and Refinement of the 3D structure models of vaccine constructs were achieved using protein modeling web servers. Our analysis revealed promising epitopes that exhibit strong binding affinities with low energies against two TLR receptors (TLR3 and TLR4). To ensure atomic-level stability, we evaluated the docking complexes of epitopes and receptors through all-atom molecular dynamics simulations (MDS). Encouragingly, our 100 nanoseconds MDS showed stable complexes with minimal RMSF values. Our study offers valuable insights into these conserved T cell epitopes as promising candidates for a broad-spectrum BT vaccine. We therefore encourage for their evaluation in animal models and natural hosts to assess their immunogenicity, safety, and efficacy for field use in the livestock.

bioinformatics↗