Arthropod-borne viruses (arboviruses)
An arthropod-borne virus (arbovirus) is a virus that requires a hematophagous (blood-sucking) arthropod vector for transmission into vertebrate hosts to maintain its life cycle (Gubler, 2001). Most arboviruses are zoonoses with vertebrate hosts other than humans as their primary reservoir. Vertebrate infection can occur after an infected arthropod takes a blood meal, and arthropod infections occur after feeding on viremic (presence of virus in the bloodstream) hosts. Usually the virus cycles silently between the primary arthropod vector and primary vertebrate host until an ecologic change occurs that allow the virus to escape this focus (Centers for Disease Control & Prevention [CDC], 2003).
The most common amplifying hosts are birds and rodents and the most important arthropod vectors are mosquitoes and ticks for arboviral diseases of public health
consequence, although exceptions to this rule exist. For instance, dengue virus has adapted completely to humans and is maintained in a mosquito-human-mosquito transmission cycle in urban centers of the tropics and sub-tropics (Gubler, 2002). In South America and East Africa, yellow fever virus cycles in both urban and jungle environments, where the sylvatic cycle is maintained in wild monkeys (Burke and Monath, 2001; CDC, 2007a). Important ecological parameters that govern these cycles
include temperature, rainfall, and humidity which influence geographic distribution of the vectors and hosts (Gubler, 2002). Figure 2-1 presents the global geographic distribution of the major arboviral encephalitides.
Although arboviruses are globally distributed, they are primarily found in tropical areas where the climate can support year-round transmission by cold-blooded arthropods (Gubler, 2002). The past 20 years has witnessed changing epidemiological trends
resulting in dramatically increased global epidemic arboviral activity. Population growth, new irrigation systems, deforestation, and uncontrolled urbanization in tropical
developing countries have especially contributed to the emergence/resurgence of
arboviral diseases (Gubler, 2001). During this time, viruses once thought to be controlled or not of major public health significance caused epidemic disease in many regions of the world. For example, dengue virus expanded globally resulting in larger and more
frequent epidemics. West Nile virus (WNV) was introduced into North America in 1999 with epidemics and epizootics of severe neurologic disease in humans, horses, and birds.
The resurgence or emergence of these pathogens necessitates a reassessment of the public health infrastructure and its ability to implement surveillance, prevention, and control programs for medically important arboviruses (Gubler, 2002).
Classification
Currently, there are over 534 viruses registered in the International Catalogue of Arboviruses (Karabatsos, 1985). Only 134 of these registered viruses have caused documented disease in humans (Karabatsos, 1985). Arboviruses are taxonomically diverse and belong to eight virus families and fourteen genera. The arboviruses that are medically important for humans belong to three virus families: the Bunyaviridae,
Figure 2-1 Global distribution of the major arboviral encephalitides.
Arboviruses have established enzootic or endemic foci on every continent, where the virus cycles between primary avian or rodent hosts and primary arthropod vectors. In 1999, West Nile virus emerged in the western
hemisphere in New York City, effectively escaping its previous restriction to the eastern hemisphere.
Figure appears courtesy of the Centers for Disease Control & Prevention (CDC, 2005a) Adapted by author to show the emergence of WN in the western hemisphere.
Flaviviridae, and Togaviridae (Gubler & Roehrig, 1998). The Bunyaviridae and Togaviridae families will briefly be described, emphasizing the viruses vectored by arthropods. The Flaviviridae family will be covered in greater detail in the next section.
Bunyaviridae (genus Bunyavirus)
Recognized as the largest and most diverse arboviral family, the Bunyaviridae has at least 248 identified viruses belonging to five genera (Gubler, 2001), including the Bunyavirus, Phlebovirus, Nairovirus, Tospovirus, and Hantavirus genera (CDC, 2004a).
The Bunyaviridae are single stranded negative-sense RNA viruses, where all genera include viruses transmitted by arthropods, with the exception of hantavirus, which is rodent-borne (CDC, 2004a). First classified as California serogroup arboviruses, the Bunyavirus genus has at least 167 arbovirus members found on five continents.
California encephalitis virus (CEV), La Crosse virus (LACV), Jamestown Canyon virus (JCV), and Snowshoe hare virus (SSHV) are the medically important arboviruses found in North America (Calisher, 1994; Schmaljohn and Hooper, 2001).
For example, LACV is a mosquito-borne pathogen that maintains an enzootic life cycle with the tree-hole mosquito, Aedes triseriatus that feeds on Eastern gray squirrels and chipmunks, which serve as amplifying hosts for LACV. Mosquito LACV infection is lifelong and mosquitoes can become dually infected with other bunyaviruses allowing for development of intra-genus reassortants (Bennett et al, 2007). LACV has been identified in several Midwestern and Mid-Atlantic states, with an average of 75 cases of LAC encephalitis reported to the CDC each year (CDC, 2005b). While California serogroup arboviruses (other than LACV or CEV) have previously been isolated in Florida (Lewis
et al, 1965; Quick et al, 1965; Bigler et al, 1975), they are not significant human pathogens in the state.
Togaviridae (genus Alphavirus)
The Togaviridae family was restructured in 1984 (Karabatsos, 1985) and now contains only two genera, Alphavirus and Rubivirus. Rubella virus is the sole member of the Rubivirus genus and is more commonly known as German measles, which is
transmitted person-to-person (Schlesinger and Schlesinger, 2001; Chantler, Wolinsky and Tingle, 2001). In contrast, the genus Alphavirus includes 28 viruses (Gubler, 2001) and were initially classified as serologic Group A arboviruses (Casals and Brown, 1954). The alphaviruses are all transmitted by arthropods, are restricted geographically in
distribution, and share a common replication strategy. The pathogenic alphaviruses can be divided into two groups, those causing human diseases characterized by encephalitis, usually found in the New World (e.g.Eastern Equine Encephalitis virus [EEEV]), and viruses that cause arthritis and rash, found primarily in the Old World (e.g. Chikungunya virus) [Griffin, 2001]. The emergence of West Nile virus in the western hemisphere has raised concerns that Chikungunya virus may be introduced into the United States by infected travelers returning from Africa, India, or Asia, where the virus has caused epidemics. A recent study found that infected travelers had high titers of Chikungunya viremia, sufficient to potentially infect Aedes aegypti and Aedes albopictus mosquitoes and could facilitate local transmission in the United States (Lanciotti et al, 2007).
Alphaviruses can be transmitted by a wide range of mosquito species, but each virus typically has a preferred mosquito vector for the enzootic cycle that uses either birds or mammals as primary amplifying hosts (Scott and Weaver, 1989). Viruses which
use avian amplifying hosts, such as EEE complex viruses in North America, may be more efficiently dispersed over wide geographic regions, enhancing gene flow, and thus far have remained highly conserved. On the other hand, viruses which utilize mammalian enzootic hosts, such as Venezuelan equine encephalitis virus (VEEV) and strains of EEEV which amplify in rodent hosts in the tropics, have a smaller range of dispersal due to limited mobility of the host, which has resulted in genotypic evolution within multiple geographic foci in South America (Cilnis et al, 1996; Weaver et al, 1997).
Recombination between alphaviruses has been difficult to achieve in vitro, but is estimated to have occurred naturally thousands of years ago when a Sindbis-like virus and EEEV recombined to form the Western Equine Encephalitis complex viruses
(Western Equine Encephalitis virus (WEEV), Highlands J virus (HJV), and Fort Morgan virus). In Florida, surveillance programs have found that EEEV and HJV are enzootic throughout the region, with EEEV an important human pathogen (Bigler et al, 1976;
Stark and Kazanis, 2004, 2005, 2006).
Flaviviridae (genus Flavivirus)
The Flaviviridae family (from the Latin flavus or “yellow” referring to the prototype yellow fever virus) has three genera, including the Flavivirus, Pestivirus, and Hepacivirus. Pestiviruses are animal pathogens (e.g. bovine viral diarrhea virus) and the human pathogen hepatitis C virus is the only member of the hepaciviruses (Lindenbach and Rice, 2001). The genus Flavivirus includes about 70 viruses (Gubler, 2001; King et al, 2007), which were originally classified as serologic Group B arboviruses (Casals and Brown, 1954). Forty of these flaviviruses are significant human pathogens, including Japanese encephalitis virus (JEV), the 4 serotypes of dengue virus (DENV 1-4), yellow
fever virus (YFV), tick-borne encephalitis virus (TBEV), St. Louis encephalitis virus (SLEV) and West Nile virus (WNV) [Lindenbach and Rice, 2001]. These viruses are arthropod-borne and transmitted to vertebrates through infected mosquitoes or ticks (Chambers et al, 1990). Yellow fever virus was the first flavivirus isolated (1927), the first filterable agent proven to cause human disease and the first virus proven to be transmissible by an arthropod vector (Burke and Monath, 2001).
Flaviviruses can be categorized into antigenic complexes and subcomplexes based on serological criteria or into clusters, clades and species based on molecular phylogenetics (Lindenbach and Rice, 2001). The Japanese Encephalitis (JE) antigenic serocomplex includes 10 arboviruses, including the medically important flaviviruses in the Americas. The American pathogenic JE viruses with mosquito vectors include St.
Louis encephalitis virus, West Nile virus and Rocio virus. JE serocomplex viruses demonstrate extensive antigenic cross-reactivity with family members, often
complicating diagnosis of disease (Chambers et al, 1990). However, only SLEV and WNV are enzootic to the United States (Kramer and Chandler, 2001). Table 2-1 lists the medically important viruses of the Flavivirus genus, including geographic distribution, primary vertebrate hosts and associated clinical syndromes.
Virus Life Cycle
Flaviviruses are able to enter cells via interactions between the viral surface glycoprotein and several cellular receptors. The immune response may enhance viral uptake into cells if viral particles are opsonized with non-neutralizing antibodies and bind to cells expressing Fc receptors (antibody-dependent enhancement) [Lindenbach and Rice, 2003]. The virus enters a cell by receptor-mediated endocytosis, mediated by the
Table 2-1 Medically Important Vector-borne Flaviviruses
Flaviviruses pose a significant risk to the health of millions of people around that world that live in regions with endemic, enzootic, or epidemic transmission of these arboviruses. This table summarizes characteristics of each virus, including the clinical disease frequently associated with infection, the vector and primary vertebrate host integral to the transmission cycle, and geographic distribution.