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Mikania micrantha is one of the worst invasive species globally and can cause significant negative impacts on agricultural and forestry economics, particularly in Asia and the Pacific region. The rust Puccinia spegazzinii has been used successfully as a biological control agent in several countries to help manage M. micrantha. However, the response mechanisms of M. micrantha to P. spegazzinii infection have never been studied. To investigate the response of M. micrantha to infection by P. spegazzinii, an integrated analysis of metabolomics and transcriptomics was performed. The levels of 74 metabolites, including organic acids, amino acids, and secondary metabolites in M. micrantha infected with P. spegazzinii, were significantly different compared to those in plants that were not infected. After P. spegazzinii infection, the expression of the TCA cycle gene was significantly induced to participate in energy biosynthesis and produce more ATP. The content of most amino acids, such as L-isoleucine, L-tryptophan and L-citrulline, increased. In addition, phytoalexins, such as maackiain, nobiletin, vasicin, arachidonic acid, and JA-Ile, accumulated in M. micrantha. A total of 4978 differentially expressed genes were identified in M. micrantha infected by P. spegazzinii. Many key genes of M. micrantha in the PTI (pattern-triggered immunity) and ETI (effector-triggered immunity) pathways showed significantly higher expression under P. spegazzinii infection. Through these reactions, M. micrantha is able to resist the infection of P. spegazzinii and maintain its growth. These results are helpful for us to understand the changes in metabolites and gene expression in M. micrantha after being infected by P. spegazzinii. Our results can provide a theoretical basis for weakening the defense response of M. micrantha to P. spegazzinii, and for P. spegazzinii as a long-term biological control agent of M. micrantha. [ABSTRACT FROM AUTHOR]

Dengue is a major public health concern, affecting almost 400 million people worldwide, with about 70% of the global burden of disease in Asia. Despite revised clinical classifications of dengue infections by the World Health Organization, the wide spectrum of the manifestations of dengue illness continues to pose challenges in diagnosis and patient management for clinicians. When the Zika epidemic spread through the American continent and then later to Africa and Asia in 2015, researchers compared the characteristics of the Zika infection to Dengue, considering both these viruses were transmitted primarily through the same vector, the Aedes aegypti female mosquitoes. An important difference to note, however, was that the Zika epidemic diffused in a shorter time span compared to the persisting feature of Dengue infections, which is endemic in many Asian countries. As the pathogenesis of viral illnesses is affected by host immune responses, various immune modulators have been proposed as biomarkers to predict the risk of the disease progression to a severe form, at a much earlier stage of the illness. However, the findings for most biomarkers are highly discrepant between studies. Meanwhile, the cross-reactivity of CD8+ and CD4+ T cells response to Dengue and Zika viruses provide important clues for further development of potential treatments. This review discusses similarities between Dengue and Zika infections, comparing their disease transmissions and vectors involved, and both the innate and adaptive immune responses in these infections. Consideration of the genetic identity of both the Dengue and Zika flaviviruses as well as the cross-reactivity of relevant T cells along with the actions of CD4+ cytotoxic cells in these infections are also presented. Finally, a summary of the immune biomarkers that have been reported for dengue and Zika viral infections are discussed which may be useful indicators for future anti-viral targets or predictors for disease severity. Together, this information appraises the current understanding of both Zika and Dengue infections, providing insights for future vaccine design approaches against both viruses. [ABSTRACT FROM AUTHOR]

The brown planthopper (BPH), Nilaparvata lugens, is an important pest that affects rice (Oryza sativa) production in Asia. The flavone tricin (5,7,4′-trihydroxy-3′,5′-dimethoxy flavone) is a valuable secondary metabolite commonly found in rice plants that can defend rice plants against infestation by BPH. BPH damage can reduce the metabolic level of tricin in rice. Our preliminary transcriptome research results showed that BPH salivary protein 7 (NlSP7), is highly responsive to tricin stimuli. However, the function of NlSP7 in mediating the interaction between the rice plant and the BPH is unknown. In this study, we cloned the NlSP7 gene in N. lugens and found that its mRNA level was greater in the presence of high tricin content than low tricin content, regardless of whether the BPHs were fed a rice plant diet or an artificial diet containing 100 mg/L tricin. Knocking down NlSP7 resulted in BPH individuals spending more time in the non-penetration and pathway phase, and less time feeding on the phloem of rice plants. These changes decreased BPH food intake, feeding behavior, and fitness, as well as the tricin content of the rice plants. These findings demonstrate that the salivary protein 7 of BPH functions as an effector for tricin metabolism in rice. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) plays a key role in promoting the initiation and progression of tumors, leading to chemoradiotherapy resistance and immunotherapy failure. Targeting of the TME is a novel anti-tumor therapeutic approach and is currently a focus of anti-tumor research. Panax ginseng C. A. Meyer (ginseng), an ingredient of well-known traditional Asia medicines, exerts beneficial anti-tumor effects and can regulate the TME. Here, we present a systematic review that describes the current status of research efforts to elucidate the functions and mechanisms of ginseng active components (including ginsenosides and ginseng polysaccharides) for achieving TME regulation. Ginsenosides have variety effects on TME, such as Rg3, Rd and Rk3 can inhibit tumor angiogenesis; Rg3, Rh2 and M4 can regulate the function of immune cells; Rg3, Rd and Rg5 can restrain the stemness of cancer stem cells. Ginseng polysaccharides (such as red ginseng acidic polysaccharides and polysaccharides extracted from ginseng berry and ginseng leaves) can regulate TME mainly by stimulating immune cells. In addition, we propose a potential mechanistic link between ginseng-associated restoration of gut microbiota and the tumor immune microenvironment. Finally, we describe recent advances for improving ginseng efficacy, including the development of a nano-drug delivery system. Taken together, this review provides novel perspectives on potential applications for ginseng active ingredients as anti-cancer adjuvants that achieve anti-cancer effects by reshaping the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Orientia (O.) tsutsugamushi-induced scrub typhus is endemic across many regions of Asia and the Western Pacific, where an estimated 1 million cases occur each year; the majority of patients infected with O. tsutsugamushi end up with a cytokine storm from a severe inflammatory response. Previous reports have indicated that blocking tumor necrosis factor (TNF)-α reduced cell injury from a cytokine storm. Since TNF-α production is known to be associated with intracellular Ca2+ elevation, we examined the effect of store-operated Ca2+ entry (SOCE) inhibitors on TNF-α production in O. tsutsugamushi-infected macrophages. We found that 2-aminoethoxydiphenyl borate (2-APB), but not SKF96365, facilitates the suppression of Ca2+ mobilization via the interruption of Orai1 expression in O. tsutsugamushi-infected macrophages. Due to the decrease of Ca2+ elevation, the expression of TNF-α and its release from macrophages was repressed by 2-APB. In addition, a novel role of 2-APB was found in macrophages that causes the upregulation of heat shock protein 70 (HSP70) expression associated with ERK activation; upregulated TNF-α production in the case of knockdown HSP70 was inhibited with 2-APB treatment. Furthermore, elevated HSP70 formation unexpectedly did not help the cell survival of O. tsutsugamushi-infected macrophages. In conclusion, the parallelism between downregulated Ca2+ mobilization via SOCE and upregulated HSP70 after treatment with 2-APB against TNF-α production was found to efficiently attenuate an O. tsutsugamushi-induced severe inflammatory response. [ABSTRACT FROM AUTHOR]

Background: Japanese flounder (Paralichthys olivaceus) is an economically important marine fish in Asia and has suffered from disease outbreaks caused by various pathogens, which requires more information for immune relevant genes on genome background. However, genomic and transcriptomic data for Japanese flounder remain scarce, which limits studies on the immune system of this species. In this study, we characterized the Japanese flounder spleen transcriptome using an Illumina paired-end sequencing platform to identify putative genes involved in immunity. Methodology/Principal Findings: A cDNA library from the spleen of P. olivaceus was constructed and randomly sequenced using an Illumina technique. The removal of low quality reads generated 12,196,968 trimmed reads, which assembled into 96,627 unigenes. A total of 21,391 unigenes (22.14%) were annotated in the NCBI Nr database, and only 1.1% of the BLASTx top-hits matched P. olivaceus protein sequences. Approximately 12,503 (58.45%) unigenes were categorized into three Gene Ontology groups, 19,547 (91.38%) were classified into 26 Cluster of Orthologous Groups, and 10,649 (49.78%) were assigned to six Kyoto Encyclopedia of Genes and Genomes pathways. Furthermore, 40,928 putative simple sequence repeats and 47, 362 putative single nucleotide polymorphisms were identified. Importantly, we identified 1,563 putative immune-associated unigenes that mapped to 15 immune signaling pathways. Conclusions/Significance: The P. olivaceus transciptome data provides a rich source to discover and identify new genes, and the immune-relevant sequences identified here will facilitate our understanding of the mechanisms involved in the immune response. Furthermore, the plentiful potential SSRs and SNPs found in this study are important resources with respect to future development of a linkage map or marker assisted breeding programs for the flounder. [ABSTRACT FROM AUTHOR]

Asian schistosomiasis is a zoonotic parasitic disease infecting up to a million people and threatening tens of millions more. Control of this disease is hindered by the animal reservoirs of the parasite, in particular the water buffalo (Bubalus bubalis), which is responsible for significant levels of human transmission. A transmission-blocking vaccine administered to buffaloes is a realistic option which would aid in the control of schistosomiasis. This will however require a better understanding of the immunobiology of schistosomiasis in naturally exposed buffaloes, particularly the immune response to migrating schistosome larvae, which are the likely targets of an anti-schistosome vaccine. To address this need we investigated the immune response at the major sites of larval migration, the skin and the lungs, in previously exposed and re-challenged water buffaloes. In the skin, a strong allergic-type inflammatory response occurred, characterised by leukocyte and eosinophil infiltration including the formation of granulocytic abscesses. Additionally at the local skin site, interleukin-5 transcript levels were elevated, while interleukin-10 levels decreased. In the skin-draining lymph node (LN) a predominant type-2 profile was seen in stimulated cells, while in contrast a type-1 profile was detected in the lung draining LN, and these responses occurred consecutively, reflecting the timing of parasite migration. The intense type-2 immune response at the site of cercarial penetration is significantly different to that seen in naive and permissive animal models such as mice, and suggests a possible mechanism for immunity. Preliminary data also suggest a reduced and delayed immune response occurred in buffaloes given high cercarial challenge doses compared with moderate infections, particularly in the skin. This study offers a deeper understanding into the immunobiology of schistosomiasis in a natural host, which may aid in the future design of more effective vaccines. Author Summary: Schistosomiasis is caused by a parasitic blood fluke, and in parts of Asia it infects both humans and livestock such as water buffaloes. This makes controlling the disease more difficult, because both humans and livestock must be treated regularly. A vaccine given to buffaloes is likely to reduce human infection rates and improve buffalo health by providing long-lasting protection from re-infection; at present no vaccines are available. Older buffaloes are known to have some immunity to schistosomiasis which is acquired over time; however how this occurs is not understood. In this study we investigated the immune response of buffalo against the schistosome larvae, which are vulnerable to immune attack, and hence are the ideal stage to target for vaccination. We found that the buffalo produces a profound allergic type-2 response as larvae penetrate the skin, with significant cellular infiltrates and abscesses. When the larvae move next to the lungs, a uniquely type-1 response was induced. This skin response is much greater than more susceptible animals such as mice, and may be a mechanism for larval killing in the buffalo. This study offers insight into the immunobiology of an important host for schistosomiasis and may help in designing better vaccines. [ABSTRACT FROM AUTHOR]

Background: Hantaan virus (HTNV) infection in humans is a serious public health concern in Asia. A potent T cell activation peptide vaccine from HTNV structure protein represents a promising immunotherapy for disease control. However, the T cell epitopes of the HTNV restricted by the HLA alleles and the role of epitope-specific T cell response after HTNV infection remain largely unexplored. Methodology/Principal Findings: Five well-conserved novel CD8+ T-cell epitopes of the HTNV nucleoprotein restricted by the most popular HLA alleles in Chinese Han population were defined with interferon-γ enzyme-linked immunospot assay in 37 patients infected with HTNV during hospitalization. Two epitopes aa129–aa137 and aa131–aa139 restricted by HLA-A2 and B35, respectively, were selected to evaluate the epitope-specific CD8+ T-cell response. HLA-peptide pentamer complex staining showed that the frequency of single epitope-specific CD8+ T cell could be detected in patients (95% confidence interval for aa129–aa137: 0.080%–0.208%; for aa131–aa139: 0.030%–0.094%). The frequency of epitope-specific pentamer+ CD8+ T-cell response was much higher in mild/moderate patients than in severe/critical ones at the acute stage of the disease. Moreover, the frequency of epitope-specific CD8+ T cells at acute stage was inversely associated with the peak level of serum creatinine and was positively associated with the nadir platelet counts during the hospitalization. The intracellular cytokine staining and the proliferation assay showed that the effective epitope-specific CD8+ T cells were characterized with the production of interferon-γ, expression of CD69 and the strong capacity of proliferation. Conclusion/Significance: The novel HLA class I restricted HTNV nucleoprotein epitopes-specific CD8+ T-cell responses would be closely related with the progression and the severity of the disease, which could provide the first step toward effective peptide vaccine development against HTNV infection in humans. Author Summary: Hantaan virus (HTNV), the prototype of the Hantavirus genus, is a rodent-borne pathogen that causes human hemorrhagic fever with renal syndrome (HFRS) with a mortality rate of approximately 15% in Asia. Since effective prevention is not available currently and the non-specific symptoms at the early stage of the disease always lead to the delay of visiting to hospital or misdiagnosis, alternative vaccinations against HTNV are of priority to overcome the problem. We defined five novel HTNV nucleoprotein CD8+ T-cell epitopes restricted by the most popular HLA alleles in Chinese Han population. For the first time, we quantitated the HTNV epitope-specific CD8+ T-cell frequency during HTNV infection and evaluated the correlations between the CD8+ T-cell response and the different outcomes of the HFRS severity. We also found that effective HTNV nucleoprotein epitope-specific CD8+ T-cell responses were characterized by the interferon-γ secretion with a strong capacity of activation and proliferation. Our results add weight to understanding the important role of epitope-specific CD8+ T-cell responses in the disease control after acute zoonotic HTNV infections in humans and provide a rationale foundation to speed up the process of peptide vaccine development. [ABSTRACT FROM AUTHOR]

Background: Scrub typhus, caused by Orientia tsutsugamushi infection, is one of the main causes of febrile illness in the Asia-Pacific region. Although cell-mediated immunity plays an important role in protection, little is known about the phenotypic changes and dynamics of leukocytes in scrub typhus patients. Methodology/Principal Findings: To reveal the underlying mechanisms of immunological pathogenesis, we extensively analyzed peripheral blood leukocytes, especially T cells, during acute and convalescent phases of infection in human patients and compared with healthy volunteers. We observed neutrophilia and CD4+ T lymphopenia in the acute phase of infection, followed by proliferation of CD8+ T cells during the convalescent phase. Massive T cell apoptosis was detected in the acute phase and preferential increase of CD8+ T cells with activated phenotypes was observed in both acute and convalescent phases, which might be associated or correlated with elevated serum IL-7 and IL-15. Interestingly, peripheral Treg cells were significantly down-regulated throughout the disease course. Conclusions/Significance: The remarkable decrease of CD4+ T cells, including Treg cells, during the acute phase of infection may contribute to the loss of immunological memory that are often observed in vaccine studies and recurrent human infection. [ABSTRACT FROM AUTHOR]

Background: Japanese encephalitis virus (JEV) is a major mosquito-borne pathogen that causes viral encephalitis throughout Asia. Vaccination with an inactive JEV particle or attenuated virus is an efficient preventative measure for controlling infection. Flavivirus NS1 protein is a glycoprotein secreted during viral replication that plays multiple roles in the viral life cycle and pathogenesis. Utilizing JEV NS1 as an antigen in viral vectors induces a limited protective immune response against infection. Previous studies using E. coli-expressed JEV NS1 to immunize mice induced protection against lethal challenge; however, the protection mechanism through cellular and humoral immune responses was not described. Results: JEV NS1 was expressed in and purified from Drosophila S2 cells in a native glycosylated multimeric form, which induced T-cell and antibody responses in immunized C3H/HeN mice. Mice vaccinated with 1 µg NS1 with or without water-in-oil adjuvant were partially protected against viral challenge and higher protection was observed in mice with higher antibody titers. IgG1 was preferentially elicited by an adjuvanted NS1 protein, whereas a larger load of IFN-γ was produced in splenocytes from mice immunized with aqueous NS1. Mice that passively received anti-NS1 mouse polyclonal immune sera were protected, and this phenomenon was dose-dependent, whereas protection was low or delayed after the passive transfer of anti-NS1 MAbs. Conclusion: The purified NS1 subunit induced protective immunity in relation with anti-NS1 IgG1 antibodies. NS1 protein efficiently stimulated Th1-cell proliferation and IFN-γ production. Protection against lethal challenge was elicited by passive transfer of anti-NS1 antisera, suggesting that anti-NS1 antibodies play a substantial role in antiviral immunity. [ABSTRACT FROM AUTHOR]

A new commercial anti-Japanese encephalitis virus IgM and IgG indirect immunofluorescence test (IIFT) was evaluated for the detection of the humoral immune response after Japanese encephalitis vaccination. The IgM IIFT was compared to two IgM capture ELISAs and the IgG IIFT was analysed in comparison to a plaque reduction neutralization test (PRNT50) and an IgG ELISA. Moreover, the course of the immune reaction after vaccination with an inactivated JEV vaccine was examined. For the present study 300 serum samples from different blood withdrawals from 100 persons vaccinated against Japanese encephalitis were used. For the IgM evaluation, altogether 78 PRNT50 positive samples taken 7 to 56 days after vaccination and 78 PRNT50 negative sera were analyzed with the Euroimmun anti-JEV IgM IIFT, the Panbio Japanese Encephalitis – Dengue IgM Combo ELISA and the InBios JE Detect IgM capture ELISA. For the IgG evaluation, 100 sera taken 56 days after vaccination and 100 corresponding sera taken before vaccination were tested in the PRNT50, the Euroimmun anti-JEV IgG IIFT, and the InBios JE Detect IgG ELISA. The Euroimmun IgM IIFT showed in comparison to the Panbio ELISA a specificity of 95% and a sensitivity of 86%. With respect to the InBios ELISA, the values were 100% and 83.9%, respectively. The analysis of the Euroimmun IgG IIFT performance and the PRNT50 results demonstrated a specificity of 100% and a sensitivity of 93.8%, whereas it was not possible to detect more than 6.6% of the PRNT50 positive sera as positive with the InBios JE Detect IgG ELISA. Thus, the IIFT is a valuable alternative to the established methods in detecting anti-JEV antibodies after vaccination in travellers and it might prove useful for the diagnosis of acutely infected persons. Author Summary: Japanese encephalitis, caused by the Japanese encephalitis virus, is the most prominent viral encephalitis in Asia. Three billion people live in endemic areas and at least 50,000 clinical cases occur each year, although reliable vaccines are available. Concerning the burden caused by this disease, more should be done to prevent it. Good and reliable diagnostics are one of the prerequisites for an effective fight against the virus, but it is nearly impossible to produce and evaluate an in-house assay according to high standard quality criteria as done for commercial tests. Only a few commercial assays are available and the thorough evaluation of these assays is of great importance for diagnostic laboratories. The sensitivity and specificity are statistical measures to assess the performance of a diagnostic assay. In this study the Euroimmun IgM indirect immunofluorescence test (IIFT) was compared to the Panbio and InBios IgM ELISAs. It showed a specificity of 95% and 100%, and a sensitivity of 86% and 93.8%, respectively. The specificity of the IgG IIFT in comparison to PRNT50 was 100% and the sensitivity was 93.8%. Overall, the IIFT showed a comparable performance and could be used as an alternative to the established assays. [ABSTRACT FROM AUTHOR]

Epinephelus coioides, or grouper, is a high economic value fish species that plays an important role in the aquaculture industry in Asia. However, both viral and bacterial diseases have threatened grouper for many years, especially nervous necrosis virus, grouper iridovirus and Vibrio harveyi, which have caused a bottleneck in the grouper industry. Currently, intestinal microbiota can provide novel insights into the pathogenesis-related factors involved in pathogen infection. Hence, we investigated the comparison of intestinal microbiota communities in control group and pathogen-infected grouper through high-throughput sequencing of the 16S rRNA gene. Our results showed that microbial diversity was decreased, whereas microbial richness was increased during pathogen infection. The individuals in each group were distributed distinctly on the PLSDA diagram, especially the GIV group. Proteobacteria and Firmicutes were the most abundant bacterial phyla in all groups. Interestingly, beneficial genera, Faecalibacterium and Bifidobacterium, predominated in the intestines of the control group. In contrast, the intestines of pathogen-infected grouper had higher levels of harmful genera such as Sphingomonas, Atopostipes, Staphylococcus and Acinetobacter. Additionally, we investigated the expression levels of innate and adaptive immune-related genes after viral and bacterial infection. The results revealed that immunoglobulin T and proinflammatory cytokine levels in the intestine increased after pathogen infection. Through these unique bacterial compositions in diseased and uninfected fish, we could establish a novel therapeutic approach and bacterial marker for preventing and controlling these diseases. [ABSTRACT FROM AUTHOR]

Foot-and-mouth disease (FMD) is a highly contagious viral disease, which has been reported for over 100 years, and against which the struggle has lasted for the same amount of time. It affects individuals from the order Artiodactyla, such as cattle, swine, sheep, wild animals from this order, and a few non-cloven hoofed species, such as mice and elephants. FMD causes large-scale economic losses for agricultural production systems; morbidity is almost 100% in an affected population, accompanied by a high mortality rate in young animals due to myocarditis or an inability to suckle if a mother is ill. The aetiological agent is an Aphthovirus from the family Picornaviridae, having seven serotypes: A, O, C, SAT1, SAT2, SAT3, and Asia 1. Serotype variability means that an immune response is serospecific and vaccines are thus designed to protect against each serotype independently. A host's adaptive immune response is key in defence against pathogens; however, this virus uses successful strategies (along with most microorganisms) enabling it to evade a host's immune system to rapidly and efficiently establish itself within such host, and thus remain there. This review has been aimed at an in-depth analysis of the immune response in cattle and swine regarding FMD virus, the possible evasion mechanisms used by the virus and describing some immunological differences regarding these species. Such aspects can provide pertinent knowledge for developing new FMD control and prevention strategies. [ABSTRACT FROM AUTHOR]

Background: Japanese encephalitis virus (JEV) is the leading cause of viral encephalitis in Asia. JEV infection of mice and humans can lead to an uncontrolled inflammatory response in the central nervous system (CNS), resulting in a detrimental outcome. Pigs act as important amplification and reservoir hosts, and JEV infection of pigs is mostly subclinical. Information on virus spread in the CNS and immune responses controlling JEV infection in the CNS of pigs, however remains scarce.Methods: Nine-week-old pigs were inoculated intranasal or intradermal with a relevant dose of 105 TCID50 of JEV genotype 3 Nakayama strain. Clinical signs were assessed daily, and viral spread was followed by RT-qPCR. mRNA expression profiles were determined to study immune responses in the CNS.Results: Besides a delay of 2 days to reach the peak viremia upon intranasal compared to intradermal inoculation, the overall virus spread via both inoculation routes was highly similar. JEV appearance in lymphoid and visceral organs was in line with a blood-borne JEV dissemination. JEV showed a particular tropism to the CNS but without the induction of neurological signs. JEV entry in the CNS probably occurred via different hematogenous and neuronal pathways, but replication in the brain was mostly efficiently suppressed and associated with a type I IFN-independent activation of OAS1 expression. In the olfactory bulb and thalamus, where JEV replication was not completely controlled by this mechanism, a short but strong induction of chemokine gene expression was detected. An increased IFNy expression was simultaneously observed, probably originating from infiltrating T cells, correlating with a fast suppression of JEV replication. The chemokine response was however not associated with the induction of a strong inflammatory response, nor was an induction of the NLRP3 inflammasome observed.Conclusions: These findings indicate that an adequate antiviral response and an attenuated inflammatory response contribute to a favorable outcome of JEV infection in pigs and help to explain the limited neurological disease compared to other hosts. We show that the NLRP3 inflammasome, a key mediator of neurologic disease in mice, is not upregulated in pigs, further supporting its important role in JEV infections. [ABSTRACT FROM AUTHOR]