Introduction
  In 1998, Aa highly fataln infectious disease with a high fatality rate causing encephalitis symptoms started to breakbroke out in Malaysia in 1998, which led to the discovery of. A a new causative virus called Nipah virus was discovered. Such eEmerging viral infections such as this one have recently occurred in many places all over the world without discrimination, and Japan should always also permanently considerbe prepared with countermeasures, so as to be able to respond to cope with possible occurrences. Nipah virus infection is an example where the causes could bewere elucidated promptly after the outbreak leading to the successful control of the disease, and the infection could be successfully brought under control, and where the route of infection and the natural host could be clearlywas also identified. In tThis article, we will give an overview of the backgroundhistory to of this infectious diseasen from its initial discovery outbreak to the elucidation of its etiology, and we will briefly describeas well as its pathological manifestations and recent outbreaks. We will also , followed by introduce thea description of progress of research into on this illnessdisease.
1. Initial Background to the manifestationoutbreak of Nipah virus infection and process of elucidation of its etiology
  In 1997, Ppatients presenting encephalitis symptoms began to show upbe seen in Malaysia, in the pig farming area of in Ipoh, in the State of Perak, a state located in the Nnorth of the Malay Peninsula in Malaysia in 1997. One of these patients died. In October 1998, encephalitis broke out and struckaffecting mainly adult males, resulting in 15 deaths. Fifteen patients passed away in the neighborhood of Ipoh alone until by February of the following year1999. During the same period, A a major epidemic of a violent severe respiratory disease hit was seen among pigs in the Ipoh pig farming region during the same period. The number of hospitalized patients hit affected by Nipah virus infection from during this 1998 through -1999 epidemic was totaled 265, and with the mortality rate reachinged approximatel nearly 40%. At that timeDuring this period in Singapore, where pigs had been imported from Malaysia, eleven 11 people became ill in Singapore also, which had imported pigs from Malaysia, and one of the patients passed awaywere affected resulting in 1 death. This illnessThe disease was initially diagnosed as Japanese encephalitis (JE) for the following reasons:, since Malaysia is a country where that disease isJE is endemic to Malaysia,; JE is a mosquito-borne disease in which pigs propagate the disease as the Japanese encephalitis virus is spread by mosquitoes serve as amplifiers of the virus; and specific IgM antibodies to Japanese encephalitisJE virus were detected in the patients' sera. The Malaysian authorities thus immediately instructed carried out an the immunization program of people and pigs against Japanese encephalitisJE in people and pigs. However, the possibility of another infectious diseasen was suspectedremained, since as some the epidemiological findings showed that some points weredid not matching the characteristics of a Japanese encephalitisJE outbreak. Later iIn March 1999, a virus forming that induces multinucleated giant cells in Vero cells was isolated from patient samples of patients byat the University of Malaya. Polymorphous pParamyxovirus-like polymorphous particles of 160-300 nm were observed by means of electron microscopy. All the studies ontests for the arboviruses, to which Japanese encephalitisJE belongs, showed that the virus wasproved negative,negative, and while a cross reactivity with antibodies to Hendra virus, which was isolated in Australia, was observedfound. For this reason, the virus was called Hendra-like virus during a certain period offor some time. A Ddetailed genetic analysis allowed to identifyrevealed that it is a new virus whose genome sequence is significantly different from the sequencethat of Hendra virus. This new virus was christened named Nipah virus after the name of the village where it was isolated.
2. Natural host and route of infection of Nipah virus
  Studies attempting to find the origin of Nipah virus were hastened by Sthosetudies on the search forconducted to find the natural host carried out during an outbreak of Hendra virus, which is was found to be the closest to Nipah virus according to the resultsas a result of genetic analysis, served as a reference for identifying the origin of Nipah virus. In the case of Hendra virus,A a large-scale survey on of wild animals living in Australia was conducted on Hendra virus, and which identified fruit bats were identified as the natural host of the virus. Fruit bats are also distributed in Malaysia, although of species different from those in Australia live in Malaysia too, and the Ipoh pig farming region is also very close to forests with large populations of fruit bats. Serological tests on in fruit bats and on insectivorous bats allowed to resulted in the detection of neutralizing antibodies to Nipah virus from five 5 species of fruit bats. The seroconversion seropositive rates waswere several %a few to 27%. percent. Afterward Nipah virus was later detected isolated from the urine of fruit bats, whose genome sequence . Since the genetic sequence matched that of the virus isolated from humanspeople,. it became evidentThis revealed that the causative virus of this outbreak originated from with fruit bats.
  The route of Nipah virus infection of Nipah virus from fruit bats to pigs has not been clearly identified. However, since Nipah virus is discharged fromexcreted the in urine and the saliva and the virus is has been isolated from the urine of fruit bats and from half-eaten fruit gnawed at by thems, pigs assumedly becameare presumed to have been infected with the virus by coming into through close contacts with these contaminated materials. This Ttransmission between among pigs is also presumed to occurred through dischargesexcretions, such as saliva and urine. However, it is considered that one significant contributing factor to the rapid spread of the epidemic that brought increased damage was the JE immunization of pigs conducted as part the emergency measures during the initial phase, in which the same immunization needle was used on of a large population ofmany pigs against Japanese encephalitis with the same needles during the initial emergency measures had probably a strong impact on the rapid spread of the epidemic and on the magnitude of the damages. As regardsWith respect to the route of transmission of the infection to humanspeople, there is no example case in Malaysia evidencingwhere it was proved that the virus was directly infection transmittedof from humans by fruit bats to people. Since In addition, a great number of patients were pig farmers in who come in direct contact with pigs. These facts seem to suggest that, the virus was probably transmitted by from fruit bats to pigs, in which it was amplified, and was then passed on to humans people in who come in close contact with pigs after propagating inside their bodies. There was seemed to be virtually no probability possibility of person-to-person spreadtransmission, since no transmission between to patients' family members of households andor to persons who treated and nursed the patientsprovided treatment or care was seen was observed. However, as we will mention later ondescribed in a later section, pigs are presumed not to be involved in virus transmission in new recent outbreaks observed occurred in recent years in Bangladesh were assumedly due to infection not transmitted through pigs.
3. Present status ofCurrent outbreaks
  No new outbreaks have occurred in Malaysia after since the epidemic that ended in 1999. However, Nipah virus remains present in the fruit bat populations, and cases of serum antibody-positive cases amid fruit bats have been reported even also in areas free of infection. Separately Apart from this epidemic, outbreaks of Nipah-like virus infection showing causing encephalitis the symptoms of Japanese encephalitis have been reported in Bangladesh, resulting in 9, 8 and 38 deaths in. Nine cases were notified in 2001, eight in 2003 and thirty-eight in 2004, respectively. This epidemic isThese outbreaks are now considered as a re-emergence of Nipah virus infection. The estimated mortality rates is assumedly were 50-70%, although these percentage figures includes also cases where Nipah virus infection has could not be been established as the cause. Since this these new outbreaks does did not occur in pig raising farming areas and many patients are were young persons people who had never come in had any contact with pigs, the infection is suspected to have been transmitted not through pigs but by direct contact with fruit bats or through half-eaten fruit gnawed at by thems without being spread through pigs. It has beenis also assumed presumed that the infection was spread transmitted from person to person through close contacts between among household family members. Nonetheless There have nonetheless been no reported cases of infection transmitted to health care providers who treated the patients were reported.
4. Clinical manifestations
  Encephalitis symptoms are the main clinical signs symptoms observed in humanspeople. After Tanhe incubation period is of 4-18 days., The ssymptoms begin with fever and are, followed by headache and drowsiness. Some patients complain of neck stiffness, anxiety, paralysis, nausea and vertigo. Furthermore Additional symptoms of that may occur include disorientation, mental confusion, abnormal behavior and loss of memory may also occur. In severe cases, Severely affected the patients may fall into a coma after 3-30 days and pass awaydie. Respiratory symptoms are rare. The fatality rate was approximately 40% in hospitalized patients during the epidemic in Malaysia. Although there are no confirmed cases caused byof onset due to person-to-person spread transmission have been confirmed in Malaysia, it will beis still necessary to take measures to control the infectionprevent transmission among people, since because the virus discharges have been observedhas been found excreted in the patients' urines and pharynx swabs, of patients and cases ofelevations in antibody elevation titers have been noted amid in the some nursing staffcaregivers.
  Symptoms observed in pigs are primarily acute respiratory symptoms. Symptoms iIn weanling piglets, include dyspnea and harsh severe coughing are observed, and severe cases may present with neurological symptoms such as twitches, etcspasm. follow when the course of the disease becomes more serious. The sSymptoms exhibited byin adult pigs are acute fever, open mouth breathing, hypersalivation and nasal discharges occasionally tinged with blood. They may at times beare in some cases accompanied by neurological symptoms, such as behavioral anomaliesabnormal behavior and convulsions. The infection rates in pigs is are high, and most of the animals raised in the one same farms will become infected. However, the lethality mortality rate is low, on the order of ( 2-5%). Infection in animals other than pigs has been observed in dogs, cats and horses.
5. Diagnosis and treatment
  Since there have been so far no infection casespatients infected with Nipah virus in Japan so far, it will beis necessary to monitor primarily individuals immediately who have recently after returningreturned to Japan after residing or travelingfrom in, mainly, South East Asian countries where they resided or traveled to, in particular individuals those with who have a history of direct contacts with pigs. Moreover, since as there may be in future a risk ofcases of Nipah virus infection without a history of contacts with pigs may occur in the future, it will bise necessary to collect on a permanent basis informationkeep ourselves informed and to provide this information to travelers to regions inhabited by fruit bats. The finalA definitive diagnosis is can be made with RT-PCR, virus isolation and immunohistochemical tests using serum, urine and throat swab samples, and RT-PCR, virus isolation and immunohistochemical tests are performedor in post-mortem cases on using specimens of brain, lungs, and kidney samples, among others, etc. ELISA and neutralization techniques assays are used in antibody tests.
  Treatment relies on symptomatic therapy for the usualcommon viral diseases. There is no efficacious treatment methodtherapy. When the condition aggravates, the lethality increasesMortality rates are high in severe cases, and there are many cases of which may exhibitdeveloping neurological symptoms sequelae as sequels even after recovery.
6. Current Sstatus of research
  Sero-epidemiological surveys on of fruit bats are beingextensively carried out extensively in South East Asia. A detailed study is ongoing under way for the elucidation of the route of infection in recent epidemics where pigs are were not the intermediatesinvolved in virus transmission. Fundamental studies on of functions of each individual viral proteins function and research on diagnostic techniques are under way in various countries including Japan. The WHO and the U.S. Centers for Disease Control and Prevention (CDC) are recommending isolation containment facilities of at P3 and oveor P4 containment levelr for research involving manipulations handling of infectious viral particles and P4 isolation containment facilities for infection experiments on infections. Therefore studies Studies involving infection experiments on infections arehave thus been carried out mostly in France and in in the U.S.-based CDC that wherehave access to P4 experimental containment laboratories are available. Research for theand development of an effective techniques to induce immunity induction technique is also in progressing. For the moment, It has been shown so far in infection experiments on infections using animal models have shown that the a recombinant vaccinia virus that expresses Nipah virus the membrane proteins of Nipah virus induces an effective immunocompetenceimmunity. In Japan, No no research has been conducted involvingthat involves manipulations handling of infectious virusess is being done in Japan, since as no P4 containment facilities are runningin operation. However, but testing methods procedures available to be followed in case of necessity have been established in Japan also by several organizationsinstitutions. We The authors have also established an antigen detection process methods using RT-PCR and as well as an ELISA systems detecting for the detection of Nipah virus antibodiesy and antigens, by means ofusing a methods using that utilize proteins expressed from gene fragments. Furthermore, we have developed a reverse genetics system for the creation of a recombinant viruses, and, through collaborative studies with foreign countries where P4 containment facilities are available, we are doing working on virological fundamental research studies as well as and studies forresearch and the development of for an efficacious vaccines jointly with foreign countries where P4 facilities are available.