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Dengue fever is an mosquito-borne illness caused by any one of the four different dengue virus (DENV) serotypes (1-4) and manifests in the form of symptoms ranging from mild or asymptomatic to severe disease with vascular leakage, leading to shock, and viral hemorrhagic syndrome. Increased risk of severe disease occurs during secondary infection with a virus serotype distinct from that of prior dengue infection. This occurs by antibody dependent enhancement (ADE) of infection, wherein sub-neutralizing antibodies against the virus particles opsonize dengue virus entry via formation of immune complexes that interact with fragment crystallizable gamma receptors (FcγR) on monocytes, dendritic cells, and macrophages. The ADE phenomenon has two components: Extrinsic and Intrinsic ADE. While extrinsic ADE contributes to enhanced virus entry, intrinsic ADE results in heightened virus production by inhibition of type1 interferon and activation of interleukin-10 biosynthesis, thereby favoring a Th2 type immune response. Intrinsic ADE has greater contribution in enhancing Dengue replication as compared to extrinsic ADE. Detailed elucidation of intrinsic ADE during secondary dengue infection can increase our understanding of DENV-pathogenesis and aid in the development of host-targeting antivirals. Here we review literature focusing on intrinsic factors contributing to severe dengue pathology and suggest possible avenues for further research.

Interferons (IFNs) are multifaceted proteins that play pivotal roles in orchestrating robust antiviral immune responses and modulating the intricate landscape of host immunity. The major signaling pathway activated by IFNs is the JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway, which leads to the transcription of a battery of genes, collectively known as IFN-stimulated genes (ISGs). While the well-established role of IFNs in coordinating the innate immune response against viral infections is widely acknowledged, recent years have provided a more distinct comprehension of the functional significance attributed to non-canonical, IFN-independent induction of ISGs. In this review, we summarize the non-conventional signaling pathways of ISG induction. These alternative pathways offer new avenues for developing antiviral strategies or immunomodulation in various diseases.

Polycystic ovary syndrome (PCOS) is the most common cause of infertility in reproductive-age women, and its etiology and exact treatment are not yet established. Adropin is a unique hepatokine involved in maintaining energy homeostasis, and its level has been reported to decline in serum and follicular fluid of PCOS women. Thus, present study was designed to investigate the effect of adropin on hormonal and reproductive abnormalities in PCOS mice. PCOS was induced in adult mice by administering letrozole (6 mg/kg body weight) orally for 21 days. PCOS mice were subsequently treated with adropin (450 nmol/kg body weight) for 15 days. Adropin treatment drastically decreased serum testosterone by suppressing the ovarian expression of 17β-HSD in PCOS mice. It also improved the follicular proliferation and survival by enhancing the ovarian expression of PCNA and BCL2 and suppressing the BAX, cleaved caspase 3, and TUNEL-positive cells in PCOS mice. Most of the effects of adropin are comparable to metformin (current PCOS treatment). Notably, adropin shows more efficacy than metformin in treating reproductive abnormalities in PCOS mice, as evidenced by early regularization of cyclicity and enhanced ovarian expression of 3β-HSD and aromatase proteins. Thus, adropin may be an alternative therapeutic option for managing PCOS.

Zika virus (ZIKV) is spreading rapidly into regions around the world where other flaviviruses, such as dengue virus (DENV) and West Nile virus (WNV), are endemic. Antibody-dependent enhancement has been implicated in more severe forms of flavivirus disease, but whether this also applies to ZIKV infection is unclear. Using convalescent plasma from DENV- and WNV-infected individuals, we found substantial enhancement of ZIKV infection in vitro that was mediated through immunoglobulin G engagement of Fcγ receptors. Administration of DENV- or WNV-convalescent plasma into ZIKV-susceptible mice resulted in increased morbidity—including fever, viremia, and viral loads in spinal cord and testes—and increased mortality. Antibody-dependent enhancement may explain the severe disease manifestations associated with recent ZIKV outbreaks and highlights the need to exert great caution when designing flavivirus vaccines.

Alzheimer's disease (AD) is a major neurodegenerative disease, affecting more than two-third cases of dementia in the world. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used anti-inflammatory analgesic agents, representing 7.7% of worldwide prescriptions, of which 90% are in patients over 65 years old. Based on mixed findings by different randomized clinical trials (RCTs), a systematic review and meta-analysis were conducted to develop a better understanding of the protective role of NSAIDs in AD. Database search was Pubmed, WebScience, and Embase. RCTs investigating the effect of NSAIDs on AD or test scores assessing cognitive function in people without AD at baseline were included. Two indicators were the Mini-Mental State Examination (MMSE) Score and Hazard Ratio. 09 studies were included in the present Meta-analysis. For the MMSE score difference, the pooled effect size was − 0.06 (−0.22, 0.10) which was not statistically significant (P value = 0.47). For the MMSE score, the pooled effect size was − 0.0036(−0.0320, 0.0248), which was also not statistically significant (P value = 0.87). For Hazard Ratio (HR), the pooled HR calculated using the random effect model was 1.20 (95% CI: 0.95, 1.51), which was not statistically significant (P value = 0.15). Present meta-analysis shows that NSAIDs, in general, are not effective in the treatment of AD. They also have no protective effect against the development of AD on their sustained use.

Flaviviruses comprise several important human pathogens which cause significant morbidity and mortality worldwide. Like any other virus, they are obligate intracellular parasites. Therefore, studying the host cellular factors that promote or restrict their replication and pathogenesis becomes vital. Since inhibiting the host dependency factors or activating the host restriction factors can suppress the viral replication and propagation in the cell, identifying them reveals potential targets for antiviral therapeutics. Clustered regularly interspaced short palindromic repeats (CRISPR) technology has provided an effective means of producing customizable genetic modifications and performing forward genetic screens in a broad spectrum of cell types and organisms. The ease, rapidity, and high reproducibility of CRISPR technology have made it an excellent tool for carrying out genome-wide screens to identify and characterize viral host dependency factors systematically. Here, we review the insights from various Genome-wide CRISPR screens that have advanced our understanding of Flavivirus-Host interactions.

Zika virus (ZIKV) is a mosquito borne flavivirus, which was a neglected tropical pathogen until it emerged and spread across the Pacific Area and the Americas, causing large human outbreaks associated with fetal abnormalities and neurological disease in adults. The factors that contributed to the emergence, spread and change in pathogenesis of ZIKV are not understood. We previously reported that ZIKV evades cellular antiviral responses by targeting STAT2 for degradation in human cells. In this study, we demonstrate that Stat2-/- mice are highly susceptible to ZIKV infection, recapitulate virus spread to the central nervous system (CNS), gonads and other visceral organs, and display neurological symptoms. Further, we exploit this model to compare ZIKV pathogenesis caused by a panel of ZIKV strains of a range of spatiotemporal history of isolation and representing African and Asian lineages. We observed that African ZIKV strains induce short episodes of severe neurological symptoms followed by lethality. In comparison, Asian strains manifest prolonged signs of neuronal malfunctions, occasionally causing death of the Stat2-/- mice. African ZIKV strains induced higher levels of inflammatory cytokines and markers associated with cellular infiltration in the infected brain in mice, which may explain exacerbated pathogenesis in comparison to those of the Asian lineage. Interestingly, viral RNA levels in different organs did not correlate with the pathogenicity of the different strains. Taken together, we have established a new murine model that supports ZIKV infection and demonstrate its utility in highlighting intrinsic differences in the inflammatory response induced by different ZIKV strains leading to severity of disease. This study paves the way for the future interrogation of strain-specific changes in the ZIKV genome and their contribution to viral pathogenesis.

The SARS-CoV-2 non-structural protein 1 (Nsp1) contains an N-terminal domain and C-terminal helices connected by a short linker region. The C-terminal helices of Nsp1 (Nsp1-C-ter) from SARS-CoV-2 bind in the mRNA entry channel of the 40S ribosomal subunit and blocks mRNA entry, thereby shutting down host protein synthesis. Nsp1 suppresses host immune function and is vital for viral replication. Hence, Nsp1 appears to be an attractive target for therapeutics. In this study, we have in silico screened Food and Drug Administration (FDA)-approved drugs against Nsp1-C-ter. Among the top hits obtained, montelukast sodium hydrate binds to Nsp1 with a binding affinity (K D ) of 10.8 ± 0.2 µM in vitro. It forms a stable complex with Nsp1-C-ter in simulation runs with –95.8 ± 13.3 kJ/mol binding energy . Montelukast sodium hydrate also rescues the inhibitory effect of Nsp1 in host protein synthesis, as demonstrated by the expression of firefly luciferase reporter gene in cells. Importantly, it shows antiviral activity against SARS-CoV-2 with reduced viral replication in HEK cells expressing ACE2 and Vero-E6 cells. We, therefore, propose montelukast sodium hydrate can be used as a lead molecule to design potent inhibitors to help combat SARS-CoV-2 infection.

Background: Ictal cognitive assessments carried out in Epilepsy Monitoring Units (EMUs) have been standardized on the Western population which is unable to capture the socioeducational differences present in the Indian population. Objective: This study focuses on modifying and rearranging components of the International League Against Epilepsy's Ictal Testing Battery (ILAE-ITB) in a local setting at an Indian epilepsy center. Methods: The Customizable Ictal Testing Battery (C-ITB) was modified using ILAE-ITB by enabling variable order of item administration, prioritizing items testing the suspect seizure onset region. The consenting participants were assessed using both batteries. The diagnostic performance and localization ability of C-ITB were also measured. Results: 116 patients with drug-resistant epilepsy were recruited. Association between both batteries was statistically significant using the Chi-square/Fisher's exact test (P value < 0.001). The Cohen's kappa was 85.6 and the sensitivity and specificity indices were 100% and 80% respectively. C-ITB demonstrated an inherent validity of 94.8%. There was a significant association between the localization demonstrated by C-ITB and vEEG, MRI. The localization capabilities of C-ITB and ILAE-ITB were comparable. Significance: C-ITB is a comprehensive measure of ictal functioning adapted according to the requirements of Indian patients with epilepsy and might facilitate further research into the domain of ictal response deficits.

Induction of vast transcriptional programs is a central event of innate host responses to viral infections. Here we report a transcriptional program with potent antiviral activity, driven by E74-like ETS transcription factor 1 (ELF1). Using microscopy to quantify viral infection over time, we found that ELF1 inhibits eight diverse RNA and DNA viruses after multi-cycle replication. Elf1 deficiency results in enhanced susceptibility to influenza A virus infections in mice. ELF1 does not feed-forward to induce interferons, and ELF1's antiviral effect is not abolished by the absence of STAT1 or by inhibition of JAK phosphorylation. Accordingly, comparative expression analyses by RNA-seq revealed that the ELF1 transcriptional program is distinct from interferon signatures. Thus, ELF1 provides an additional layer of the innate host response, independent from the action of type I interferons.