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On August 13, 2010, public health officials in Southwest Michigan informed community members that a third person had contracted an infection from Eastern Equine Encephalitis Virus. Before the end of the summer, one more person would become infected, bringing the annual total in that small corner of the state to four (Emerging Disease Issues). Though four cases does not make for an epidemic, this sudden increase in prevalence had health officials concerned, especially considering the average annual number of cases of human EEEV infections in the United States is six (Centers for Disease Control), and that since 1964 there have only been 13 confirmed cases in the entire state of Michigan (Centers for Disease Control). In an effort to appreciate the seriousness of this somewhat obscure virus as an infectious agent in Michigan, this paper will look at the morphology and "lifestyle" of EEEV, and will discuss at length the disease it causes and its impact on public health. The status of current research and prospects for future research into EEEV will also be discussed.
Structure and Classification
Public health officials have long been aware of EEEV and the risk it poses to both horses and people. It was first isolated in horses in 1933, and in humans in 1938 (Aguilar et al., 4920). It is a member of the family Togaviridae and the genus Alphavirus (Centers for Disease Control). There are four subtypes of EEEV based on antigenic differences between strains (Arrigo et al., 1014). Subtype I includes all North American and Caribbean strains, while subtypes II, III, and IV include strains from South and Central America (Arrigo et al., 1014). The subtypes of EEEV vary at the nucleotide level by as much as 38%. Interestingly, the North American subtype is known to cause disease in humans while the South American strains do not (Arrigo et al., 1015).
EEEV is an enveloped virus with an icosahedral capsid, and possesses a non-segmented, single-stranded RNA genome, making it a member of the Baltimore classification IV (Aguilar et al., 4920). The genome is approximately 11.7 kilabases in size and is of a positive sense, meaning it can function directly as an mRNA transcript and be read from 5' to 3' by the host cell ribosome during translation (Aguilar et al., 4920).
Similar to other Alphaviruses, EEEV replication occurs in the cytoplasm of infected cells. The genome has both a 5' Cap and a poly (A) tail that function to recruit the cell ribosome for translation and to prevent degradation, respectively (Arrigo et al., 1014). Like other positive sense RNA viruses, translation of the two open reading frames of the EEEV genome results in the formation of a large polypeptide that is later cleaved into smaller protein units (Aguilar et al., 4920). The genome encodes three major structural proteins, the capsid and two envelope proteins (Aguilar et al., 4920). The envelope proteins, E1 and E2, are quite versatile and are involved in host cell receptor recognition and binding to these receptors during attachment (Aguilar et al., 4920). They are also the key proteins involved in penetration and membrane fusion during entry into the host cell (Aguilar et al., 4922). Additionally, the envelope proteins interact with the capsid during viral assembly and release of particles (Aguilar et al., 4923). The EEEV genome also encodes four non-structural proteins, including a protease, that are used for viral replication, RNA, and polypeptide processing (Aguilar et al., 4920).
EEEV is endemic to North America, where its natural reservoir is wild birds (Schmitt et al., 636). The avian hosts of EEEV typically reside in freshwater hardwood swamps (Centers for Disease Control). EEEV is considered an arbovirus, an acronym standing for arthropod-born virus (Centers for Disease Control). Transmission from bird to bird is typically carried out by the mosquito Culiseta melanura, a species of mosquito that feeds almost exclusively on birds (Centers for Disease Control). Transmission of EEEV to non-bird species, including humans, however, is usually carried out by mosquito species of the genera Coquillettidia and Aedes (Michigan Department of Natural Resources and Environment). These mosquitoes function as bridge vectors, transferring the virus from infected birds to uninfected mammals, reptiles, and amphibians (Schmitt et al., 635). Animals besides birds are said to be "dead-end hosts" because they cannot pass the infection on to other animals and do not circulate enough virus in their blood to pass the infection on through mosquitoes (Centers for Disease Control).
Once in the body, EEEV travels via lymphatic ducts to lymph nodes where it replicates in neutrophils and macrophages (Cooper and Scott, 1405). Following an incubation period of between four and ten days, these cells begin to exhibit cytopathic effects. Cells become shriveled and display elongated cytoplasmic edges (Vogel et al., 163). At this stage of infection, the host innate immune response is typically activated as evidenced by the release of interferons from host lymphocytes (Vogel et al., 162). The EEEV infection can either be cleared from the body or result in disease, namely encephalitis (swelling of the brain) or systemic viremia (Centers for Disease Control). The type of illness contracted depends on a variety of host factors including age and immune system health (Centers for Disease Control).
Systemic viremia infection typically lasts one to two weeks and is characterized by fever, chills, lethargy, and myalgia (Roy et al.). Provided there is no involvement with the central nervous system, recovery from systemic EEEV infection is usually complete. The encephalitic form of the disease (Eastern Equine Encephalitis, or EEE) usually arises after one to several days of systemic infection, except in infants where signs of encephalitis appear rapidly (Vogel et al. 162). Symptoms of encephalitis include fever above 103-degrees Fahrenheit, headache, vomiting, diarrhea, a stiff neck and back, anorexia, convulsions, and coma (Centers for Disease Control).
The Centers for Disease Control report that nearly one-third of people who contract an encephalitic infection from EEEV die from the disease. Of those who recover, many are left with debilitating chronic mental and physical problems such as seizures, intellectual impairment, nerve dysfunction, and personality disorders (Centers for Disease Control). The disease is even more deadly in horse populations, where it kills between 75 and 90 percent of the animals it infects (Schmitt et al., 637).
The high fatality rate makes EEE one of the most dangerous mosquito-born diseases in North America, and to date there is no cure. The disease does not typically respond to aciclovir or other commonly used antiviral drugs (Centers for Disease Control). Symptoms are treated with anticonvulsants and anti-inflammatory medications such as corticosteroids (Centers for Disease Control). Other measures are taken to provide supportive care for patients, including administration of intravenous fluids and antipyretic drugs (fever reducers), and tracheal intubation (Centers for Disease Control). In horses, the antiviral drug Ribavirin has been used to treat encephalitic illness with some modest success (Michigan Department of Natural Resources and Environment).
As previously stated, EEEV is transmitted to humans only through the bite of an infected mosquito. Because the natural reservoir for EEEV is wild birds, this virus's primary transmission cycle is rural in nature, occurring mainly in scarcely populated hardwood swampy areas (Michigan Department of Natural Resources and Environment). Consequently, infections in humans are relatively rare. Since 1964, an average of only six cases of human EEEV infection have been reported annually in the United States (Centers for Disease Control). People living and working in rural areas are at highest risk of infection, though only about 4% of human EEEV infections actually result in Eastern Equine Encephalitis, and the majority of those occur in people older than 50 or younger than 15 (Centers for Disease Control). Those infected by EEEV acquire life-long immunity against re-infection, but do not gain immunity against other encephalitic viruses of the Alphavirus genus such as Venezuelan Equine Encephalitis or Western Equine Encephalitis (Centers for Disease Control).
In the United States, most cases of human EEEV infection occur in the southeast states of Georgia, Florida, Louisiana, North Carolina, South Carolina, and Mississippi, though infections periodically occur in states in the northeast and Great Lakes. Since 1964 when the CDC began keeping records on EEEV infections, no state West of Texas has reported a human infection (Centers for Disease Control). The virus has an overall geographic distribution that extends north into the Eastern Canadian provinces of Ontario, Quebec, and New Brunswick, and south into the eastern portion of Mexico, through Central America, and as far into South America as Eastern Argentina (Centers for Disease Control).
With the advent of the molecular era of biology, much of the current research on Eastern Equine Encephalitis Virus is directed at understanding this pathogen on a small scale. Some evolutionary biologists are using RNA sequence data to better understand the similarities and differences that exist between the EEEV and other closely related Alphaviruses like Western Equine Encephalitis Virus, Venezuelan Equine Encephalitis Virus, and Sindbis Virus (Arrigo et al., 1016). Also, a good deal of current research is focused on understanding the virus-host interactions between EEEV and the many animals it can infect, especially on the bird species that serve as its natural reservoir. Perhaps the greatest amount of resources, though, is devoted to disease prevention and epidemiological studies to track outbreaks of EEEV in the United States.
Potential for Weaponization
Though many infectious viruses are considered as possible agents of biological warfare, few possess as many of the characteristics necessary for successful weaponization as the Alphaviruses (Croddy and Wirtz, 125). In fact, the former Soviet Union reportedly had a large stockpile of weaponized EEEV (Croddy and Wirtz, 126). The United States also conducted research into the use of EEEV as a weapon before it ratified the Biological Weapons Convention in 1972, putting a stop to all biological warfare activity (Croddy and Wirtz, 127). The virus can be grown easily in large quantities inexpensively. Being a BSL-1 or 2 agent, EEEV is in stock in numerous research laboratories in the United States and could most likely be attained with relative ease. A recent study on guinea pigs, the animal model of choice for evaluating the impact of many aerosolized infections, concluded that EEEV particles are stable and highly infective in aerosol form (Roy et al.,). Furthermore, the multiple serotypes of EEEV make the development of effective defensive vaccines against it quite difficult (Croddy and Wirtz, 128).
Public health officials in Michigan have confirmed 130 cases of Eastern Equine Encephalitis in horses so far in 2010 (Michigan Department of Natural Resources and Environment). However, it is the four confirmed human cases, the first in Michigan since 2002, which have that state's residents most concerned (Emerging Disease Issues) One possible reason for this increase in prevalence of this disease is the weather (Michigan Department of Natural Resources and Environment). In 2010, Michigan experienced one of its hottest and wettest summers on record, making conditions very favorable for mosquito growth and reproduction. Additionally, local veterinarians fear that poor local economies have resulted in less horses being vaccinated against the disease. According to one estimation, EEEV vaccination in Michigan horses is down by as much as 40% compared to just ten years ago (Emerging Disease Issues). This speculation, of course, bears no impact on the number of human cases, as mammals are dead-end hosts for EEEV. County, State, and Federal health officials closely monitor all suspected and confirmed cases of EEE in Michigan, and great measures are taken to reduce mosquito populations during peak times of the year.
Future research into EEEV will likely steer down many roads. Evolutionary biologists will continue to uncover the molecular relationships between the variants of EEEV and other closely related Alphaviruses. Epidemiologists will continue tracking outbreaks of the EEEV disease and local public health authorities will continue to work to reduce mosquito populations during peak summer months. Virologists and pathologists will continue to elucidate the mechanisms by which EEEV causes disease in animals and humans, and hopefully uncover the reasons why the immune systems of some are able to clear the infection while others develop debilitating and often fatal encephalitis.
The deadliness of EEEV infections makes the virus a legitimate public health concern. Though the rise in prevalence of human EEE in my home area of Michigan may have been the result of an unusually hot summer with very high precipitation creating conditions optimal for mosquito growth, it also may have been a simple statistical anomaly. We will probably never know. What is known, though, is that in the absence of a means of eradicating this disease, which would mean eradicating the birds who serve as its natural reservoir, continued measures are needed to ensure close monitoring and prompt response to EEEV outbreaks, modest as they may be.