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Known by hundreds of different names over spans of thousands of years, yellow fever was once one of the most feared and devastating diseases in the world. Endogenous to equatorial regions of Africa and South America, it has been recorded throughout the centuries to appear occasionally out of its endemic areas to threaten entire cities with near-annihilation (Tomori 393). One such occasion in the late 1800s earned it the title "The American Plague," and during the great Mississippi Valley epidemic of yellow fever in 1878, the population of the city of Memphis, Tennessee was so devastated that it actually lost its charter (Caplinger; Rousey 357).
Yellow fever is a disease caused by the Baltimore class IV virus which bears its name. Its positive-stranded RNA is coiled inside an icosahedral capsid and surrounded by a glycoprotein-encrusted envelope (Perera et al. 12; Tomori 395). A relatively small genome codes for its ten viral proteins: three structural and seven nonstructural (NS) (Perera et al. 12; Tomori 395). The capsid (C), envelope (E) and premembrane/membrane (prM/M) proteins are crucial for viral attachment, egress, and maturation, and the seven NS proteins are mostly dedicated to replication of the viral genome (De Beeck et al. 813; Perera et al. 12; Tomori 395).
Its taxonomical family, Flaviviridae, was derived from the Latin word for "yellow," referring to the jaundice experienced by many patients with this disease (Caplinger). Flaviviridae also includes west nile virus and dengue virus, among others, and resides under the broader category of arthropod-borne viruses, or arboviruses, which are transmitted between mammalian hosts primarily by an arthropod vector (Perera et al. 12; Tomori 395). In the case of yellow fever, the vector is usually a female Aedes mosquito, and the natural host is one of several species of African or South American monkeys (Tomori 397, 405). Disease in humans occurs when zoonotic or human-to-human transfer of the virus is facilitated by an infected mosquito (Tomori 406; Monath 2222).
As she takes a bloodmeal, the mosquito injects a cocktail of fluids, rich in viral particles, into the bloodstream of a new host (Monath 2222). Though the specific host cell receptors and mechanisms for viral entry have not been fully elucidated (Perera et al. 12), an Arg-Gly-Asp domain on the viral E protein correspond to heparin sulfate-like receptors on human cells, which most likely facilitate attachment and endocytosis into a variety of cell types (Tomori 395). Low pH levels in the subsequently-formed endosome cause conformational changes to the proteins in the envelope and capsid, allowing viral RNA to seep into the host cell's cytoplasm (Perera et al. 12; Tomori 395).
Translation, associated with intracellular plasma membranes, begins when viral RNA hijacks host ribosomes, and a single concatamer is produced (Perera et al. 12). Host and viral proteases cleave this into the ten viral proteins described previously (De Beeck et al. 813; Perera et al. 12; Tomori 395). Viral RNA-dependent RNA polymerase transcribes the plus-stranded viral RNA into its complementary negative strand, which is then used as a template for transcribing many more copies of the plus-stranded genome. Capsid proteins and viral genome copies are assembled in the endoplasmic reticulum (ER), where the envelope, rich with E and prM proteins, is also acquired (Perera et al. 12). Cellular furin in the golgi apparatus cleaves prM into mature M proteins; this changes the entire surface of the virion from a "spiky" to a "smooth" appearance, and renders the virus mature and infectious (Perera et al. 12).
Most data gathered about yellow fever's pathogenesis has been taken from patient autopsies and primate models, although Tesh et al. seem to have established recently a relevant, more affordable animal model with golden hamsters (1431). Their studies, and those of Xiao et al., further support previously-established in vitro characteristics of the disease-cytoplasmic vacuoles, apoptosis-as well as establishing sound in vivo pathological effects on specific organs: liver necrosis, petechial hemorrhage, and massive pleocytosis of immune cells into the liver and spleen (1439-40). These data support clinical findings relevant to the pathological course of yellow fever.
Though it seems to have no pathogenic effects on its arthropod hosts, yellow fever establishes a substantial pathogenesis in humans, almost always associated with a biphasic fever and viremia, resulting in severe morbidity and mortality in about 50% of those infected ("Yellow Fever," cdc.gov). The viremia is supported by copious amounts of viral replication in secondary organs such as the liver, spleen, and salivary glands (Xiao et al, 1440), often rendering these organs dysfunctional, which, in the case of the liver, leads to the appearance of jaundice for which the disease acquired its name.
After a 3-6 day incubation period, patients enter an acute phase and develop fever and flu-like symptoms including nausea, muscle pain, headache, and malaise ("Yellow Fever," cdc.gov; mayoclinic.com). Some people's immune systems will completely clear the virus after this first phase; others are not so fortunate. The toxic phase is more severe, often resulting in more pain, jaundice, bruising, and hemorrhage due to viral inhibition of coagulation pathways ("Yellow Fever," cdc.gov; MayoClinic.com). Occasionally encephalitis ensues which can present as seizures, dementia, or coma ("Yellow Fever," cdc.gov; MayoClinic.com). In about half of patients who reach the toxic phase, this disease is fatal (Tomori 391; "Yellow Fever," cdc.gov).
A live attenuated vaccine for the prevention of yellow fever has been approved for use (Tomori 415), although there have been some rare cases of extreme toxicity associated with it and its precursor (Barrett and Teuwen 308; Tomori 415). In North America, Europe, and other low-risk countries, the vaccine is typically only recommended for travelers going to areas known to be endemic for yellow fever ("Yellow Fever," cdc.gov; MayoClinic.com). Great efforts to control mosquito populations and encourage the use of insect repellant and mosquito nets have been relatively effective, and the frequency of outbreaks in non-endemic areas has been significantly reduced over the years ("Yellow Fever," cdc.gov). Though treatment is typically only supportive, current studies are ongoing concerning steps of the viral replication cycle that may be selected for antiviral drug development against Flaviviruses in general (Perera et al. 12).
The worldwide incidence of infection has drastically declined since the development of the vaccine, but yellow fever remains a problem in impoverished equatorial countries-especially in Africa-partially because of the physical and logistical impracticalities of getting large quantities of the vaccine into some of those areas (Tomori 418). The World Health Organization has undertaken campaigns to decrease the occurrence of yellow fever in many African countries, with very good success (Tomori 420).
Perhaps it is the decline of yellow fever infections in recent years in the United States that has resulted in a shortage of data on the effect of ethnicity or race on risk, but, interestingly, during the great Mississippi Valley epidemic of the 1870s, the white population seemed to be notably higher-risk for increased morbidity and mortality from yellow fever than the black population (Rousey 363). For example, with about equal numbers of white and black people in Memphis, ten times as many whites died from yellow fever as blacks (Rousey 363). Whether this resulted from behavioral or genetic differences, and whether it means that more white people were exposed or infected than blacks is unclear, but it is, nonetheless, interesting.
Though it has been some time since an epidemic hit the United States, yellow fever still infects and kills thousands of people worldwide every year. Diligent planning and prevention techniques help keep infections under control in non-endemic countries, but such techniques seem to be on the decline in some at-risk countries in Africa and South America. New animal models for studying Flaviviruses and developing treatments are becoming available; promising research is heightening our understanding of yellow fever, dengue, west nile, and other arboviruses. The more we know, the better our chances of preventing another devastating outbreak of this disease.