The History and Evolution of Human Dengue Emergence

Nikos Vasilakis; Scott C. Weaver    Center for Tropical Diseases and Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-0609

I Introduction to Flaviviruses

Dengue viruses (DENV) are members of the genus Flavivirus in the Family Flaviviridae. Flaviviruses are single-stranded RNA viruses of positive polarity and most, but not all, require hematophagous arthropods (mosquitoes or ticks) to complete their horizontal transmission cycle. They are responsible for a broad spectrum of pathogenic manifestations in humans, domestic animals, and birds (Heinz et al., 2000). Flaviviruses are widely distributed nearly throughout the world, except Antarctica. More than 50% of all known flaviviruses have been associated with human disease and include some of the most important human pathogens, such as Yellow fever virus (YFV), DENV, Japanese encephalitis virus (JEV), and Tick-borne encephalitis virus (TBEV). For example, DENV is responsible for the highest incidence of human morbidity and mortality among all flaviviruses: ca. 100 million infections annually, resulting in approximately 500,000 cases of DEN hemorrhagic fever (DHF) with a case fatality rate of about 5% (Halstead, 1997). The majority of human infections with flaviviruses are asymptomatic, whereas symptomatic infections commonly manifest themselves as a flu-like disease that is characterized by sudden onset of fever, arthralgia, myalgia, retro-orbital headaches, maculopapular rash, leukopenia, vascular leakage, and/or encephalitis (Belov et al., 1995; Burke et al., 1988; Gritsun et al., 2003; Lumsden, 1958; Work et al., 1957). Depending on the flavivirus, the infection may also cause severe encephalitis with lifelong neurologic sequelae (Brinker and Monath, 1980; Charrel et al., 2004), persistent disease (Ravi et al., 1993; Sharma et al., 1991), or even death (McLean and Donohue, 1959; Tsai and Mitchell, 1989; Work et al., 1957). In animals, flavivirus infections occur in a wide range of animals including sheep, cattle, equids, monkeys, muskrats, rodents, bats, birds, and seabirds (Autorino et al., 2002; Clifford et al., 1971; Gritsun et al., 2003; Lanciotti et al., 1999; Lvov et al., 1971; Malkinson and Banet, 2002; Shope, 2003; St George et al., 1977; Swanepoel, 1994; Swanepoel and Coetzer, 1994; Varelas-Wesley and Calisher, 1982). Infection of animals, as in humans, varies from asymptomatic to lethal.

The name flaviviruses comes from the Latin word “flavus,” meaning yellow that signifies jaundice, a common sign of infection with the prototypic Yellow fever virus. The genus Flavivirus includes 56 species (Heinz et al., 2000). Yellow fever virus was among the first filterable agents shown to cause human diseases (along with DENV) (Ashburn and Craig, 1907; Reed and Carroll, 1902), the first virus isolated whose transmission involves the mosquito vector Aedes (Stegomyia) aegypti (Reed and Carroll, 1902; Reed et al., 1900), and the first flavivirus to be cultivated in vitro (Lloyd et al., 1936). Viruses in the Flavivirus genus are grouped taxonomically into three groups with regard to their vector association and antigenic relationships: (1) tick-borne, (2) mosquito-borne, and (3) viruses with no known arthropod vector (NKV). Within the tick-borne group are two antigenically distinct clades: mammalian and seabird virus groups (Fig. 1). The mammalian group includes several important human pathogens, such as Kyasanur Forest disease (KFDV), Powassan (POWV), Omsk hemorrhagic fever (OHFV), TBEV, and Louping ill viruses (LIV). The mosquito-borne viruses can be divided into groups that principally use Aedes spp. or Culex spp. mosquito vectors. The DENV belong to the former group (Fig. 1). Although the closest relative of the DENV as depicted in this tree is an African virus, Kedougou virus from Senegal, this grouping is not robust and a large group of mosquito-borne viruses from Africa, Asia, and the New World group with DENV with equivalently poor statistical support. Therefore, the current flavivirus tree is not informative as to the probable origins of the DENV.

Several other members of the mosquito-borne group are the causative agents of severe diseases in humans: St. Louis encephalitis (SLEV), West Nile (WNV), Ilheus (ILHV), Zika (ZIKV), Wesselsbron (WESSV), and YFV. Lastly, within the viruses with no known arthropod vector, there are three antigenically distinct groups: Entebbe bat, Yokose, and Sokoluk viruses group phylogenetically with the mosquito-borne clade, while Modoc-virus and Rio Bravo-like viruses are phylogenetically distinct from the vector-borne groups. Members of these groups have been isolated mainly from bats or rodents and some have been associated with establishment of persistent infections (Baer and Woodall, 1966; Constantine and Woodall, 1964). A handful of these viruses, such as Dakar bat, Modoc, and Rio Bravo, have been isolated from humans in nature (Karabatsos, 1985b; Shope, 2003), or in several laboratory infections probably due to aerosol transmission (Apoi and Rio Bravo virus) (Karabatsos, 1985a; Sulkin et al., 1962). Most common manifestation of human disease from these viruses is febrile illness and rarely encephalitis (Calisher and Gould, 2003; Shope, 2003).

II Dengue Viruses

A Classification of dengue viruses

DENV is considered a species within the genus Flavivirus (family Flaviviridae) and includes four distinct but antigenically related serotypes (DENV-1, -2, -3, and -4) in DEN antigenic complex (Calisher et al., 1989). Of the flaviviruses, DENV are among the most restricted with regard to their natural vertebrate host range, which is believed to include only primates. Currently, all four DENV serotypes can be found in nearly all urban and peri-urban environments throughout the tropics and neotropics where the principal vector, Aedes aegypti, is abundant. This distribution puts at risk of infection nearly a third of the global human population.

Initially, DENV of all serotypes were classified genetically into clusters called topotypes using T1 RNase fingerprinting (Repik et al., 1983; Trent et al., 1990). Later, nucleic acid sequencing allowed for the classification of DENV into genetically distinct groups or genotypes within each serotype (Rico-Hesse, 1990). Rico-Hesse defined these ‘genotypes’ as clusters of DENV viruses having nucleotide sequence divergence not greater than 6% within a given genome region (in this case the E/NS1 junction), which was based on the clustering of strains for which associations could be inferred on epidemiological grounds (Rico-Hesse, 1990).

Various phylogenetic analyses based on partial E/NS1 or complete E nucleotide...