User:Sami.vanhoven/sandbox

Getah Virus

Getah virus is an arbovirus belonging to the Alphavirus genus in the Togavirdae family. The virus was first isolated in 1955 from a mosquito on a rubber plantation in Malaysia. In Malay, the Malaysian language, the word for rubber is Getah which is how the Getah virus obtained its name. This virus has been known to cause disease in pigs and horses, although antibodies have been found in other species of animals as well such as humans. Humans and other species are not technically considered hosts because they do not show symptoms when exposed to this virus, even though antibodies have been found. The main host of Getah virus is the horse, especially horses found in race horse training facilities where many horses are in close proximity to each other and where they are likely to be infected by the same mosquitos. The first outbreak occurred in race horses in Japan and other cases since then have mostly been limited to the Western Hemisphere. The largest outbreaks have all occurred in Japan, but there was one other significant outbreak in India. This virus is spread mainly by mosquitos, specifically the Culex and Aedes species, but it is also hypothesized that there could be some spreading through direct contact between infected animals .

Structure and Genome

Getah virus was first isolated in 1955 from the Culex gelidus mosquito in Malaysia and since then has been isolated many times from mosquitos, pigs, horses and other animals. There are thirty one known strains of Getah virus that have been isolated and eight of them have fully sequenced RNA genomes and the majority of other strains have almost totally sequenced genomes. Getah virus has a positive single-stand RNA genome that is about 11 kb in length. The make-up of this genome is as follows: a 5' cap, four nonstructural protein genes, nsP1, nsP2, nsP3 and nsP4, five structural protein genes, C (encoding for the capsid proteins), E1, E2, E3 and 6K, and then a 3' poly-A tail . The genome first produces a protein called P123 which is then cleaved into the non structural proteins. The nsP1 protein is an enzyme involved with creating the 5' cap for the RNA in the cytoplasm, because all of the host cell capping mechanisms are in the nucleus. The nsP2 protein has two parts, the C section and the N section. The N-terminal section contains part of what makes up the RNA polymerase as well as containing activity for RNA triphosphatase and RNA helicase. The C-terminal section contains the protease that cleaves the four nonstructural proteins from P123, as well as inhibits the cellular protein replication and therefore enhances viral replication. The nsP3 protein is essential in the synthesis of the negative strand RNA, and the nsP4 protein is the RNA dependant RNA polymerase.

Replication Cycle

The replication cycle of this virus is a cycle between various vertebrate hosts, most commonly horses and pigs, and the mosquitos that transmit the disease. Mosquitos bite the hosts and the virus is then spread through the blood stream. The virus then enters the cells through endocytosis where they are brought into the cytoplasm of the cell in an endosome. Replication occurs in the cytoplasm of the host cell utilizing the lysosome and endosome membranes as a mechanism to avoid being detect by the host cell defense mechanisms. After the virus replicates its genome, the virions are released by the nucleocapsid budding through the envelope, where it also picks up the E1 and E2 envelope gylcoproteins it previously encoded for.

Interaction with Host

In horses, the main animal affected by Getah virus, symptoms are a fever, anorexia, body rash, nasal dishcharge, and edema in the legs. The other species commonly affected by this virus is pigs. They experience very different symptoms than horses including reproduction disorders usually leading to fetal death without any other physiological symptoms. Neutralizing antibodies have been found in humans and other species of vertebrates, although no symptoms have been observed in these species. These antibodies are specific to the E1 and E2 envelope glycoproteins on the outside of the Getah virus. The antibodies for the E1 protein are generalized across all of the alphaviruses, but the antibodies to the E2 glycoprotein are specific to the one type of virus containing that protein. There is speculation that fevers have been observed in humans, but it has not been proven that it is actually Getah virus causing the headaches in the subjects observed. Other species have been experimentally infected with Getah virus and have experienced symptoms such as pyrexia, anorexia, diarrhea, and signs of mild depression. These experiments show that in nature this virus could possibly begin to infect and cause symptoms to more species of animals, although as of right now the hosts are still mainly horses and pigs.

Outbreaks

First Outbreaks

The majority of outbreaks occur during the later months of the year including August through November, which correlates to peak mosquito season in the Western Hemisphere. The first outbreak of Getah virus occurred at the Miho training facility in Japan during September of 1978. During this outbreak, 722 of the 1,903 horse being kept at this facility were affected with the virus. Since then, there were two other smaller outbreaks that happened in Japan in the years 1979 and 1983, and both of the facilities where these outbreaks occurred were facilities that were not using the vaccine. Another outbreak occurred in India in 1990. This outbreak lasted twenty one days with symptoms for individual horses lasting about seven days. Although this outbreak was smaller than the previous outbreaks in Japan, it was a big deal because it was the first instance of Getah virus outside of Japan that was large enough to be considered an outbreak. There were twenty six out of eighty eight horses that developed symptoms. After this outbreak, horses on other farms in India were tested and there was a presence of antibodies to Getah virus in 17% of the horses tested. This signifies that Getah virus is present in many horses although the onset of clinical symptoms is relatively low, and it is still unconfirmed why certain populations are more likely to develop the sickness from this virus.

Most Recent Outbreak

The most recent outbreak occurred at the same training facility as the first outbreak, the Miho Training facility in Japan, as well as another outbreak occurring recently after at the Ritto training center also in Japan. It is still unclear how this outbreak happened because it was the first time ever an outbreak had occurred in a facility where the horses were being vaccinated. The MI-110 strain used in the vaccine and current circulating strains have been completely sequenced, analyzed and then compared. The phylogenetic analysis of these Getah virus strains shows that there are genetic differences between the strains circulating now and the MI-110 strain that the vaccine was isolated from in 1978. The comparison of these two genomes showed that the main differences between the genomes were occurring in the nonstructural protein 3 region (nsP3) where there were 7 amino acid changes as well as a few other amino acid changes between other nonstructural protein regions. There were very little recorded differences (<1%) between the amino acid sequenced encoding for the capsid proteins, although there were many differences in other coding parts of the genome. This means that the outbreak that occurred in 2014 most likely was not because of the genetic differences between the two strains, and remains unclear. The main hypothesis as to how this outbreak happened is because there is a lot of transferring of horses between the race centers and the surrounding farms, where horses are not vaccinated. The horses at the training facility are less likely to be infected because of the idea of herd immunity, so if the vaccine was not 100% successful they are less likely to get sick, but because of this frequent transferring between the farms and training facilities the horses are exposed to non-vaccinated horses where they could get sick because the amount of the virus circulating exceeded the herd immunity.

Vaccine and Prevention

There is a vaccine for Getah virus which has been the primary reason for the small number of outbreaks since 1979, when the vaccine was introduced. The virus strain used in the vaccine is the MI-110 strain which was isolated from a sick horse during the first outbreak in 1978 at the Miho training facility. This vaccine is given to the horses twice within the first year of their life, and then a booster is also given every year before peak mosquito season. The vaccine has proven to be very effective over the past 30 years, and although thirty one different strains of Getah virus have been isolated across the world over this time period , from 1979 up until 2014 there were no outbreaks in vaccinated horses due to the effectiveness of the MI-110 strain in the vaccine.