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Frontiers in Neurology 2023Japanese encephalitis (JE) is a severe infectious disease affecting the central nervous system (CNS). However, limited risk factors have been identified for predicting...
Japanese encephalitis (JE) is a severe infectious disease affecting the central nervous system (CNS). However, limited risk factors have been identified for predicting poor prognosis (PP) in adults with severe JE. In this study, we analyzed clinical data from thirty-eight severe adult JE patients and compared them to thirty-three patients without organic CNS disease. Machine learning techniques employing branch-and-bound algorithms were used to identify clinical risk factors. Based on clinical outcomes, patients were categorized into two groups: the PP group (mRs ≥ 3) and the good prognosis (GP) group (mRs ≤ 2) at three months post-discharge. We found that the neutrophil-to-lymphocyte ratio (NLR) and the percentage of neutrophilic count (N%) were significantly higher in the PP group compared to the GP group. Conversely, the percentage of lymphocyte count (L%) was significantly lower in the PP group. Additionally, elevated levels of aspartate aminotransferase (AST) and blood glucose were observed in the PP group compared to the GP group. The clinical parameters most strongly correlated with prognosis, as indicated by Pearson correlation coefficient (PCC), were NLR (PCC 0.45) and blood glucose (PCC 0.45). In summary, our findings indicate that increased serum NLR, N%, decreased L%, abnormal glucose metabolism, and liver function impairment are risk factors associated with poor prognosis in severe adult JE patients.
PubMed: 38178886
DOI: 10.3389/fneur.2023.1242317 -
EMBO Molecular Medicine Jan 2024Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to...
Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to induce autophagy for antiviral effects. Four drugs were tested in the JE mouse model based on in vitro protective effects on neuronal cell death, inhibition of viral replication, and anti-inflammatory effects. The antipsychotic phenothiazines Methotrimeprazine (MTP) & Trifluoperazine showed a significant survival benefit with reduced virus titers in the brain, prevention of BBB breach, and inhibition of neuroinflammation. Both drugs were potent mTOR-independent autophagy flux inducers. MTP inhibited SERCA channel functioning, and induced an adaptive ER stress response in diverse cell types. Pharmacological rescue of ER stress blocked autophagy and antiviral effect. MTP did not alter translation of viral RNA, but exerted autophagy-dependent antiviral effect by inhibiting JEV replication complexes. Drug-induced autophagy resulted in reduced NLRP3 protein levels, and attenuation of inflammatory cytokine/chemokine release from infected microglial cells. Our study suggests that MTP exerts a combined antiviral and anti-inflammatory effect in JEV infection, and has therapeutic potential for JE treatment.
Topics: Animals; Mice; Encephalitis Virus, Japanese; Methotrimeprazine; Neuroinflammatory Diseases; Encephalitis, Japanese; Antiviral Agents; Autophagy; Anti-Inflammatory Agents
PubMed: 38177535
DOI: 10.1038/s44321-023-00014-w -
Nature Communications Jan 2024Cytoskeleton is extensively recruited by flaviviruses for their infection. In this study, we uncovered an essential role of a nuclear membrane protein, SAD1/UNC84 domain...
Cytoskeleton is extensively recruited by flaviviruses for their infection. In this study, we uncovered an essential role of a nuclear membrane protein, SAD1/UNC84 domain protein 2 (SUN2) linking cytoskeleton and nucleoskeleton in the flavivirus replication. CRISPR/Cas9-mediated knockout of SUN2, but not SUN1, significantly reduces the replication of Zika virus (ZIKV), dengue virus (DENV), and Japanese encephalitis virus (JEV). In contrast, SUN2 does not affect the infection of non-flaviviridae RNA viruses. All three regions of SUN2 are required for its proviral effect. Mechanistically, SUN2 facilitates rearrangement of cytoskeleton and formation of replication organelles induced by viral infection, and hence promotes viral RNA synthesis. SUN2 is required for the interaction between cytoskeleton actin and ZIKV nonstructural protein 1 (NS1). Expression of dominant negative Nesprin-1 and Nesprin-2, which connect SUN2 to cytoskeleton proteins, alleviates the interaction between actin and NS1 and reduces viral replication levels. In a neonatal mouse infection model, SUN2 knockout dramatically alleviates the in vivo ZIKV replication and development of neuropathology. This work elucidates that recruitment of cytoskeleton proteins by flavivirus is coordinated by nuclear membrane proteins SUN2 and Nesprins, providing evidence for a link between nuclear membrane proteins and flavivirus infection.
Topics: Animals; Mice; Actins; Cytoskeleton; Membrane Proteins; Viral Nonstructural Proteins; Virus Replication; Zika Virus; Zika Virus Infection
PubMed: 38177122
DOI: 10.1038/s41467-023-44580-6 -
Nature Communications Jan 2024To curb viral epidemics and pandemics, antiviral drugs are needed with activity against entire genera or families of viruses. Here, we develop a cell-based multiplex...
To curb viral epidemics and pandemics, antiviral drugs are needed with activity against entire genera or families of viruses. Here, we develop a cell-based multiplex antiviral assay for high-throughput screening against multiple viruses at once, as demonstrated by using three distantly related orthoflaviviruses: dengue, Japanese encephalitis and yellow fever virus. Each virus is tagged with a distinct fluorescent protein, enabling individual monitoring in cell culture through high-content imaging. Specific antisera and small-molecule inhibitors are employed to validate that multiplexing approach yields comparable inhibition profiles to single-virus infection assays. To facilitate downstream analysis, a kernel is developed to deconvolute and reduce the multidimensional quantitative data to three cartesian coordinates. The methodology is applicable to viruses from different families as exemplified by co-infections with chikungunya, parainfluenza and Bunyamwera viruses. The multiplex approach is expected to facilitate the discovery of broader-spectrum antivirals, as shown in a pilot screen of approximately 1200 drug-like small-molecules.
Topics: Humans; Antiviral Agents; High-Throughput Screening Assays; Viruses; Virus Diseases; Cell Culture Techniques; Virus Replication
PubMed: 38168091
DOI: 10.1038/s41467-023-44339-z -
Open Forum Infectious Diseases Dec 2023The objective of this study was to evaluate the impact of the FilmArray meningitis/encephalitis panel (FAME) on length of stay (LOS) and duration of antimicrobial...
BACKGROUND
The objective of this study was to evaluate the impact of the FilmArray meningitis/encephalitis panel (FAME) on length of stay (LOS) and duration of antimicrobial treatment in children and adults in a Japanese community hospital.
METHODS
This retrospective cohort study was conducted in Japan between January 2016 and December 2022. We included hospitalized patients with cerebrospinal fluid (CSF) samples and those aged <2 months or who had 5 or more white blood cells/μL in the CSF. To compare the days of therapy (DOT) and LOS between the pre-FAME and FAME periods, multivariate Poisson regression analyses were conducted without an offset term.
RESULTS
The number of cases undergoing pathogen-specific polymerase chain reaction increased from 3.7% in the pre-FAME period to 57.5% in the FAME period ( < .001). The pathogen identification rate also increased during the FAME period, from 0.4% to 18.7% ( < .001). While the antibacterial DOT was not statistically different between the 2 periods (adjusted rate ratio [aRR], 1.06 [95% confidence interval {CI}, 1.00-1.13]; = .063]), the antiviral DOT was significantly shorter in the FAME period (aRR, 0.80 [95% CI, .71-.89]; < .001).
CONCLUSIONS
This study revealed a significant reduction in antiviral use during the FAME period, whereas LOS and antibacterial use did not decrease. Given the possibility of factors (eg, the COVID-19 pandemic) affecting the epidemiology of meningitis and encephalitis, the indications and impact of the FAME test should be evaluated with continuous monitoring of the epidemiology of meningitis and encephalitis and its clinical impact.
PubMed: 38156045
DOI: 10.1093/ofid/ofad634 -
PLoS Neglected Tropical Diseases Dec 2023Transmission intensity for mosquito-borne diseases are highly heterogenous and multi-factorial. Understanding risk factors associated to disease transmission allow the...
BACKGROUND
Transmission intensity for mosquito-borne diseases are highly heterogenous and multi-factorial. Understanding risk factors associated to disease transmission allow the optimization of vector control. This study sets out to understand and compare the combined anthropogenic and environmental risk factors of four major mosquito-borne diseases, dengue, malaria, chikungunya and Japanese encephalitis in Thailand.
METHODS
An integrated analysis of mosquito-borne diseases, meteorological and ambient air pollutants of 76 provinces of Thailand was conducted over 2003-2021. We explored the use of generalized linear models and generalized additive models to consider both linear and non-linear associations between meteorological factors, ambient air pollutants and mosquito-borne disease incidence. Different assumptions on spatio-temporal dependence and nonlinearity were considered through province-specific and panel models, as well as different spline functions. Disease-specific model evidence was assessed to select best-fit models for epidemiological inference downstream.
RESULTS
Analyses indicated several findings which can be generally applied to all diseases explored: (1) higher AH above mean values was positively associated with disease case counts (2) higher total precipitation above mean values was positively associated with disease case counts (3) extremely high temperatures were negatively associated with disease case counts (4) higher SO2 and PM2.5 surface concentrations were negatively associated with disease case counts. However, the relationships between disease and RH, non-extreme temperatures and CO surface concentration were more mixed, with directions of associations changing across the different diseases considered.
CONCLUSIONS
This study found protective and enhancing effects of meteorological and ambient air pollutant factors on mosquito-borne diseases burdens in Thailand. Further studies should employ these factors to understand and predict risk factors associated with mosquito-borne disease transmission.
Topics: Animals; Humans; Air Pollutants; Air Pollution; Environmental Pollutants; Thailand; Mosquito-Borne Diseases; Temperature
PubMed: 38150471
DOI: 10.1371/journal.pntd.0011763 -
Frontiers in Microbiology 2023Various interferon (IFN)-stimulated genes (ISGs), expressed via Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway-stimulated... (Review)
Review
Various interferon (IFN)-stimulated genes (ISGs), expressed via Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway-stimulated IFNs to increase antiviral effects or regulate immune response, perform different roles in virus-infected cells. In recent years, a novel ISG, , which is located in the genomic region 19p13.2 and comprises two isoforms, has been studied as a virus-inhibiting agent. Studies have shown that SHFL suppressive effects on human immunodeficiency virus-1 (HIV), Zika virus (ZIKV), dengue virus (DENV), hepatitis C virus (HCV), Japanese encephalitis virus (JEV), porcine epidemic diarrhea virus (PEDV), Human enterovirus A71 (EV-A71) and Kaposi's sarcoma-associated herpes virus (KSHV). SHFL interacts with various viral and host molecules to inhibit viral life circle and activities, such as replication, translation, and ribosomal frameshifting, or regulates host pathways to degrade viral proteins. In this review, we summarized the functional features of SHFL to provide insights to underlying mechanisms of the antiviral effects of SHFL and explored its potential function.
PubMed: 38149274
DOI: 10.3389/fmicb.2023.1323231 -
Vaccines Dec 2023Japanese encephalitis (JE) is a very severe disease characterized by high fatality rates and the development of permanent behavioral, psychiatric, and neurological...
Japanese encephalitis (JE) is a very severe disease characterized by high fatality rates and the development of permanent behavioral, psychiatric, and neurological sequelae among survivors. Japanese encephalitis virus (JEV), a flavivirus, is responsible for JE. In Asia, Genotype I (GI) has emerged as the dominant strain, replacing Genotype III (GIII). However, no clinically approved drug is available to treat JEV infection, and currently available commercial vaccines derived from JEV GIII strains provide only partial protection against GI. Utilizing a reverse genetics system, this study attempted to produce a novel chimeric JEV strain with high efficacy against JEV GI. Accordingly, a GI/GIII intertypic recombinant strain, namely SA14-GI env, was generated by substituting the E region of the GIII SA14-14-2 strain with that of the GI strain, K05GS. The neurovirulence of the mutant virus was significantly reduced in mice. Analysis of the immunogenicity of the chimeric virus revealed that it induced neutralizing antibodies against JEV GI in mice, and the protective efficacy of SA14-GI env was higher than that of SA14-14-2. These findings suggest that SA14-GI env may be a safe and effective live-attenuated vaccine candidate against JEV GI.
PubMed: 38140231
DOI: 10.3390/vaccines11121827 -
Pathogens (Basel, Switzerland) Dec 2023Flaviviruses are a group of positive-sense, single-stranded RNA viruses predominantly transmitted by arthropods (mainly mosquitoes) that cause severe endemic infections... (Review)
Review
Flaviviruses are a group of positive-sense, single-stranded RNA viruses predominantly transmitted by arthropods (mainly mosquitoes) that cause severe endemic infections and epidemics on a global scale. They represent a major cause of systemic morbidity and death and are expanding worldwide. Among this group, dengue fever, the West Nile virus, yellow fever, Japanese Encephalitis, and, recently, the Zika virus have been linked to a spectrum of ocular manifestations. These manifestations encompass subconjunctival hemorrhages and conjunctivitis, anterior and posterior uveitis (inclusive of vitritis, chorioretinitis, and retinal vasculitis), maculopathy, retinal hemorrhages, and optic neuritis. Clinical diagnosis of these infectious diseases is primarily based on epidemiological data, history, systemic symptoms and signs, and the pattern of ocular involvement. Diagnosis confirmation relies on laboratory testing, including RT-PCR and serological testing. Ocular involvement typically follows a self-limited course but can result in irreversible visual impairment. Effective treatments of flavivirus infections are currently unavailable. Prevention remains the mainstay for arthropod vector and zoonotic disease control. Effective vaccines are available only for the yellow fever virus, dengue virus, and Japanese Encephalitis virus. This review comprehensively summarizes the current knowledge regarding the ophthalmic manifestations of the foremost flavivirus-associated human diseases.
PubMed: 38133340
DOI: 10.3390/pathogens12121457 -
Journal of the American Mosquito... Dec 2023Mosquito-borne diseases (MBDs) pose a significant public health concern globally, and India, with its unique eco-sociodemographic characteristics, is particularly...
Mosquito-borne diseases (MBDs) pose a significant public health concern globally, and India, with its unique eco-sociodemographic characteristics, is particularly vulnerable to these diseases. This comprehensive review aims to provide an in-depth overview of MBDs in India, emphasizing their impact and potential implications for global health. The article explores distribution, epidemiology, control or elimination, and economic burden of the prevalent diseases such as malaria, dengue, chikungunya, Japanese encephalitis, and lymphatic filariasis, which collectively contribute to millions of cases annually. It sheds light on their profound effects on morbidity, mortality, and socioeconomic burdens and the potential for international transmission through travel and trade. The challenges and perspectives associated with controlling mosquito populations are highlighted, underscoring the importance of effective public health communication for prevention and early detection. The potential for these diseases to spread beyond national borders is recognized, necessitating a holistic approach to address the challenge. A comprehensive literature search was conducted, covering the past five decades (1972-2022), utilizing databases such as Web of Science, PubMed, and Google Scholar, in addition to in-person library consultations. The literature review analyzed 4,082 articles initially identified through various databases. After screening and eligibility assessment, 252 articles were included for analysis. The review focused on malaria, dengue, chikungunya, Japanese encephalitis, and lymphatic filariasis. The included studies focused on MBDs occurrence in India, while those conducted outside India, lacking statistical analysis, or published before 1970 were excluded. This review provides valuable insights into the status of MBDs in India and underscores the need for concerted efforts to combat these diseases on both national and global scales through consilience.
Topics: Animals; Humans; Mosquito-Borne Diseases; Elephantiasis, Filarial; Chikungunya Fever; Encephalitis, Japanese; India; Malaria; Dengue
PubMed: 38108431
DOI: 10.2987/23-7131