**2. Viral related diseases**

Viral infections are important in the induction of encephalitis. Arboviruses are transmitted by arthropods (e.g., mosquitoes, ticks, sand flies) and are maintained through biological transmission between a vertebrate host (Kuno & Chang, 2005). Biological transmission of such a pathogen involves several factors (Reviewed by Scott, 1988). The virus must be able to reproduce in both the arthropod and vertebrate host, then be able to produce a high enough viral titer in the blood of the vertebrate to be passed back to the vector Reviewed by Scott, 1988). It is well known that RNA viruses tend to have a high mutation rate because of unfaithful replication in host cells, among other things (Domingo, 1997). However, to maintain a relationship with both vertebrate and arthropod vectors, observed mutation rates are reduced, as is with New World Alpha viruses (Weaver et al., 1991). When selective pressures are applied to the virus between two alternating hosts, the virus population responds with adaptations fit for both environments in order to optimize suitability in a dual host system (Weaver et al., 1999; Cooper & Scott, 2001).

Zoonotic and Animal Vector Mediated Encephalitides 5

seroprevalence of the virus, with up to 77.2% of the forestry workers testing positive for the antibody (Valassina et al., 2003). This virus is responsible for encephalitis complications,

Rift Valley Fever Virus (RVFV) is named from the region of Kenya from which it was first isolated (Daubney et al., 1931). A wide range of mosquito genera have been shown to maintain the enzoonic cycle (e.g., *Aedes*, *Ochlerotatus*, *Stegomyia*, *Anopheles*, *Culex*, *Neomelaniconion*, *Eretmapodites)*, with *Aedes vexans* and *Culex erraticus* showing successful transmission to other animals to serve as bridge vectors (as reviewed by Pfeffer and Dobler (2010)). Infection in pregnant ruminants induces abortion at all stages of pregnancy to the magnitude that this event is referred to as an "abortion storm" (Kasari et al., 2008). Aborted fetuses, birthing material and body fluids of infected animals carry high viral loads and contact with these materials is a possible pathway for human infection (Pepin et al., 2010). Encephalitis was reported in outbreaks in Egypt and Saudi Arabia (Laughlin et al., 1979;

without accompanying meningitis (Dionisio et al., 2001; Valassina et al., 2003).

**2.3 Flaviviridae Family: Japanese Encephalitis Virus Serogroup, Tick Borne** 

**2.3.1 Japanese Encephalitis Virus Serogroup: Japanese, St. Louis, and Australian** 

With over 50,000 cases occurring each year, the Japanese Encephalitis Virus (JEV) is responsible for the most cases of epidemic encephalitis worldwide (Weaver & Barrett, 2004). Pigs are suspected to be the main amplification host for the virus involving human infection due to their proximity to human habitation. Ardeid birds (e.g., herons and egrets) serve as the natural hosts. The mosquito vector, *Culex tritaeniorhynchus*, feeds on all hosts (birds, pigs and humans) and finds suitable habitat in the flooded rice paddies of Southeast Asia. Humans and horses are susceptible, but are considered dead end hosts (reviewed by Pfeffer

The primary vectors for the St. Louis Encephalitis Virus (SLEV) are *Cx. Pipiens* and *Cx. Quinquefasciatus,* in the western U.S., *Cx. Tarsalis,* and *Cx. Nigripalpus* in Florida. Various birds serve as reservoirs (McLean et al., 1993; Georgiev, 2009). Outbreaks have been reported in almost every American state, along with Canada, and Central and South America (Calisher, 1994). Evidence suggests that SLEV was introduced into North America from South America and is locally circulated. Sequence comparisons from various strains show that the overall genome sequence is more conserved than other members of the Japanese serogroup (May et al., 2008). Basal diversification northward is estimated to have initiated around 177-247 years ago (Baillie et al., 2008). Vertical transmission of the St. Louis virus was studied by Flores et al. (2010). Vertical transmission is used as an overwinter mechanism for *Culex quinquefasciatus* in the temperate areas of Argentina, where St. Louis encephalitis is endemic. Lab studies confirmed that larva and adults both are capable of

Australian Encephalitis can be caused by two viral agents, the Murray Valley Encephalitis Virus or Kunjin Virus, which are distributed in both Australia and Papua New Guinea. In Western Australia, the virus is monitored through the testing of serum from sentinel chickens (Hall et al., 1995). The virus is focused in the western part of the country, linked to the growth of the primary mosquito vector, *Culex annulirostris*. This habitat also supports

**2.2.3 Rift Valley Fever Virus** 

Madani et al., 2003).

and Dobler (2010)).

acquiring the virus.

**Encephalitis and Dengue Fever Encephalitis** 

**Encephalitis Virus and West Nile Virus** 

These viruses can be maintained in either a zoonotic or an epizootic cycle; the former involving endemic birds, rodents or non-human primates as reservoir hosts (Weaver et al., 1999), the latter is involved in epidemics or outbreaks of the disease in livestock or humans. Reservoir hosts are abundant and readily available in the vector habitat, are attractive to the vector as a potential host, and allow for viral replication sufficient to infect previously uninfected vectors, but low enough to prevent a fatal infection (Scott, 1988). Epidemics of these diseases arise when efficient bridge vectors are able to pass on the virus to new, and potentially dead-ended, hosts (e.g. humans) (Weaver et al., 1999; Armstrong & Theodore, 2010). Also critical to the success of viral transmission is the vector competence, or the ability of the vector to successfully infect a new host with the virus; moreover the vector is able to become infected with the pathogen from wild caught samples, able to efficiently bite the host, and the presence of the virus detectable in wild-caught vertebrate samples (Sudia et al., 1969). But these viruses are not limited to arthropod transfer. Other viruses are linked to bats and other wild animals to ensure their survival. The viral families included in this review are Arenaviridae, Bunyaviridae, Flaviviridae, Paramyxoviridae, Rhabdoviridae and Togaviridae.

#### **2.1 Family Arenaviridae: Lymphocytic Choriomeningitis (LCM) Virus**

The Arenaviridae are a family of viruses whose members are generally associated with rodent-transmitted disease in humans. The Lymphocytic Choriomeningitis (LCM) Virus is released in mouse urine and feces, as well as nasal secretions, saliva, milk and semen. The infectious route can be through direct contact with infected items or inhalation of aerosolized virus particles. Hamsters and guinea pigs are other rodent that can be infected (Barton & Mets, 2001). Meningoencephalitis was reported by Barton and Hyndman (2000) after infection with Lymphocytic Choriomeningitis Virus. Maternal infection has been shown to produce teratogenic effects (Larsen et al., 1993; Barton et al., 1995; Bonthius & Perlman, 2007).

#### **2.2 Bunyaviridae Family: Californian Serogroup, Toscana Virus and Rift Valley Fever Virus**

#### **2.2.1 Californian Serogroup: Jamestown Canyon and La Cross Virus**

The Jamestown Canyon Virus is endemic to Michigan and is primarily transmitted by *Aedes stimulans* (Woodland mosquito) with the white tail deer as its preferred host, and is able to pass the virus transovarially (Boromisa & Grimstad, 1986; Zamparo et al., 1997). In one study, 27% of the population showed specific neutralizing antibody to the virus (Grimstad et al., 1986), however this virus has been detected along the east coast of the U.S. as well (Zamparo et al., 1997). Fatal cases of encephalitis have been reported (Grimstad et al., 1982). The La Cross virus is transmitted through *Ochlerotatus triseriatus* (Eastern treehole mosquito) as well as *Ae. albopictus* (Tiger mosquito) in Tennessee (Erwin et al., 2002) with small rodent hosts primarily in the Midwest and southern Appalachian region (Georgiev, 2009). Numerous outbreaks of the virus have been reported (Rust et al., 1999; McJunkin et al., 2001).

#### **2.2.2 Toscana Virus**

The Toscana virus (TOSV) (genus *Phlebovirus*), is located primarily in the Mediterranean. It was first isolated in Italy, with subsequent cases in Spain, Portugal, France, Greece, Portugal and Germany and Cyprus (Charrel et al., 2005). The sandfly, *Phlebotomus perniciosus* is the primary vector and reservoir, with no connection yet as to a specific mammalian or avian host (Charrel et al., 2005). Occupational exposure to sandfly habitat correlated with seroprevalence of the virus, with up to 77.2% of the forestry workers testing positive for the antibody (Valassina et al., 2003). This virus is responsible for encephalitis complications, without accompanying meningitis (Dionisio et al., 2001; Valassina et al., 2003).

#### **2.2.3 Rift Valley Fever Virus**

4 Non-Flavivirus Encephalitis

These viruses can be maintained in either a zoonotic or an epizootic cycle; the former involving endemic birds, rodents or non-human primates as reservoir hosts (Weaver et al., 1999), the latter is involved in epidemics or outbreaks of the disease in livestock or humans. Reservoir hosts are abundant and readily available in the vector habitat, are attractive to the vector as a potential host, and allow for viral replication sufficient to infect previously uninfected vectors, but low enough to prevent a fatal infection (Scott, 1988). Epidemics of these diseases arise when efficient bridge vectors are able to pass on the virus to new, and potentially dead-ended, hosts (e.g. humans) (Weaver et al., 1999; Armstrong & Theodore, 2010). Also critical to the success of viral transmission is the vector competence, or the ability of the vector to successfully infect a new host with the virus; moreover the vector is able to become infected with the pathogen from wild caught samples, able to efficiently bite the host, and the presence of the virus detectable in wild-caught vertebrate samples (Sudia et al., 1969). But these viruses are not limited to arthropod transfer. Other viruses are linked to bats and other wild animals to ensure their survival. The viral families included in this review are Arenaviridae,

Bunyaviridae, Flaviviridae, Paramyxoviridae, Rhabdoviridae and Togaviridae.

The Arenaviridae are a family of viruses whose members are generally associated with rodent-transmitted disease in humans. The Lymphocytic Choriomeningitis (LCM) Virus is released in mouse urine and feces, as well as nasal secretions, saliva, milk and semen. The infectious route can be through direct contact with infected items or inhalation of aerosolized virus particles. Hamsters and guinea pigs are other rodent that can be infected (Barton & Mets, 2001). Meningoencephalitis was reported by Barton and Hyndman (2000) after infection with Lymphocytic Choriomeningitis Virus. Maternal infection has been shown to produce teratogenic effects (Larsen et al., 1993; Barton et al., 1995; Bonthius &

**2.2 Bunyaviridae Family: Californian Serogroup, Toscana Virus and Rift Valley Fever** 

The Jamestown Canyon Virus is endemic to Michigan and is primarily transmitted by *Aedes stimulans* (Woodland mosquito) with the white tail deer as its preferred host, and is able to pass the virus transovarially (Boromisa & Grimstad, 1986; Zamparo et al., 1997). In one study, 27% of the population showed specific neutralizing antibody to the virus (Grimstad et al., 1986), however this virus has been detected along the east coast of the U.S. as well (Zamparo et al., 1997). Fatal cases of encephalitis have been reported (Grimstad et al., 1982). The La Cross virus is transmitted through *Ochlerotatus triseriatus* (Eastern treehole mosquito) as well as *Ae. albopictus* (Tiger mosquito) in Tennessee (Erwin et al., 2002) with small rodent hosts primarily in the Midwest and southern Appalachian region (Georgiev, 2009). Numerous outbreaks of

The Toscana virus (TOSV) (genus *Phlebovirus*), is located primarily in the Mediterranean. It was first isolated in Italy, with subsequent cases in Spain, Portugal, France, Greece, Portugal and Germany and Cyprus (Charrel et al., 2005). The sandfly, *Phlebotomus perniciosus* is the primary vector and reservoir, with no connection yet as to a specific mammalian or avian host (Charrel et al., 2005). Occupational exposure to sandfly habitat correlated with

**2.1 Family Arenaviridae: Lymphocytic Choriomeningitis (LCM) Virus** 

**2.2.1 Californian Serogroup: Jamestown Canyon and La Cross Virus** 

the virus have been reported (Rust et al., 1999; McJunkin et al., 2001).

Perlman, 2007).

**2.2.2 Toscana Virus** 

**Virus** 

Rift Valley Fever Virus (RVFV) is named from the region of Kenya from which it was first isolated (Daubney et al., 1931). A wide range of mosquito genera have been shown to maintain the enzoonic cycle (e.g., *Aedes*, *Ochlerotatus*, *Stegomyia*, *Anopheles*, *Culex*, *Neomelaniconion*, *Eretmapodites)*, with *Aedes vexans* and *Culex erraticus* showing successful transmission to other animals to serve as bridge vectors (as reviewed by Pfeffer and Dobler (2010)). Infection in pregnant ruminants induces abortion at all stages of pregnancy to the magnitude that this event is referred to as an "abortion storm" (Kasari et al., 2008). Aborted fetuses, birthing material and body fluids of infected animals carry high viral loads and contact with these materials is a possible pathway for human infection (Pepin et al., 2010). Encephalitis was reported in outbreaks in Egypt and Saudi Arabia (Laughlin et al., 1979; Madani et al., 2003).

#### **2.3 Flaviviridae Family: Japanese Encephalitis Virus Serogroup, Tick Borne Encephalitis and Dengue Fever Encephalitis**

#### **2.3.1 Japanese Encephalitis Virus Serogroup: Japanese, St. Louis, and Australian Encephalitis Virus and West Nile Virus**

With over 50,000 cases occurring each year, the Japanese Encephalitis Virus (JEV) is responsible for the most cases of epidemic encephalitis worldwide (Weaver & Barrett, 2004). Pigs are suspected to be the main amplification host for the virus involving human infection due to their proximity to human habitation. Ardeid birds (e.g., herons and egrets) serve as the natural hosts. The mosquito vector, *Culex tritaeniorhynchus*, feeds on all hosts (birds, pigs and humans) and finds suitable habitat in the flooded rice paddies of Southeast Asia. Humans and horses are susceptible, but are considered dead end hosts (reviewed by Pfeffer and Dobler (2010)).

The primary vectors for the St. Louis Encephalitis Virus (SLEV) are *Cx. Pipiens* and *Cx. Quinquefasciatus,* in the western U.S., *Cx. Tarsalis,* and *Cx. Nigripalpus* in Florida. Various birds serve as reservoirs (McLean et al., 1993; Georgiev, 2009). Outbreaks have been reported in almost every American state, along with Canada, and Central and South America (Calisher, 1994). Evidence suggests that SLEV was introduced into North America from South America and is locally circulated. Sequence comparisons from various strains show that the overall genome sequence is more conserved than other members of the Japanese serogroup (May et al., 2008). Basal diversification northward is estimated to have initiated around 177-247 years ago (Baillie et al., 2008). Vertical transmission of the St. Louis virus was studied by Flores et al. (2010). Vertical transmission is used as an overwinter mechanism for *Culex quinquefasciatus* in the temperate areas of Argentina, where St. Louis encephalitis is endemic. Lab studies confirmed that larva and adults both are capable of acquiring the virus.

Australian Encephalitis can be caused by two viral agents, the Murray Valley Encephalitis Virus or Kunjin Virus, which are distributed in both Australia and Papua New Guinea. In Western Australia, the virus is monitored through the testing of serum from sentinel chickens (Hall et al., 1995). The virus is focused in the western part of the country, linked to the growth of the primary mosquito vector, *Culex annulirostris*. This habitat also supports

Zoonotic and Animal Vector Mediated Encephalitides 7

Both Hendra (formerly equine morbillivirus) and Nipah are emerging encephalitic viruses. Though first associated with equine infection in 1994, other human fatal human cases followed in Australia (O'Sullivan et al., 1997). Flying foxes or fruit bats (genus *Pteropus*) serve as the virus reservoir (Halpin et al., 2000), while transmission to domestic animals (horses, pigs, cows) allows for virus amplification and a pathway for human infection. Domesticated animals are suspected to become infected with the virus after contact with bat urine, discarded fruit or birthing material (as reviewed by Wang et al. (2008)). Bats themselves transfer the virus both horizontally through feces, urine or saliva (Plowright et

Nipah virus is another highly fatal paramyxovirus transmitted by bats with a domesticated livestock amplification host (Harcourt et al., 2000; Epstein et al., 2006). The first outbreak was among pig farmers in Malaysia (Mohd Nor et al., 2000), and further south into Singapore (Paton et al., 1999), in 1998-1999. The Malaysia outbreak showed no spill over from its pig farming source, with a morality rate of 40% of infected people. The second, more severe outbreak was in Bandladesh, with a mortality rate of 75%. This strain of Nipah was shown to be different than the Malaysian strain, and characterized by its lack of amplifying host (Epstein et al., 2006) and ability to be transferred from human to human, supported by in increased risk of infection when cohabitating with an infected individual (Vincent P. Hsu, 2004). Pig to pig transmission is through inhalation of aerosolized virus particles and is highly infectious (Mohd Nor et al., 2000). Similar to Hendra, partially eaten fruit from an infected bat is a possible mechanism to initial infection in pigs, due to significant viral presence in bat saliva, or through contact with bat urine (Chua et al., 2002). The farm where the first outbreak occurred had numerous fruit trees, a major attractant for the bats (Chua et al., 2002). More recent studies looked at date palm sap, commonly consumed by humans and bats. Harvesting season coincided with the Banglash outbreak, so Salah et al. (2011) experiment with physical barriers to restrict bat consumption and help curb the spillover into humans facilitated by consumption of contaminated date palm sap.

**2.5 Rhabdoviridae Family: Rabies and Chandipura virus and Australian bat lyssavirus** 

The rabies virus (genus *Lyssavirus*) is still an important cause of fatal cases of encephalitis (Mallewa et al., 2007). The most likely route for human infection is through bite wound, where the virus contaminated saliva enters into the bloodstream of the new host. The virus can also be obtained through mucous membrane passage or virus inhalation from batinfested caves. The only documented human-human transfer was via corneal transplant (as reviewed by Krebs et al. (1995)). Rabies infections have largely been brought under control in developing countries through the vaccination of domestic dogs, though dogs bites in developing countries is the main pathway of human infection. Raccoons (Smith et al., 1995), as well as bats (silver-haired and eastern pipistrelle) are the most common animals to be infected in the U.S., with bats presenting more cryptic cases of rabies infections due to a lack of obvious bite wounds (Messenger et al., 2002). Mutations of the virus through serial passes through hosts can create quasispecies, suggesting a mechanism to the accommodation to a novel hosts (Morimoto et al., 1998; Kissi et al., 1999). Bourhy et al. (1999) showed, through an analysis of European strains of the virus, local genetic differentiation is taking place, facilitated by physical barriers. Evidence suggests substitution rates in the nucleoprotein

gene is related to its infection adaption in bats (Hughes et al., 2005).

**(ABLV)** 

**2.4 Paramyxoviridae Family: Hendra and Nipah Viruses** 

al., 2008) and can be passed through the placenta (Williamson et al., 2000).

important reservoir species, wading birds, of which, the rufous night heron (*Nycticorax caledonicus*) is of particular importance (as reviewed by Russell et al. (2000)). The last outbreak of the disease was in 1974; 22 patients were admitted, with four deaths reported, but eleven recovered without lasting effects (Bennett, 1976). In 2000, the wet season brought record breaking rainfall, increasing the breeding ground for the vector which resulted in nine cases of encephalitis in Western Australia. A survey of sentinel chickens showed that the virus was moving southward and human infections were outside a previously determined enzootic area. New monitoring boundaries were established for the disease after this outbreak occurred (Broom et al., 2002).

West Nile Virus (WNV) was first isolated from the West Nile region of Uganda, with a relatively recent emergence of the virus in the U.S., first infecting several birds in a New York City zoo, which displayed meningoencephalitis and myocarditis. From these samples, nationwide awareness of the virus was sparked and linked to extensive bird mortality in the U.S. (Briese et al., 1999; Hayes, 2001; McLean et al., 2001). Further investigation using antigenic mapping and phylogenetic analysis linked the origin of the virus to Israel, isolated from a deceased goose (Lanciotti et al., 1999). The cycle is maintained between birds, mainly passerine, and *Culex sp.*, which serves as the predominate vector (as reviewed by Pfeffer and Dobler (2010)). Central nervous system infection can result in encephalitic onset in approximately 1% of the patients (Solomon et al., 2003).

#### **2.3.2 Tick Borne Encephalitis and Powassan virus**

There are three main groups of Tick Borne Encephalitis Virus (TBEV): Western (Central, eastern and northern Europe), Siberian (Russia, eastern Europe), Far-Eastern (Eurasia, Asia and Japan) and one main group of Powassan virus (North America, Far eastern Russia), all of which have been reported to be the causative agent in meningoencephalitis (reviewed by Günther & Haglund (2005)). The virus is transmitted by Ixodes ticks (*Ix. Ricinus* and *Ix. Persulcatu*) and small rodents (*Myodes* and *Apodemus*) (Pfeffer & Dobler, 2010). Because of a tick's extended feeding time on a host, high viral titers in the parasite's saliva glands are not necessary for successful pathogen transmission and enable another means of infecting ticks attached in the same area. Saliva-assisted transmission (SAT) occurs between ticks of close proximity by pharmacological active molecules released into the wound site, which facilitates co-feeding, allowing for passage of the virus from tick to tick in close proximity to each other (Kaufman, 2010). Human and domesticated animals are not considered to be reservoirs, so passage from tick to tick is an important part of the pathogenic cycle (Pfeffer & Dobler, 2010). The Powassan Virus, originally known as Deer Tick Virus, has had several outbreaks, mainly in North America (New York, Ontario and Quebec) that have lead to encephalitic onset of those infected (Gholam et al., 1999). This virus has three distinct enzootic cycles: *Ix. cookei* and woodchucks and mustelids, *Ix. marxi* and squirrels, and *Ix. Scapularis* and white-footed mice (Ebel, 2009).

#### **2.3.3 Dengue Fever Encephalitis**

There are four serotypes of the Dengue Fever Virus (DEN-1-4). In this lifecycle, humans serve as the amplifying host and are able to re-infect new female mosquitoes (*Ae. aegypti* in urban areas, *Ae. Albopictus* in suburban/rural areas) (Becker et al., 2010). Central nervous system involvement is suspected to be responsible for potential encephalitic onset (Lum et al., 1996; Muzaffar et al., 2006). The wide geographical breath of this disease puts approximately 2.5 billion people as risk of disease contraction (WHO, 2009).

important reservoir species, wading birds, of which, the rufous night heron (*Nycticorax caledonicus*) is of particular importance (as reviewed by Russell et al. (2000)). The last outbreak of the disease was in 1974; 22 patients were admitted, with four deaths reported, but eleven recovered without lasting effects (Bennett, 1976). In 2000, the wet season brought record breaking rainfall, increasing the breeding ground for the vector which resulted in nine cases of encephalitis in Western Australia. A survey of sentinel chickens showed that the virus was moving southward and human infections were outside a previously determined enzootic area. New monitoring boundaries were established for the disease after

West Nile Virus (WNV) was first isolated from the West Nile region of Uganda, with a relatively recent emergence of the virus in the U.S., first infecting several birds in a New York City zoo, which displayed meningoencephalitis and myocarditis. From these samples, nationwide awareness of the virus was sparked and linked to extensive bird mortality in the U.S. (Briese et al., 1999; Hayes, 2001; McLean et al., 2001). Further investigation using antigenic mapping and phylogenetic analysis linked the origin of the virus to Israel, isolated from a deceased goose (Lanciotti et al., 1999). The cycle is maintained between birds, mainly passerine, and *Culex sp.*, which serves as the predominate vector (as reviewed by Pfeffer and Dobler (2010)). Central nervous system infection can result in encephalitic onset in

There are three main groups of Tick Borne Encephalitis Virus (TBEV): Western (Central, eastern and northern Europe), Siberian (Russia, eastern Europe), Far-Eastern (Eurasia, Asia and Japan) and one main group of Powassan virus (North America, Far eastern Russia), all of which have been reported to be the causative agent in meningoencephalitis (reviewed by Günther & Haglund (2005)). The virus is transmitted by Ixodes ticks (*Ix. Ricinus* and *Ix. Persulcatu*) and small rodents (*Myodes* and *Apodemus*) (Pfeffer & Dobler, 2010). Because of a tick's extended feeding time on a host, high viral titers in the parasite's saliva glands are not necessary for successful pathogen transmission and enable another means of infecting ticks attached in the same area. Saliva-assisted transmission (SAT) occurs between ticks of close proximity by pharmacological active molecules released into the wound site, which facilitates co-feeding, allowing for passage of the virus from tick to tick in close proximity to each other (Kaufman, 2010). Human and domesticated animals are not considered to be reservoirs, so passage from tick to tick is an important part of the pathogenic cycle (Pfeffer & Dobler, 2010). The Powassan Virus, originally known as Deer Tick Virus, has had several outbreaks, mainly in North America (New York, Ontario and Quebec) that have lead to encephalitic onset of those infected (Gholam et al., 1999). This virus has three distinct enzootic cycles: *Ix. cookei* and woodchucks and mustelids, *Ix. marxi* and squirrels, and *Ix.* 

There are four serotypes of the Dengue Fever Virus (DEN-1-4). In this lifecycle, humans serve as the amplifying host and are able to re-infect new female mosquitoes (*Ae. aegypti* in urban areas, *Ae. Albopictus* in suburban/rural areas) (Becker et al., 2010). Central nervous system involvement is suspected to be responsible for potential encephalitic onset (Lum et al., 1996; Muzaffar et al., 2006). The wide geographical breath of this disease puts

approximately 2.5 billion people as risk of disease contraction (WHO, 2009).

this outbreak occurred (Broom et al., 2002).

approximately 1% of the patients (Solomon et al., 2003).

**2.3.2 Tick Borne Encephalitis and Powassan virus** 

*Scapularis* and white-footed mice (Ebel, 2009).

**2.3.3 Dengue Fever Encephalitis** 

#### **2.4 Paramyxoviridae Family: Hendra and Nipah Viruses**

Both Hendra (formerly equine morbillivirus) and Nipah are emerging encephalitic viruses. Though first associated with equine infection in 1994, other human fatal human cases followed in Australia (O'Sullivan et al., 1997). Flying foxes or fruit bats (genus *Pteropus*) serve as the virus reservoir (Halpin et al., 2000), while transmission to domestic animals (horses, pigs, cows) allows for virus amplification and a pathway for human infection. Domesticated animals are suspected to become infected with the virus after contact with bat urine, discarded fruit or birthing material (as reviewed by Wang et al. (2008)). Bats themselves transfer the virus both horizontally through feces, urine or saliva (Plowright et al., 2008) and can be passed through the placenta (Williamson et al., 2000).

Nipah virus is another highly fatal paramyxovirus transmitted by bats with a domesticated livestock amplification host (Harcourt et al., 2000; Epstein et al., 2006). The first outbreak was among pig farmers in Malaysia (Mohd Nor et al., 2000), and further south into Singapore (Paton et al., 1999), in 1998-1999. The Malaysia outbreak showed no spill over from its pig farming source, with a morality rate of 40% of infected people. The second, more severe outbreak was in Bandladesh, with a mortality rate of 75%. This strain of Nipah was shown to be different than the Malaysian strain, and characterized by its lack of amplifying host (Epstein et al., 2006) and ability to be transferred from human to human, supported by in increased risk of infection when cohabitating with an infected individual (Vincent P. Hsu, 2004). Pig to pig transmission is through inhalation of aerosolized virus particles and is highly infectious (Mohd Nor et al., 2000). Similar to Hendra, partially eaten fruit from an infected bat is a possible mechanism to initial infection in pigs, due to significant viral presence in bat saliva, or through contact with bat urine (Chua et al., 2002). The farm where the first outbreak occurred had numerous fruit trees, a major attractant for the bats (Chua et al., 2002). More recent studies looked at date palm sap, commonly consumed by humans and bats. Harvesting season coincided with the Banglash outbreak, so Salah et al. (2011) experiment with physical barriers to restrict bat consumption and help curb the spillover into humans facilitated by consumption of contaminated date palm sap.

#### **2.5 Rhabdoviridae Family: Rabies and Chandipura virus and Australian bat lyssavirus (ABLV)**

The rabies virus (genus *Lyssavirus*) is still an important cause of fatal cases of encephalitis (Mallewa et al., 2007). The most likely route for human infection is through bite wound, where the virus contaminated saliva enters into the bloodstream of the new host. The virus can also be obtained through mucous membrane passage or virus inhalation from batinfested caves. The only documented human-human transfer was via corneal transplant (as reviewed by Krebs et al. (1995)). Rabies infections have largely been brought under control in developing countries through the vaccination of domestic dogs, though dogs bites in developing countries is the main pathway of human infection. Raccoons (Smith et al., 1995), as well as bats (silver-haired and eastern pipistrelle) are the most common animals to be infected in the U.S., with bats presenting more cryptic cases of rabies infections due to a lack of obvious bite wounds (Messenger et al., 2002). Mutations of the virus through serial passes through hosts can create quasispecies, suggesting a mechanism to the accommodation to a novel hosts (Morimoto et al., 1998; Kissi et al., 1999). Bourhy et al. (1999) showed, through an analysis of European strains of the virus, local genetic differentiation is taking place, facilitated by physical barriers. Evidence suggests substitution rates in the nucleoprotein gene is related to its infection adaption in bats (Hughes et al., 2005).

Zoonotic and Animal Vector Mediated Encephalitides 9

host for the virus (Chamberlain et al., 1954; Komar et al., 1999) and *Culiseta melanura*, a mainly ornithophic mosquito, maintains the lifecycle in endemic areas between bird hosts, though other genera have be able to become infected (Armstrong & Theodore, 2010). The virus starts its replication in the mid-gut epithelial cells and maintains a persistent infection in the mosquito, eventually reaching the salivary glands to ensure viral transfer (Georgiev, 2009). Mosquito with a wider range of hosts (*Coquillettidia, Culex, Ochlerotatus, Aedes, spp.*) serve to infect dead-end hosts (humans and horses) (Pfeffer & Dobler, 2010), with often fatal

Western Equine Encephalitis virus undergoes a similar endemic cycle in birds as EEEV does, with *Culex tarsalis* as the maintaining mosquito vector, although there is a cycle between rodents and *Ochlerotatus melanimon* in South America (Pfeffer & Dobler, 2010). WEEV can be found in North, South and Central America (Weaver et al., 1997), though *C. tarsalis* is well sustained in the Western U.S. in areas of agriculture and stream drainages (Zacks &

Unlike the previous alpha viruses, the Venezuelan Equine Encephalitis Virus (VEEV) is maintained mainly in a mosquito/rodent cycle and amplification and further amplification is seen in horses and humans (Pfeffer & Dobler, 2010). *C. Melanoconion* serves as the enzootic strain vector among rodent hosts. The key to epidemic/epizootic transmission is through a the selection of the E2 envelope protein mutation of ID or IE subtypes (Pfeffer & Dobler, 2010), from which the IAB and IC subtypes emerge, and go on to infect equines and humans through *Ochlerotatus taeniorhynchus* (Georgiev, 2009). For additional details of the VEEV virus, mosquito vectors (both enzoonic and epizoonic), as well as the transmission cycle,

There are six 'classical' strains of *Brucella* genus, found in specific animals*, Brucella ovis, Brucella canis, Brucella neotomae, Brucella abortus, Brucella melitensis, and Brucella suis* (Moreno et al., 2002), with the latter three strains capable of infecting humans and human producing brucellosis (de Jong et al., 2010). These three strains are also able to infect reticuloendothelial tissues as well as reproductive tract cells, which results in abortions or sterility (de Jong et al., 2010). Neurological affects can manifest into Neurobrucellosis, with meningoencephalitis as a potential complication, though a rare occurrence among those affected (Shakir et al., 1987; Al Deeb et al., 1989). *Brucella* has also been detected in terrestrial wildlife populations (Godfroid, 2002), as well as marine mammals (Foster et al., 2002) and has been shown to jump from wildlife reservoirs to domestic herds in close proximity to each other. The study done by Beja-Pereira et al. (2009) showed that elk were the origin species for the *Brucella* outbreak in cattle herds in the greater Yellowstone area. For the greater population, human infection is usually caused by consumption of dairy products contaminated with the bacterium (De Massis et al., 2005). The risk of infection increases with animal contact, especially around periods of perturbation, which puts farm workers/ranchers, veterinarians and meat-packing employers

Leptospirosis is caused by two species of *Leptospira*; *L. interrogans* and *L. borgpetersenii*. *L. interrogans* is effective in surviving in the environment, while *L. borgpetersenii* is host

consequences for both (Pfeffer & Dobler, 2010).

please see the review by Weaver et al. (2004).

at greater risk of infection (Seleem, Boyle et al. 2010).

**3.2 Leptospirosis:** *Leptospira*

**3. Bacterial Encephalitides** 

**3.1 Brucellosis:** *Brucella*

Paessler, 2010).

One of the lesser known viral encephalides is the Chandipura virus (genus *Vesiculovirus*). Even though it is not well reported in the literature (Van Ranst, 2004), it was responsible for considerable encephalitic outbreaks in India in the last decade, in 2003 and again in 2007 (Rao et al., 2004; Narasimha Rao et al., 2008; Gurav et al., 2010). Viral transmission is through Phlebotomid sandflies (genus *Sergentomyia)* (Mavale et al., 2005) and is mainly found in India, but has also been isolated from sand flies in West Africa (Fontenille et al., 1994). The potential and need for further research in this emerging human pathogen is great (Potharaju & Potharaju, 2006).

Australian bat lyssavirus (ABLV) is another encephalitic virus found in Pteropid bats, and as the name implies, this rabies-like virus is found in Australia (Warrilow et al., 2002). Two fatal encephalitis cases were confirmed to be caused by ABLV. The first in 1996 from an animal handler (Allworth et al., 1996); the second had been bitten by a flying fox (Hanna et al., 2000). Serologic testing done in the Philippines suggest that this virus is also present there, though no active infections were found in the bats sampled (Arguin et al., 2007).
