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Hepatitis C virus (HCV) infection is a major public health problem despite effectual direct-acting antivirals (DAAs) therapy. Development of a prophylactic vaccine is essential to block spread of HCV infection. The HBV small surface antigen (HBsAg-S) can self-assemble into virus-like particles (VLPs), has higher immunogenicity and is used as a vaccine against HBV infections. Chimeric HBsAg-S proteins with foreign epitopes allow VLP formation and induce the specific humoral and cellular immune responses against the foreign proteins. In this study, we investigated the immune responses induced by chimeric VLPs with HCV neutralizing epitopes and HBV S antigen in mice. The chimeric HCV-HBV VLPs expressing neutralizing epitopes were prepared and purified. BALB/c mice were immunized with purified chimeric VLPs and the serum neutralizing antibodies were analyzed. We found that these chimeric VLPs induced neutralizing antibodies against HCV in mice. Additionally, the murine serum neutralized infections with HCV pseudoparticles and cell-cultured viruses derived from different heterologous 1a, 1b and 2a genotypes. We also found that immunization with chimeric VLPs induced anti-HBsAg antibodies. This study provides a novel strategy for development of a HCV prophylactic neutralizing epitope vaccine and a HCV-HBV bivalent prophylactic vaccine. [ABSTRACT FROM AUTHOR]

Abstract: Human natural killer (NK) cells constitute an important cellular component of innate immunity, capable of killing infected and transformed cells. The proliferation and activation of NK cells are regulated by various cytokines. Interleukin-18 (IL-18) promotes NK cell activation; however, whether the effects of IL-18 on NK cell are associated with other cytokines is still unknown. In this study, we observed that IL-18 induced NK cell apoptosis and inhibited NK cell expansion in the presence of low concentrations of interleukin-2 (IL-2), while high concentrations of IL-2 overcame these effects of IL-18, and high concentrations of IL-2 promoted the stimulatory activity of IL-18 on NK cells. At a low concentration of IL-2, IL-18 induced NK cell apoptosis in part through activation of the FasL/Fas- and TNFα/TNFR-mediated death receptor signaling by enhancing FasL expression and inhibiting c-FLIPlong expression. However, high concentrations of IL-2 strongly blocked IL-18-induced NK cell apoptosis through alleviating IL-18-induced FasL expression and activation of Fas-mediated death signaling and increasing anti-apoptosis molecule (Bcl-XL). These results reveal that the effects of IL-18 on human NK cell are associated with IL-2 concentration and suggest the importance of IL-2 level in cytokine immunotherapy. [ABSTRACT FROM AUTHOR]

Japanese encephalitis (JE) is a major reason to cause viral encephalitis, with 50% patients suffering from severe neuro-inflammation and permanent neural injury. Effective anti-viral treatment is urgently needed. Here, we found RNA binding protein quaking (QKI) was involved in the progression of JE by regulating migration and anti-viral response of macrophages. After JE virus (JEV) infection, QKI-deficient mice had lower viral loads in the brain and fewer neurological symptoms. In comparison with control mice, proinflammatory cytokines in the brain of QKI-deficient animals revealed distinct patterns, with lower levels of IL-6 (interleukin-6) and IFN- β (interferon- β) at the early stage but higher levels at the end of JE. Then we found infiltration of CCR2 positive ((C-C motif) receptor 2) peripheral macrophages and CCR2 expression on macrophages were inhibited in QKI-deficient mice, while the expression of CCR2 ligands was not changed. Bioinformatical analysis showed that a QRE (quaking response element) located on 3′UTR (untranslated region) of Ccr2. We further verified that QKI was able to interact with Ccr2 mRNA and regulate its degradation in vitro. Additionally, since the IFN- β production was increased in QKI-ablation mice after JEV infection, the anti-viral response was analyzed. Results in QKI-silenced N9 cells showed that the expression of RIG-I (retinoic acid-inducible gene-I) and TBK1 (TANK binding kinase 1) was increased, thus further inducing IRF3 (interferon regulatory factor 3) phosphorylation and interferon activation. Overall, these results revealed QKI mediated the anti-viral process via interfering migration of macrophages to CNS (central nervous system) and enhancing RIG-I/IRF3/IFN- β pathway to restrict virus dissemination. • Myeloid QKI deficiency protected mice from JEV infection. • QKI deficiency inhibited local neuroinflammation by restricting infiltration of peripheral macrophages into CNS. • Recruitment of macrophages into CNS reduced in QKI-depletion mice by QKI interacting with mRNA of Ccr2 directly. • QKI silenced cells exerted enhanced anti-viral response through RIG-I/IRF3/IFN- β pathway. [ABSTRACT FROM AUTHOR]

Itraconazole is a common antifungal which may have promise for treating various human cancers. We report that itraconazole was cytotoxic to MCF-7 and SKBR-3 breast cancer cell lines via apoptosis by altering mitochondria membrane potential, reducing BCL-2 expression and elevating caspase-3 activity. Itraconazole also induced autophagic cell death via LC3-II expression upregulation, P62/SQSTM1 degradation, autophagosome formation and increases in autophagic puncta. Itraconazole treatment inhibited hedgehog pathway key molecular expression, such as SHH and Gli1, resulting in promotion of apoptosis and autophagy. The anti-proliferation effect of itraconazole-induced apoptosis and autophagy via hedgehog pathway inhibition was confirmed with Gli1 inhibitor GANT61 and SHH siRNA, GANT61 and SHH siRNA synergistically enhanced cytotoxicity induced by itraconazole. A human xenograft nude mouse model corroborated the anti-breast cancer activity as evidenced by reduced tumor size, and increased tumor tissue apoptosis and autophagy. Thus, itraconazole has a potent anti-breast cancer activity that may be improved when combined with hedgehog pathway inhibitors. [ABSTRACT FROM AUTHOR]

Hantaan virus (HTNV) is a rodent-borne virus that causes hemorrhagic fever with renal syndrome (HFRS) in Asia and can be transmitted to humans through bites or the inhalation of aerosolized urine, droppings, or saliva of infected rodents. Keratinocytes predominate in the epidermis and reportedly serve as a replication site for multiple vector-borne viruses, little is known about the susceptibility of human skin cells to HTNV infection. Therefore, we aimed to evaluate whether human keratinocytes support HTNV replication and elicit an immune response against HTNV infection. We found that a human keratinocyte cell line, HaCaT, supports HTNV replication. In addition, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation associated gene-5 (MDA5) play key roles in the detection of HTNV infection in HaCaT cells and in the up-regulation of interferon (IFN)-β expression, which subsequently leads to the production of a large amount of antiviral interferon-stimulated genes (ISGs) and other chemokines used for immune cell recruitment. Furthermore, we suggest that interferon regulatory factor (IRF)-3, as opposed to NF-κB/p65 or IRF-7, is translocated to the nucleus to induce IFN-β. However, the early induction of chemokine CXCL10 was a direct result of HaCaT cells counteracting HTNV infection and was not due to the induction of IFN. Overall, our data demonstrate, for the first time, the permissiveness of human keratinocytes to HTNV infection. [ABSTRACT FROM AUTHOR]

• Axl-deficient (Axl−/−) mice exhibited increased susceptibility and decreased survival rate compared with WT mice under JEV infection. • JEV replication in Axl−/− primary neurons is significantly enhanced and the up-regulation of antiviral ISGs in Axl−/− neurons was significantly lower than that in WT neurons. • Axl might play a positive antiviral role in neurons through upregulating ISGs to inhibit JEV replication. Japanese encephalitis virus (JEV) causes the most commonly diagnosed viral encephalitis in Asia. JEV is a highly neurotropic flavivirus that can replicate efficiently in the brain. Axl belongs to the TAM (Tyro3, Axl, Mer) family, a group of tyrosine kinase receptors involved in the viral entry, micked as apoptotic bodies and regulation of innate immunity. However, the underlying mechanisms on its regulation in the neurons for JEV are unclear. Here, we found that Axl was upregulated in neurons after JEV infection. Unexpectedly, Axl deficient (Axl−/−) mice were more susceptible to JEV infection with increased viral loads in neurons. The RNA-sequencing analysis between the wild type neurons and Axl−/− neurons infected with JEV showed that many interferon-stimulated genes were downregulated in the Axl−/− neurons which innate immunity was attenuated largely. The rescue experiment in Axl−/− neurons indicated that Axl may be positively involved in the regulation of antiviral immunity. Taken together, our data demonstrated that Axl may play an antiviral role in JEV replication within neurons by modulating neuronal innate immunity. [ABSTRACT FROM AUTHOR]

• We show a highly integrated internet of things (IoT) system based on polymerase chain reaction for disease detection and monitoring its spreading. • The detection results were automatically uploaded via a Bluetooth interface to user's smartphone. • Together with global positioning system coordinates of the test spot at further sent via global network. • The map of the infectious disease outbreak was instantly produced. • This device can be used for other diseases and become a basic block of the IoT helping to tackle infectious disease outbreak. During infectious disease outbreaks, the centers for disease control need to monitor particular areas. Considerable effort has been invested in the development of portable, user-friendly, and cost-effective systems for point-of-care (POC) diagnostics, which could also create an Internet of Things (IoT) for healthcare via a global network. However, at present IoT based on a functional POC instrument is not available. Here we show a fast, user-friendly, and affordable IoT system based on a miniaturized polymerase chain reaction device. We demonstrated the system's capability by amplification of complementary deoxyribonucleic acid (cDNA) of the dengue fever virus. The resulting data were then automatically uploaded via a Bluetooth interface to an Android-based smartphone and then wirelessly sent to a global network, instantly making the test results available anywhere in the world. The IoT system presented here could become an essential tool for healthcare centers to tackle infectious disease outbreaks identified either by DNA or ribonucleic acid. [ABSTRACT FROM AUTHOR]