The Global Distribution and Burden of Dengue and Japanese Encephalitis Co-Infection in Acute Encephalitis Syndrome

Dengue is widespread throughout the tropics globally in more than hundred countries and coincides with various climatic factors for co-infection with other flaviviral infections of the central nervous system (CNS). Dengue and Japanese encephalitis virus co-infection are highly prevalent, with diagnosis dilemma including significant mortality and morbidity in Southeast Asia. Both dengue and Japanese encephalitis transmissions intensify during the rainy season, during which the vector population increases. CNS involvement during dengue and Japanese encephalitis co-infection-associated acute encephalitis syndrome (AES) is still poorly understood, and therefore, there is a desperate need to understand the etiology, therapeutics, clinical management, and prevention of these tropically neglected diseases. AES can be differentiated from other etiologies of encephalopathy through considering its essential features: sudden onset of fever, cerebrospinal fluid (CSF) comprising inflammatory cells, magnetic resonance imaging (MRI)-based confirmation, and presence of pathogen or pathogen-specific antibodies. Complementary and alternative medicine is progressively being used globally and can be effective for the overall management of this co-infection

Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection

Japanese Encephalitis Virus (JEV) is a mosquito borne flavivirus infection. Transmission of JEV starts with the infected mosquito bite where human dermis layer act as the primary site of infection. Once JEV makes its entry into blood, it infects monocytes wherein the viral replication peaks up without any cell death and results in production of TNF-α. One of the most characteristics pathogenesis of JEV is the breaching of blood brain barrier (BBB). JEV propagation occurs in neurons that results in neuronal cell death as well as dissemination of virus into astrocytes and microglia leading to overexpression of proinflammatory cytokines. JEV infection results in host cells mediated secretion of various types of cytokines including type-1 IFN along with TNF-α and IFN-γ. Molecule like nitrous oxide (NO) exhibits antiviral activities against JEV infection and helps in inhibiting the viral replication by blocking protein synthesis and viral RNA and also in virus infected cells clearance. In addition, the antibody can also acts an opsonizing agent in order to facilitate the phagocytosis of viral particles, which is mediated by Fc or C3 receptor. This chapter focuses on the crucial mechanism of JEV induced pathogenesis including neuropathogenesis viral clearance mechanisms and immune escape strategies

Trends in Molecular Aspects and Therapeutic Applications of Drug Repurposing for Infectious Diseases

The pharmaceutical industry has undergone a severe economic crunch in antibiotic discovery research due to evolving bacterial resistance along with enormous time and money that gets consumed in de novo drug design and discovery strategies. Nevertheless, drug repurposing has evolved as an economically safer and excellent alternative strategy to identify approved drugs for new therapeutic indications. Virtual high throughput screening (vHTS) and phenotype-based high throughput screening (HTS) of approved molecules play a crucial role in identifying, developing, and repurposing old drug molecules into anti-infective agents either alone or in synergistic combination with antibiotic therapy. This chapter briefly explains the process of drug repurposing/repositioning in comparison to de novo methods utilizing vHTS and HTS technologies along with ‘omics- and poly-pharmacology-based drug repurposing strategies in the identification and development of anti-microbial agents. This chapter also gives an insightful survey of the intellectual property landscape on drug repurposing. Further, the challenges and applications of drug repurposing strategies in the discovery of anti-infective drugs are exemplified. The future perspectives of drug repurposing in the context of anti-infective agents are also discussed

High-Throughput Screening for Drug Discovery toward Infectious Diseases: Options and Challenges

The increase in the number of antibiotic-resistant microbial strains makes it evident to discover and develop newer efficacious anti-infective drugs. High-throughput screening (HTS) is a robust technology that plays a crucial role in identifying novel anti-infective lead compounds. This chapter briefly explains the role of virtual HTS (vHTS) and HTS technologies in lead identification using various categories of chemical libraries through structure-based drug design, ligand-based drug design, in vitro cell-based assay, and biochemical assay approaches involved in the process of drug design and discovery. The chapter also gives an insightful survey of the technologies such as fluorescence, luminescence, and atomic absorbance used for the detection of biological responses in the HTS bioassays. Applications of HTS, reverse pharmacology, current challenges, and future perspectives of HTS in the pharmaceutical and biotechnology industry are discussed in the context of anti-infective drug design, discovery, and development

Global Perspective of Novel Therapeutic Strategies for the Management of NeuroAIDS

Among Human immunodeficiency virus (HIV) infected individuals, around two-thirds of patients present with neuroAIDS, where HIV-associated neurocognitive disorders (HAND), and HIV-associated dementia (HAD) are the most prevailing neurological complications. The neuropathology of neuroAIDS can be characterized by the presence of HIV infected macrophages and microglia in the brain, with the formation of multinucleated giant cells. Global predominant subtypes of HIV-1 clade B and C infections influence the differential effect of immune and neuronal dysfunctions, leading to clade-specific clinical variation in neuroAIDS patient cohorts. Highly active antiretroviral therapy (HAART) enhances the survival rate among AIDS patients, but due to the inability to cross the Blood-Brain-Barrier (BBB), incidence of neuroAIDS during disease progression may be envisaged. The complex structure of blood-brain-barrier, and poor pharmacokinetic profile coupled with weak bio-distribution of antiretroviral drugs, are the principle barriers for the treatment of neuroAIDS. In the combined antiretroviral therapy (cART) era, the frequency of HAD has decreased; however the incidence of asymptomatic neurocognitive impairment (ANI) and minor neurocognitive disorder (MND) remains consistent. Therefore, several effective novel nanotechnology based therapeutic approaches have been developed to improve the availability of antiretroviral drugs in the brain for the management of neuroAIDS

Fabrication and Evaluation of Basil Essential Oil-Loaded Halloysite Nanotubes in Chitosan Nanocomposite Film and Its Application in Food Packaging

Increasing health concerns regarding the use of plasticware have led to the development of ecofriendly biodegradable packaging film from natural polymer and food additives. In the present study, basil essential oil (BEO) loaded halloysite nanotubes (HNTs) composite films were synthesized using a solution casting method. The effects of BEO and nanotube concentration on the mechanical, physical, structural, barrier, and antioxidant properties of films were evaluated. Scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier transform infrared (FTIR) demonstrated well-dispersed HNTs and BEO in tailored composite films. The addition of BEO in Chitosan (Ch) film caused darkening of the film color; furthermore, the incorporation of HNTs in varied concentrations increased opaqueness in Ch/BEO film. The Ch/BEO film, upon adding HNTs 5–30 wt%, exhibited a corresponding increase in the film thickness (0.108–0.135 mm) when compared with the Ch/BEO film alone (0.081 mm). The BEO-loaded HNTs composite films displayed reduced moisture content and characteristic barrier and UV properties. The Ch/BEO film with 15 wt% HNTs was found to have enhanced antioxidant activity. The Ch/BEO/HNTs composite also managed to prevent broccoli florets from losing weight and firmness during storage. The enhanced barrier and antioxidant qualities of the nanocomposite film suggest its potential application in the food processing and packaging sector. This is the first ever report on the fabrication of nanocomposite film using BEO and HNTs for food packaging. The low production cost and ecofriendly approach make the film acceptable for further research and commercialization thereafter

Antiviral Activity of Belladonna During Japanese Encephalitis Virus Infection via Inhibition of Microglia Activation and Inflammation Leading to Neuronal Cell Survival

Japanese encephalitis virus (JEV) is the main cause of viral encephalitis resulting in more than 68 000 clinical cases every year with case fatality rate as high as 30–40% for which no specific treatments are available. We have recently exhibited belladonna may be widely applicable for the treatment of various neurological disorders. Therefore, we developed a hydroalcoholic formulation of belladonna (B200) consisting of atropine and scopolamine and showed its antiviral efficacy against JEV infection. B200 treatment increases neuronal cell survival by reducing JEV induced cytopathic effects which were evident from significant reduction in necrotic cell population by flow-cytometry analysis and caspase 3 and 8 enzymatic activities. B200 treatment was found to reduce the intracellular JEV level observed by significant reduction in JEV–fluorescein isothiocyanate (FITC) expression in both neurons and microglia. Because microglia plays a crucial role in JEV pathogenesis, we further investigated the anti-JEV effects of B200 on human microglia cells and elucidated the mechanism of action by performing whole-transcriptome sequencing. Gene expression analysis revealed that B200 reduces the pro-apoptotic and inflammatory gene expression observed by significant reduction in BAD, BAX, CASP3, CASP8, IL1B, and CXCL10 and increase in IL10 responsive gene expression. Interestingly, our molecular docking analysis revealed that atropine and scopolamine interact with the His288 residue of NS3 protein, a crucial residue for RNA unwinding and ATPase activity that was further confirmed by degradation of NS3 protein. Drug likeness, ADME (absorption, distribution, metabolism, and excretion), and toxicity analysis further suggests that atropine and scopolamine both cross the blood–brain barrier, which is crucial for effective treatment of Japanese encephalitis (JE)