Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV), a novel phlebovirus reported to be endemic to China in 2011. In Japan, the first SFTS patient was identified during the autumn of 2012; since then, over 100 SFTS patients have been reported. The SFTSV has been identified throughout Japan over the past two years; however, SFTS patients are specifically localized to western Japan. The clinical symptoms of SFTS include fever, thrombocytopenia, leukocytopenia, gastrointestinal symptoms, and various other symptoms, including muscular symptoms, neurological abnormalities, and coagulopathy. SFTS is often accompanied by hemophagocytic syndrome. The histopathological findings are characterized by necrotizing lymphadenitis, with infiltration of the virus-infected cells to the local lymph nodes. Pathophysiological analyses of SFTS include studies regarding the kinetics of cytokine production and immune responses in patients with SFTS and in SFTSV-infection animal models. This article aimed to survey the history of SFTS in Japan and to review the clinical, epidemiological, and virological aspects of SFTS and SFTSV infection.

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Human parechoviruses (HPeVs) are single-stranded, positive-sense RNA viruses and are classified in the genus Parechovirus of the family Picornaviridae. Echovirus 22 and 23 were reclassified as HPeV1 and 2 in 1999. Although HPeVs were considered to be one of the common viruses which cause mild gastroenteritis and respiratory infections, the concept of HPeVs has changed significantly after the discovery of HPeV3 in 2004. HPeV3 infection is an emerging infectious disease which attracts the attention of pediatricians, because it can cause sepsis and meningoencephalitis in neonates and infants younger than 3 months, which could lead to neurological sequelae and death. In Japan, the epidemics of HPeV3 infection have occurred every 2 or 3 years since 2006 and we had an epidemic in 2014 summer. Fever, severe tachycardia, poor activity and appetite are typical symptoms of HPeV3 infection.In addition, abdominal distention, umbilical protrusion, palmar-plantar erythema,and mottled skin are occasionally observed in patients with HPeV3 infection. Currently diagnosis is usually made by PCR using serum and/or cerebrospinal fluid. The reason why severe disease occur only in neonates and young infants remain unknown; however, negative or low maternally derived neutralizing antibody titers to HPeV3 are suggested to be a risk factor for developing severe HPeV3-related diseases in neonates and young infants. So far, no specific antiviral therapy is available, thus supportive care is the only option. It is likely that epidemics of HPeV3 continue to occur given there are children with absence or lack of neutralizing antibodies against HPeV3. The research related to HPeV3 pathogenesis, specific therapy, and prevention are definitely warranted.

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Retrovirus vectors (gammaretroviral and lentiviral vectors) have been considered as promising tools to transfer therapeutic genes into patient cells because they can permanently integrate into host cellular genome. To treat monogenic, inherited diseases, retroviral vectors have been used to add correct genes into patient cells. Conventional gammaretroviral vectors achieved successful results in clinical trials: treated patients had therapeutic gene expression in target cells and had improved symptoms of diseases. However, serious side-effects of leukemia occurred, caused by retroviral insertional mutagenesis (IM). These incidences stressed the importance of monitoring vector integration sites in patient cells as well as of re-consideration on safer vectors. More recently lentiviral vectors which can deliver genes into non-dividing cells started to be used in clinical trials including neurological disorders, showing their efficacy. Vector integration site analysis revealed that lentiviruses integrate less likely to near promoter regions of oncogenes than gammaretroviruses and no adverse events have been reported in lentiviral vector-mediated gene therapy clinical trials. Therefore lentiviral vectors have promises to be applied to a wide range of common diseases in near future. For example, T cells from cancer patients were transduced to express chimeric T cell receptors recognizing their tumour cells enhancing patients' anti-cancer immunity.

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Marine microalgae, in general, explain large amount of the primary productions on the planet. Their huge biomass through photosynthetic activities is significant to understand the global geochemical cycles. Many researchers are, therefore, focused on studies of marine microalgae, i.e. phytoplankton. Since the first report of high abundance of viruses in the sea at late 1980's, the marine viruses have recognized as an important decreasing factor of its host populations. They seem to be composed of diverse viruses infectious to different organism groups; most of them are considered to be phages infectious to prokaryotes, and viruses infecting microalgae might be ranked in second level. Over the last quarter of a century, the knowledge on marine microalgal viruses has been accumulated in many aspects. Until today, ca. 40 species of marine microalgal viruses have been discovered, including dsDNA, ssDNA, dsRNA and ssRNA viruses. Their features are unique and comprise new ideas and discoveries, indicating that the marine microalgal virus research is still an intriguing unexplored field. In this review, we summarize their basic biology and ecology, and discuss how and what we should research in this area for further progress.

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After Guinea reported an outbreak of Ebola virus disease (EVD) in March 2014, EVD spread to neighboring Sierra Leone and Liberia in West Africa. Since then, the EVD outbreak spread over a wide geographic area among these three countries, and became the largest EVD epidemic ever with unprecedented numbers of confirmed cases and fatalities. As of April 2015, one year past the start of the outbreak, transmission is still ongoing. And, while six other countries, including those outside of the African continent (the United Kingdom, Spain, and the United States), have reported EVD cases, the source of the infection all originated from Guinea, Sierra Leone, or Liberia. As for the pathogen, Ebola virus, the route of transmission and associated prevention measures are well known, and change in the virulence or transmissibility of the virus has not been confirmed. However, there are specific factors that likely contributed to the unprecedented magnitude of the current EVD outbreak. In addition to the limited and poor medical and public health infrastructure in the affected countries, implementing appropriate responses rapidly was challenging for these countries, whose medical community, the general public, and governments had never experienced EVD before.

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Ebola virus causes Ebola virus disease (EVD) with high case fatality rates in humans and has caused sporadic outbreaks with less than 500 cases. An EVD outbreak in West Africa, which probably started at the end of 2013, has an unprecedented large-scale with more than 20,000 cases including more than 10,000 death and is still ongoing as of May 2015. National Institute of Infectious Diseases has developed laboratory diagnostic methods of EVD to detect pathogens (genes or protein) and antibodies. The methods have been recently used for suspected cases approximately once a year before the outbreak in West Africa, but after the outbreak for 7 times within this 6 months for suspected cases coming back from 3 countries of West Africa to Japan.

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Filoviruses (Ebola and Marburg viruses) cause severe hemorrhagic fever in humans and nonhuman primates. No effective prophylaxis or treatment for filovirus diseases is yet commercially available. The recent outbreak of Ebola virus disease in West Africa has accelerated efforts to develop anti-Ebola virus prophylaxis and treatment, and unapproved drugs were indeed used for the treatment of patients during the outbreak. This article reviews previous researches and the latest topics on vaccine and therapy for Ebola virus disease.

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Ebola virus is an enveloped virus with filamentous structure and causes a severe hemorrhagic fever in human and nonhuman primates. Host cell entry is the first essential step in the viral life cycle, which has been extensively studied as one of the therapeutic targets. A virus factor of cell entry is a surface glycoprotein (GP), which is an only essential viral protein in the step, as well as the unique particle structure. The virus also interacts with a lot of host factors to successfully enter host cells. Ebola virus at first binds to cell surface proteins and internalizes into cells, followed by trafficking through endosomal vesicles to intracellular acidic compartments. There, host proteases process GPs, which can interact with an intracellular receptor. Then, under an appropriate circumstance, viral and endosomal membranes are fused, which is enhanced by major structural changes of GPs, to complete host cell entry. Recently the basic research of Ebola virus infection mechanism has markedly progressed, largely contributed by identification of host factors and detailed structural analyses of GPs. This article highlights the mechanism of Ebola virus host cell entry, including recent findings.

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The outbreak of Ebola virus disease, reported in West Africa in 2014, has become the largest ever one in the history. Tremendous efforts by all the parties concerned are now bringing this epidemic closer to the end, while observing a large number of cases and deaths, including health care workers.
This paper features five questions:
1. Why did it emerge in West Africa?
2. Why has it spread so wide and intensely?
3. Why were so many health care workers infected?
4. Why is it being brought under control?
5. Would it emerge and spread in Japan in the same way?
Ebola virus transmits through human acts such as caregiving of the sick and attending a funeral, therefore an epidemic is not likely to subside naturally, but intentional interventions are needed to terminate its transmission. Who the outbreak response is meant for, either patients, the general public in the affected countries, or international communities, also determines its success or failure.

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Although a globe box-type highly contained laboratory with the internationally-recognized biosafety level-4 standards has been constructed in the Murayama Annex, the National Institute of Infectious Diseases, Tokyo, Japan (NIID) in 1981, the laboratory has never been operated as BSL-4 laboratory since its construction. Furthermore, there are no other BSL-4 laboratories in operation in Japan. The evidence indicates that infectious BSL-4 pathogens such as Ebola and Marburg viruses cannot be manipulated in Japan, making it impossible to study the BSL-4 pathogens using the infectious viruses.
A large-scale outbreak of ebolavirus disease (EVD) has occurred in the western Africa such as Guinea, Sierra Leone, and Liberia. Furthermore, the highly pathogenic pathogens' infectious diseases outbreaks such as SARS, Nipah encephalitis, Middle East respiratory syndrome (MERS) have emerged in the world.
However, BSL-4 laboratories are not present in Japan, making it difficult to study these pathogens and infectious diseases. Because these emerging virus infections are caused by the zoonotic pathogens, the eradiation and the elimination of these infectious diseases are impossible. We need to develop the diagnostics, therapeutics, and preventive measures based on the studies of the highly pathogenic pathogens more in detail using the infectious microbes. Therefore, BSL-4 in operation in Japan is required to minimize the risk of and combat these emerging highly pathogenic pathogens' infectious diseases.

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In outbreak response against Ebola virus disease (EVD), hospitals isolating the patients have a vital role to control disease transmission in communities. As of May 2015, there have been 7 suspected cases of EVD reported in Japan, but all of them were negative for ebolavirus. When a suspected case traveling from West Africa had no direct contact with EVD patients, the probability of EVD would be generally low. Patients with EVD seem more infectious when they have gastrointestinal symptoms. The peak of disease is usually observed at day 7-10 of illness. Over 25 patients with EVD have been treated in Europe and North America during the current outbreak. Lower mortality rate observed in the well-resourced settings could be attributable to aggressive supportive therapy including mechanical ventilation and renal replacement therapy. The safety and effectiveness of investigational drugs remain unknown. Protecting healthcare workers from infection is so important that guidelines on personal protective equipment and post-exposure prophylaxis are developing. Although the number of designated hospitals has increased across Japan, the current medical care system for patients with highly infectious diseases deserves reconsideration.

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Ebola Virus Disease (EVD) is categorized in the Category 1 Infectious Disease under the Act on Infectious Disease Control. Since the Act came into effect in 1999, no confirmed case of viral hemorrhagic fevers (VHF) has been reported, though some clinical samples have been tested for VHF in the National Institute of Infectious Diseases of Japan.
Ministry of Health, Labour and Welfare has monitored the situation of the EVD outbreak in West Africa since the first report from Guinea in March 2014 and reinforced quarantine and public health preparedness in August. The whole-of-government response was activated at the end of October, establishing the Ministerial meeting on the Response to the EVD presided by the Prime Minister. The responses have raised the level of preparedness for such a rare import disease like VHF; however elicited many lessons. Even if the current VHF outbreak is over, the risk of the global infectious diseases outbreak will be unchanged. The maintenance and improvement of preparedness and response for infectious diseases emergency such as the Category 1 Infectious Disease outbreak by the improvement of manuals and continuous exercises are crucial for a future domestic response. In addition, human resource development is essential for contributing to global response efforts.

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[in Japanese]

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[in Japanese]

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Understanding the mechanisms by which influenza viruses are recognized by the innate immune system to elicit a protective adaptive immune response is essential for the development of effective vaccines. We have demonstrated that synthetic double-stranded RNA poly(I:C) is an effective adjuvant for intranasal influenza vaccine. Furthermore, we found that influenza virus activated the NLR　family, pyrin domain-containing 3 (NLRP3) inflammasome via its M2 protein. Inflammasome activation in the lung coupled with priming signals from the commensal microbiota in the gut are essential for the generation of influenza virus-specific adaptive immune responses. These results provide a useful basis for developing effective vaccines against influenza viruses.

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Viroporins are small and hydrophobic viral proteins that form pores on host cell membranes, and their expression can increase the permeability of cellular membranes and the production of progeny virus particles. JC virus (JCV) is the causative agent of progressive multifocal leukoenchephalopathy (PML). We demonstrate that JCV Agno, which is the small and hydrophobic protein, andincreases the plasma membrane permeability and virion release, acts as a viroporin. We also demonstrate that an interaction of Agno with a host cellular protein regulates the viroporin activity of Agno. These findings indicate a new paradigm in virus-host interactions regulating viroporin activity and viral replication.

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Borna disease virus (BDV), belonging to the non-segmented, negative-stranded RNA viruses, persistently infects the central nervous system of many mammals. Neonatal BDV infection in rodent models induces neurodevelopmental disturbance without overt inflammatory responses, resulting in a wide range of neurobehavioral abnormalities, such as anxiety, abnormal play behaviors, and cognitive deficits, resembling those of autism patients. Therefore, studies of BDV could provide a valuable model to investigate neuropathogenesis of neurodevelopmental disorders. However, the detailed neuropathogenesis of BDV has not been revealed. Here, we proposed two novel mechanisms that may contribute to BDV neuropathology. The first mechanism is abnormal IGF signaling. Using transgenic mice expressing BDV P protein in glial cells (P-Tg) that show neurobehavioral abnormalities resembling those in BDV-infected animals, we found that the upregulation of insulin-like growth factor (IGF) binding protein 3 in the astrocytes disturbs the IGF signaling and induces the Purkinje cell loss in BDV infection. The other is the integration of BDV sequences into the host genome. We recently found that BDV mRNAs are reverse-transcribed and integrated into the genome of infected cells. BDV integrants have the potential to produce their translated products or piRNAs, suggesting that BDV might exhibit the pathogenicity thorough these molecules. We also demonstrated that BDV integrants affect neighboring gene expression. Collectively, BDV integrants may alter transcriptome of infected cells, affecting BDV neuropathology.

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