Candida auris is an emerging multidrug resistant fungal pathogen associated with high mortality rates, rapid global dissemination and resistance to conventional antifungal therapies. It’s remarkable ability to evade host immune responses and persist in health care setting demands the development of effective immunotherapeutic strategies. In this study, a reverse vaccinology and immunoinformatics based approach was employed to design a novel chimeric multi-epitope vaccine targeting surface expose N-terminal domain of the agglutinin like protein involved in host pathogen interactions. High affinity B-cell and T-cell (MHC class I and II) epitopes were identified and screened based on antigenicity, allergenicity, toxicity and population coverage. Selected epitopes were assembled using optimized linkers (EAAAK, AAY and GPGPG) along with an adjuvant to enhance immunogenicity and structural stability. Physicochemical characterization, structural validation, molecular docking with human Toll-like receptor 4 (TLR4), Normal Mode Analysis (NMA), immune simulation, codon optimization and in silico cloning into the pET28a+ vector were performed to evaluate the vaccine construct. The selected epitopes demonstrated a global population coverage of 97.31%. the final vaccine construct was predicted to highly antigenic, non-allergenic, structurally stable and soluble. Molecular docking analysis revealed strong and stable interactions between the vaccine construct and human TLR4, with a binding energy of − 906.1 kcal/mol. Normal Mode Analysis further supported the structural stability of the vaccine receptor complex. Immune simulations predicted robust primary and secondary responses characterized by elevated IgG and IgM antibodies along with a Th1-skewed cytokine profile dominated by IFN-γ and IL-2 expression. Codon optimization and in-silico cloning indicated favorable translational efficiency in the pET28a+ expression system. The designed chimeric multi epitope vaccine demonstrated promising immunogenic, structural and receptor binding properties against Candida auris. These findings suggest that the proposed vaccine construct may serve as a potential candidate for further experimental validation and future development of effective immunotherapeutic interventions against multidrug- resistant fungal infections.
Maha A. Aljumaa, Khaled Alzhrani, D. Fallatah et al.· Scientific Reports· 0 citations
Ethanol (EtOH)-induced gastric ulcer (GU) is a common model used to investigate mechanisms of mucosal injury and repair. Omeprazole (OMP) is a conventional anti-ulcer drug that effectively suppresses gastric acid secretion, but its efficacy may be enhanced by combining it with bioactive phytochemicals derived from a Glycyrrhiza glabra L. (licorice; LIQ) extract that possess potent antioxidant and anti-inflammatory properties. The aim of the present study was to evaluate the gastroprotective effects of OMP, LIQ extract, and their combined treatment against EtOH-induced GU in rats, focusing on modulation of TLR4/NF-κB/NLRP3 signaling and PI3K/AKT/mTOR gene expression. The ethanolic extract of LIQ was chemically characterized by LC-ESI-QTOF-MS/MS, and molecular docking was performed to evaluate the potential binding interactions of its major constituents with H+/K+-ATPase and COX-2. Thirty male Wistar rats were randomly allocated into control, ulcer (ULC), OMP-treated, LIQ-treated, and combined treatment groups. GU was induced by absolute EtOH. Subsequently, gastric pH, stomach coefficient, oxidative stress, inflammatory mediators, and PI3K, AKT, and mTOR gene expression were assessed. Histopathological and immunohistochemical analyses of mucosal architecture and the expression of TNF-α, caspase-3, and PCNA were performed. Coadministration of OMP and LIQ demonstrated the greatest gastroprotective activity, marked by a significant increase in gastric pH, restoration of antioxidant status, and substantial reduction in ROS, TLR4, NF-κB, and NLRP3 levels. The combined therapy significantly upregulated the expression of PI3K, AKT, and mTOR genes in comparison to ULC. Histopathological and immunohistochemical findings further demonstrated preservation of gastric mucosal integrity, reduced inflammatory cell infiltration, and decreased TNF-α, caspase-3, and PCNA immunoreactivity, indicating attenuation of mucosal injury. In conclusion, LIQ extract enhanced the gastroprotective effect of OMP against EtOH-induced GU, supporting its potential as an adjunct to OMP. Further studies are warranted to confirm the underlying molecular mechanisms.
Sahar Khateeb, Mody Albalawi, Amnah Obidan et al.· International Journal of Mol...· 0 citations
Human cytomegalovirus (CMV) is a globally widespread pathogen associated with significant morbidity in immunocompromised individuals. Despite its clinical importance, no licensed vaccine is currently available. This study aimed to design a rational multi-epitope vaccine candidate targeting CMV using an integrative approach combining immunoinformatics and structural biology. Viral proteins were screened to identify epitopes with high affinity for B cells, cytotoxic T cells (CTLs), and helper T cells (HTLs) using the Immune Epitope Database (IEDB). Selected epitopes were filtered according to their antigenicity and toxicity and then assembled into a chimeric construct incorporating an immunostimulatory adjuvant. The designed vaccine was evaluated for its physicochemical properties, validated by Ramchandran and ERRAT analyses. Molecular modeling demonstrated strong and stable interactions with key innate immunity receptors, including TLR7 and TLR9, interactions confirmed by molecular dynamics simulations. In silico immune simulation predicted a robust and durable immune response, characterized by high levels of IgM and IgG, as well as significant activation of CD4 + and CD8 + lymphocytes and innate immunity components. These results highlight the potential of the proposed multi-epitope construct as a promising vaccine candidate against HCMV. However, experimental validation is essential to confirm its immunogenicity, safety, and translational applicability.
O. P. Emmanuel, M. N. Y. Sandrine, Bilanda Danielle Claude et al.· Scientific Reports· 0 citations