The Emerging Role of Toll-Like Receptor-Mediated Neuroinflammatory Signals in Psychiatric Disorders and Acquired Epilepsy.

The new and evolving paradigms of psychiatric disorders pathogenesis are deeply inclined toward chronic inflammation that leads to disturbances in the neuronal networks of patients. A strong association has been established between the inflammation and neurobiology of depression which is mediated by different toll-like receptors (TLRs). TLRs and associated signalling pathways are identified as key immune regulators to stress and infections in neurobiology. They are a special class of transmembrane proteins, which are one of the broadly studied members of the Pattern Recognition Patterns family. This review focuses on summarizing the important findings on the role of TLRs associated with psychotic disorders and acquired epilepsy. This review also shows the promising potential of TLRs in immune response mediated through antidepressant therapies and TLRs polymorphism associated with various psychotic disorders. Moreover, this also sheds light on future directions to further target TLRs as a therapeutic approach for psychiatric disorders.

Taenia solium excretory secretory proteins (ESPs) suppresses TLR4/AKT mediated ROS formation in human macrophages via hsa-miR-125.

BACKGROUND: Helminth infections are a global health menace affecting 24% of the world population. They continue to increase global disease burden as their unclear pathology imposes serious challenges to patient management. Neurocysticercosis is classified as neglected tropical disease and is caused by larvae of helminthic cestode Taenia solium. The larvae infect humans and localize in central nervous system and cause NCC; a leading etiological agent of acquired epilepsy in the developing world. The parasite has an intricate antigenic make-up and causes active immune suppression in the residing host. It communicates with the host via its secretome which is complex mixture of proteins also called excretory secretory products (ESPs). Understanding the ESPs interaction with host can identify therapeutic intervention hot spots. In our research, we studied the effect of T. solium ESPs on human macrophages and investigated the post-translation switch involved in its immunopathogenesis. METHODOLOGY: T. solium cysts were cultured in vitro to get ESPs and used for treating human macrophages. These macrophages were studied for cellular signaling and miR expression and quantification at transcript and protein level. CONCLUSION: We found that T. solium cyst ESPs treatment to human macrophages leads to activation of Th2 immune response. A complex cytokine expression by macrophages was also observed with both Th1 and Th2 cytokines in milieu. But, at the same time ESPs modulated the macrophage function by altering the host miR expression as seen with altered ROS activity, apoptosis and phagocytosis. This leads to activated yet compromised functional macrophages, which provides a niche to support parasite survival. Thus T. solium secretome induces Th2 phenomenon in macrophages which may promote parasite's survival and delay their recognition by host immune system.

Recognition of immune reactive proteins as a potential multiepitope vaccine candidate of Taenia solium cysticerci through proteomic approach.

Metacestode, the larva of Taenia solium, is the causative agent for neurocysticercosis (NCC), which causes epilepsy. The unavailability of a vaccine against human NCC is a major cause for its widespread prevalence across the globe. Therefore, the development of a reliable vaccine against NCC is the need of the hour. Employing a combination of proteomics and immunoinformatics, we endeavored to formulate a vaccine candidate. The immune reactive cyst fluid antigens of T. solium were identified by immune-blotting two-dimensional gels with NCC patient's sera, followed by Matrix-assisted laser desorption-ionization analysis. We performed a detailed proteomic study of these immune reactive proteins by utilizing immune-informatics tools, identified the nontoxic, nonallergic, B-cell epitopes, and collected epitopes with the least sequence homology with human and other Taenia species. These epitopes were joined through linkers to construct a multiepitope vaccine. Different physiochemical parameters such as molecular weight (23.82 kDa), instability (39.91), and aliphatic index (49.61) were calculated to ensure the stability of the linked peptides vaccine. The vaccine demonstrated stable interactions with different immune receptors like Toll-like receptor 4 and IgG confirming that it will effectively stimulate the host immune response. We anticipate that our designed B-cell linear epitope-based vaccine will show promising results in in vitro and in vivo assays. This study provides a platform that would be useful to develop other suitable vaccine candidates to prevent helminthic neglected tropical diseases in near future.

Designing and development of multi-epitope chimeric vaccine against Helicobacter pylori by exploring its entire immunogenic epitopes: an immunoinformatic approach.

BACKGROUND: Helicobacter pylori is a prominent causative agent of gastric ulceration, gastric adenocarcinoma and gastric lymphoma and have been categorised as a group 1 carcinogen by WHO. The treatment of H. pylori with proton pump inhibitors and antibiotics is effective but also leads to increased antibiotic resistance, patient dissatisfaction, and chances of reinfection. Therefore, an effective vaccine remains the most suitable prophylactic option for mass administration against this infection. RESULTS: We modelled a multi-chimera subunit vaccine candidate against H. pylori by screening its secretory/outer membrane proteins. We identified B-cell, MHC-II and IFN-γ-inducing epitopes within these proteins. The population coverage, antigenicity, physiochemical properties and secondary structure were evaluated using different in-silico tools, which showed it can be a good and effective vaccine candidate. The 3-D construct was predicted, refined, validated and docked with TLRs. Finally, we performed the molecular docking/simulation and immune simulation studies to validate the stability of interaction and in-silico cloned the epitope sequences into a pET28b(+) plasmid vector. CONCLUSION: The multiepitope-constructed vaccine contains T- cells, B-cells along with IFN-γ inducing epitopes that have the property to generate good cell-mediated immunity and humoral response. This vaccine can protect most of the world's population. The docking study and immune simulation revealed a good binding with TLRs and cell-mediated and humoral immune responses, respectively. Overall, we attempted to design a multiepitope vaccine and expect this vaccine will show an encouraging result against H. pylori infection in in-vivo use.

Immunoinformatic Approaches for Vaccine Designing for Pathogens with Unclear Pathogenesis.

Designing a vaccine against a pathogen has been the toughest challenge to fight against any infectious diseases. To overcome this problem, use of artificial neural network with immuno-informatics is emerging as a front runner solution. For a successful designing of a potent vaccine, prediction of T-cell/B-cell epitopes, antigen processing and presentation analysis, antigenic potential analysis of epitopes, usages of linkers, population coverage, codon optimization, allergenicity assessment, toxicity prediction of construct, and finally protein-peptide docking for stability of vaccine are important steps. To achieve this, several bioinformatics software, tools and online web servers have been developed for each application, which have their own advantages and limitations. Scientists must evaluate these parameters and should take the decision to apply more suitable and precise servers for each analysis and prediction based on their accuracy, suitability, and robustness.