Introduction Japanese encephalitis (JE) is among the most important viral encephalitides in Asia, especially in rural and suburban areas where rice culture and pig farming coexist. (1-3) It has also occurred rarely and sporadically in northern Australia and parts of the Western Pacific. (4-6) JE is due to infection with the JE virus (JEV), a mosquito-borne flavivirus. The main JEV transmission cycle involves Culex tritaeniorhynchus mosquitoes and similar species that lay eggs in rice paddies and other open water sources, with pigs and aquatic birds as principal vertebrate amplifying hosts. (1,2,7) Humans are generally thought to be dead-end JEV hosts, i.e. they seldom develop enough viremia to infect feeding mosquitoes. Fewer than 1% of human JEV infections result in JE. Approximately 20-30% of JE cases are fatal and 30-50% of survivors have significant neurologic sequelae. (8) JE is primarily a disease of children and most adults in endemic countries have natural immunity after childhood infection, but all age groups are affected. In most temperate areas of Asia, JEV is transmitted mainly during the warm season, when large epidemics can occur. In the tropics and subtropics, transmission can occur year-round but often intensifes during the rainy season. (1-3) The global incidence of JE is unknown because the intensity and quality of JE surveillance and the availability of diagnostic laboratory testing vary throughout the world. Countries that have implemented high-quality childhood JE vaccination programmes have seen a dramatic decline in JE incidence. Although JE is reportable to the World Health Organization (WHO) by its Member States, reporting is highly variable and incomplete. In the late 1980s, Burke and Leake estimated that 50 000 new cases of JE occurred annually among the 2.4 billion people living in the 16 Asian countries considered endemic at the time (approximate overall annual incidence: 2 per 100 000). (2) In the intervening two decades, despite major population growth, urbanization, changes in agricultural practices and increased use of the JE vaccine in many countries, this figure has been widely quoted, including very recently. (9-13) In 2000, assuming an annual, age-group-specific incidence of 25 cases per 100 000, Tsai estimated that in the absence of vaccination 175 000 cases of JE would occur annually among Asian children aged 0-14 years living in rural areas. (14) The current study used more recent, published, local or national incidence estimates and current population data to produce an updated estimate of the annual global incidence of JE. Methods We approximated the JE-affected territory of each of the 24 countries endemic for JE using a recent update (15) of an earlier approximation by Tsai (16) with some modifications (Table 1, available at: http://www.who.int/bulletin/ volumes/89/10/10-085233). Based on these same approximations, (15,16) we then stratified the JE-affected territory of some countries (e.g. China excluding Taiwan, India and Nepal) into two or more incidence strata. Because suitable studies of JE incidence were not available for every endemic country or incidence stratum, we sorted JE-endemic countries and incidence strata into 10 incidence groups (A, B, C1, C2 and D through I) based primarily on geographic proximity, ecologic similarity, vaccine programme similarity. Table 1 briefly describes the status of each endemic country's JE vaccination programme as of 2009, according to recent publications and unpublished sources. (8,17-20) Incidence data We identified studies that contained potentially useful data on the incidence of JE in Asia in a manner similar to the one used in a recent study of global typhoid fever incidence. (21) Whenever possible, this review followed the relevant guidelines for Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). (22) The review process is described as follows and no protocol is available. …

Estimated Global Incidence of Japanese Encephalitis: A Systematic review/Estimation De L'incidence Mondiale De L'encephalite Japonaise: Une Evaluation Systematique/ Incidencia Global Estimada De la Encefalitis Japonesa: Una Revision Sistematica

Resveratrol and quercetin, widely found in foods and vegetables, are plant polyphenols reported to have a wide range of biological activities. Despite their limited bioavailabilities, both resveratrol and quercetin are known to exhibit anti-inflammation and anti-obesity effects. We hypothesized that gut microbiota may be a potential target for resveratrol and quercetin to prevent the development of obesity. The aim of this research was to confirm whether a combination of quercetin and resveratrol (CQR) could restore the gut microbiota dysbiosis induced by a high-fat diet (HFD). In this study, Wistar rats were divided into three groups: a normal diet (ND) group, a HFD group and a CQR group. The CQR group was treated with a HFD and administered with a combination of quercetin [30 mg per kg body weight (BW) per day] and resveratrol [15 mg per kg body weight (BW) per day] by oral gavage. At the end of 10 weeks, CQR reduced the body weight gain and visceral (epididymal, perirenal) adipose tissue weight. Moreover, CQR also reduced serum lipids, attenuated serum inflammatory markers [interleukin (IL)-6, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1] and reversed serum biochemical parameters (adiponectin, insulin, leptin, etc.). Importantly, our results demonstrated that CQR could modulate the gut microbiota composition. 16S rRNA gene sequencing revealed that CQR had an impact on gut microbiota, decreasing Firmicutes (P < 0.05) and the proportion of Firmicutes to Bacteroidetes (P = 0.052). CQR also significantly inhibited the relative abundance of Desulfovibrionaceae (P < 0.01), Acidaminococcaceae (P < 0.05), Coriobacteriaceae (P < 0.05), Bilophila (P < 0.05), Lachnospiraceae (P < 0.05) and its genus Lachnoclostridium (P < 0.001), which were reported to be potentially related to diet-induced obesity. Moreover, compared with the HFD group, the relative abundance of Bacteroidales_S24-7_group (P < 0.01), Christensenellaceae (P < 0.001), Akkermansia (P < 0.01), Ruminococcaceae (P < 0.01) and its genera Ruminococcaceae_UCG-014 (P < 0.01), and Ruminococcaceae_UCG-005 (P < 0.01), which were reported to have an effect of relieving HFD-induced obesity, was markedly increased in the CQR group. Overall, these results indicated that administration of CQR may have beneficial effects on ameliorating HFD-induced obesity and reducing HFD-induced gut microbiota dysbiosis.

A combination of quercetin and resveratrol reduces obesity in high-fat diet-fed rats by modulation of gut microbiota

Virus-Receptor Interactions: The Key to Cellular Invasion.

The emergence of Zika virus (ZIKV) as a major public health threat has focused research on understanding virus biology and developing a suite of strategies for disease intervention. Recent advances in cryoelectron microscopy have accelerated structure-function studies of flaviviruses and of ZIKV in particular. Structures of the mature and immature ZIKV have demonstrated its similarity with other known flaviviruses such as dengue and West Nile viruses. However, ZIKV's unique pathobiology demands an explanation of how its structure, although similar to its flavivirus relatives, is sufficiently unique to address questions of receptor specificity, transmission, and antigenicity. Progress in defining the immunodominant epitopes and how neutralizing antibodies bind to them will provide great insight as vaccines progress through clinical trials. Identification of host receptors will substantially illuminate the interesting ZIKV tropism and provide insights into pathogenesis. Although the answers to all of these questions are not yet available, rapid progress in combining structural biology with other techniques is revealing the similarities and the differences in virion structure and function between ZIKV and related flaviviruses.

Zika Virus Structure, Maturation, and Receptors.

Zika virus (ZIKV) is associated with neonatal microcephaly and Guillain-Barre syndrome1,2. While progress has been made in understanding the causal link between ZIKV infection and microcephaly3-9, the life cycle and pathogenesis of ZIKV are less well understood. In particular, there are conflicting reports on the role of AXL, a TAM family kinase receptor that was initially described as the entry receptor for ZIKV10-22. Here, we show that while genetic ablation of AXL protected primary human astrocytes and astrocytoma cell lines from ZIKV infection, AXL knockout did not block the entry of ZIKV. We found, instead, that the presence of AXL attenuated the ZIKV-induced activation of type I interferon (IFN) signalling genes, including several type I IFNs and IFN-stimulating genes. Knocking out type I IFN receptor α chain (IFNAR1) restored the vulnerability of AXL knockout astrocytes to ZIKV infection. Further experiments suggested that AXL regulates the expression of SOCS1, a known type I IFN signalling suppressor, in a STAT1/STAT2-dependent manner. Collectively, our results demonstrate that AXL is unlikely to function as an entry receptor for ZIKV and may instead promote ZIKV infection in human astrocytes by antagonizing type I IFN signalling.

AXL promotes Zika virus infection in astrocytes by antagonizing type I interferon signalling

Flaviviruses including Dengue virus (DENV), Yellow fever virus (YFV), West Nile virus (WNV), and Japanese encephalitis virus (JEV) are global health problems that caused several serious diseases such as fever, hemorrhagic fever, and encephalitis in the past century. Recently, Zika virus (ZIKV) which spreads from Asia to American and causes millions of infections emerges as a new dangerous member of the genus of Flavivirus. Unlike other well-known flaviviruses, ZIKV can be transmitted sexually and infect testes in murine models. Its impacts on sperm functions, and the exact susceptible cells, however, are not entirely clear. To investigate these issues, we infected interferon α/β and γ receptors deficient AG6 mice with ZIKV and examined the outcomes of infection using an assortment of physiological, histopathological, immunological, and virological techniques. We found that infected mice displayed signs of reproductive system disorder, altered androgen levels in serum, and high viral load in semen and testes. Additionally, histopathological examinations revealed marked atrophy of seminiferous tubules and significant reduction in lumen size. Notably, these were accompanied by positive staining of ZIKV antigens on sertoli cells, detection of viral particles and vacuole changes within cytoplasm of sertoli cells. The susceptibility of sertoli cells to ZIKV was further validated in vitro study using cell lines. Importantly, the disruption of tight junctions within testis and altered sperm morphology were also observed in ZIKV infected mice. It is well-known that tight junctions formed by adjacent sertoli cells are major component of blood testis barrier, which plays important roles in maintenance of microenvironment for spermagenesis in testis. Taken together, these results demonstrate that sertoli cells are susceptible to ZIKV infection, which results in the disruption of tight junctions in testis and causes abnormal spermatogenesis in mice. These results also imply that long-term impact of ZIKV infection on human male reproductive system requires close monitoring.

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Sertoli Cells Are Susceptible to ZIKV Infection in Mouse Testis.

Recently, Zika virus (ZIKV) outbreak has been associated with a sharp increase in cases of Guillain–Barre syndrome and severe fetal abnormalities. However, the mechanism underlying the interaction of ZIKV with host cells is not yet clear. Axl, a receptor tyrosine kinase, is postulated as a receptor for ZIKV entry; however, its in vivo role during ZIKV infection and its impact on the outcome of the disease have not been fully characterized and evaluated. Moreover, there are contradictory results on its involvement in ZIKV infection. Here we utilized Axl-deficient mice (Axl−/−) and their littermates (Axl+/−) to study the in vivo role of Axl in ZIKV infection. Our results showed that both Axl+/− and Axl−/− suckling mice supported the replication of ZIKV and presented clinical manifestations. No significant difference has been found between Axl-deficient mice and their littermates in terms of the survival rate, clinical manifestations, viral load, ZIKV distribution and histopathological changes in major organs. These results therefore indicate that Axl is not an indispensable factor for ZIKV infection in mice.

Axl is not an indispensable factor for Zika virus infection in mice.

Japanese encephalitis virus (JEV) is a flavivirus that causes Japanese encephalitis (JE), which has an unclear pathogenesis Despite vaccination, thousands of deaths attributed to JE are reported annually In this study, we report that mice deficient for Axl, a receptor tyrosine kinase that plays multiple roles in flaviviral infection, displayed greater mortality upon JEV infection The effect of Axl deficiency on JEV infection was mediated by markedly elevated serum interleukin-1α (IL-1α) levels, which devastated the blood-brain-barrier and promoted viral neuroinvasion within 24 h postinfection Using an in situ infection model, we showed that dead macrophages were the primary source of observed increased serum IL-1α levels Axl deficiency enhanced cell death and caused pyroptosis in 80% of JEV-infected macrophages by disrupting phosphatidylinositol 3-kinase (PI3K)-Akt signaling Intriguingly, the primary effector released by pyroptotic macrophages in our model was IL-1α rather than IL-1β Finally, we assessed the effect of an IL-1α antagonist and demonstrated that it effectively prevented the incidence of JE Our results indicate that Axl plays a protective role in JEV infection, identify IL-1α released by pyroptotic macrophages as a crucial factor promoting JEV neuroinvasion, and suggest that an IL-1α antagonist may be a candidate for JE therapyIMPORTANCE Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes Japanese encephalitis (JE), the most commonly diagnosed viral encephalitis worldwide The fatality rate of JE is 20%, and nearly half of the surviving patients develop neuropsychiatric sequelae Axl is a receptor tyrosine kinase that plays multiple roles in flaviviral infections Currently, the involvement of Axl in JEV infection remains enigmatic In this study, we demonstrate that Axl impedes the pathogenesis of severe JE in mice by maintaining blood-brain-barrier (BBB) integrity and restricting viral neuroinvasion Furthermore, serum IL-1α is a key mediator of this process and is primarily released by JEV-infected pyroptotic macrophages to elicit BBB breakdown, while an IL-1α antagonist can effectively reduce the incidence of severe JE Our work uncovers the protective role of Axl in antagonizing severe JE and shows that the use of an IL-1α antagonist may be a promising tactic to prevent severe JE

Axl Deficiency Promotes the Neuroinvasion of Japanese Encephalitis Virus by Enhancing IL-1α Production from Pyroptotic Macrophages.

https://link.springer.com/content/pdf/10.1007%2Fs12250-016-3780-y.pdf

Zhao-Yang Wang

Papers

Sertoli Cells Are Susceptible to ZIKV Infection in Mouse Testis.

Axl is not an indispensable factor for Zika virus infection in mice.

Axl Deficiency Promotes the Neuroinvasion of Japanese Encephalitis Virus by Enhancing IL-1α Production from Pyroptotic Macrophages.

Zika virus and Zika fever

The Multifaceted Roles of TAM Receptors during Viral Infection