Next Article in Journal
Bacterial Diversity and Potential Functions in Response to Long-Term Nitrogen Fertilizer on the Semiarid Loess Plateau
Previous Article in Journal
Toxoplasma gondii Serotypes in Italian and Foreign Populations: A Cross-Sectional Study Using a Homemade ELISA Test
Previous Article in Special Issue
Ecology of Powassan Virus in the United States
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Microorganisms
Volume 10
Issue 8
10.3390/microorganisms10081578
microorganisms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Yellow Fever: Roles of Animal Models and Arthropod Vector Studies in Understanding Epidemic Emergence

by
Divya P. Shinde
1,2,3,*,
Jessica A. Plante
1,2,
Kenneth S. Plante
1,2,4 and
Scott C. Weaver
1,2,3,4
1
World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX 77555, USA
2
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
3
Center for Vector-Borne and Zoonotic Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA
4
Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA
*
Author to whom correspondence should be addressed.
Microorganisms 2022, 10(8), 1578; https://doi.org/10.3390/microorganisms10081578
Submission received: 1 July 2022 / Revised: 31 July 2022 / Accepted: 2 August 2022 / Published: 5 August 2022
(This article belongs to the Special Issue Ecology and Emergence of Zoonotic Viruses)
Browse Figures
Review Reports Versions Notes

Abstract

:
Yellow fever virus (YFV) is a mosquito-borne flavivirus circulating throughout the tropical and sub-tropical regions of Africa and South America. It is responsible for an estimated 30,000 deaths annually, and while there is a highly successful vaccine, coverage is incomplete, and there is no approved treatment for YFV infection. Despite advancements in the field, animal models for YFV infection remain scarce, and care must be taken to select an appropriate model for a given hypothesis. Small animal models require either adapted YFV strains or immunocompromised hosts. Non-human primates (NHPs) recapitulate human disease, but they require specialized facilities and training, are often in short supply and cost-prohibitive, and can present ethical concerns. The limitations in studying the mosquito vectors for YFV infection include inconsistency in the laboratory environment, the requirement for a high containment insectary, and difficulty in maintaining sylvatic mosquitoes. In this review, we discuss the roles of animal models and arthropod vector studies in understanding epidemic emergence.

1. Introduction

Yellow fever virus (YFV) is a mosquito-borne virus of the genus Flavivirus and family Flaviviridae [1]. It has a positive sense, single-stranded RNA genome approximately 11 kb long [2]. YFV primarily circulates in three cycles: urban, sylvatic (enzootic), and intermediate (savannah) (Figure 1) [3]. In the urban cycle, YFV is transmitted between peridomestic mosquito species chiefly, Aedes aegypti and humans who serve as amplification hosts [4]. In the sylvatic cycle, YFV is transmitted between non-human primates (NHPs) and sylvatic mosquitoes including Ae. africanus in Africa [5] and Haemogogus spp. and Sabethes spp. in South America [3,6]. The enzootic vectors in South America can occasionally infect humans, an occurrence that resulted in a massive outbreak from 2016–2020. The intermediate cycle exists only in Africa in rural areas that border forest or savannah and involves the transmission of the YFV between both humans and NHP hosts and semi-domestic mosquito vectors such as Ae. furcifer, Ae. bromeliae, Ae. luteocephalis etc. [5]. The intermediate transmission can occur in areas with some human activity such as village settlements where humans can come in contact with infected semi-domestic mosquitoes [7].
Despite the availability of a safe and effective vaccine for nearly a century, yellow fever (YF) disease affects approximately 200,000 individuals, causing an estimated 30,000 deaths annually [8]. YFV continues to cause periodic, large outbreaks in Africa [4] and South America [9]. During 2016, Angola recorded 4307 suspected cases and 306 suspected deaths [4], and Brazil recorded 2251 cases and 772 deaths [9]. This ongoing high level of circulation combined with recent vaccine shortages in the face of outbreaks [10] raises alarms over the risk of importation to areas with immunologically naïve populations such as Asia and North America. Moreover, vaccinations in these areas are not widespread due to difficulty in manufacturing, and implementing it would further increase the strain on vaccine supplies. Additionally, there are restrictions with vaccinating everyone due to complications associated with adverse events, especially in the elderly [11].
YFV infection causes varying levels of disease characterized by asymptomatic to mild flu-like illness ranging to hemorrhagic manifestations and death [12]. Severe YF is a systemic illness characterized by high viremia, hepatic, renal, and myocardial injury, and hemorrhage with a case fatality rate of 20–50% [12]. In humans, the incubation period is typically 3–6 days [13], and the disease develops in three stages (Figure 2). The “period of infection” is the viremic phase with non-specific signs and symptoms such as malaise, headache, nausea, and fever. This is followed by the “period of remission”, wherein the symptoms remit in most cases, and patients recover. However, one in seven persons progress to the “period of intoxication” where they develop the severe viscerotropic disease with an enlarged and tender liver, renal dysfunction, jaundice, cardiovascular instability, and hemorrhage, which can lead to death [12].

2. Brief History of YFV Research

YFV most likely originated in Africa and arrived in the Americas with the slave trade in the 1600s [14]. Parasitologist Patrick Manson, who studied filariasis, was the first to suggest the role of mosquitoes as intermediate hosts of a pathogen [15]. His investigations influenced the work of other scientists to discover the mode of transmission of yellow fever. The most significant findings were by Carlos Juan Finlay, a Cuban physician who showed a local mosquito to be a probable vector of YFV and studied mosquito structure, biology, and behavior [16]. In 1881, Finlay hypothesized that the YFV was transmitted by Aedes aegypti (previously called Culex fasciatus) mosquitoes [17], representing the first time that an arthropod vector had been proposed for any virus. Finlay’s theories were confirmed by United States Army pathologist Walter Reed and collaborators, who proved that the virus was arthropod-borne, and that mosquitoes were the putative vector [18]. The discovery of the mode of transmission quickly led to measures by the American surgeon William Crawford Gorgas to eradicate the vector in Havana, Cuba. These actions lead to a precipitous decline in yellow fever cases [19]. The successful elimination of large YFV outbreaks as a result of vector control efforts was noted and soon replicated by other countries, including Brazil and Panama. One of the greatest challenges during the construction of the Panama Canal was massive deaths occurring due to mosquito-borne diseases such as yellow fever and malaria. Successful vector control efforts in this area facilitated the completion of the Panama Canal [19].
In 1927, British physician Adrian Stokes isolated YFV from a Ghanian patient, Mr. Asibi, for whom this prototypical YFV strain is named [20]. This groundbreaking work was the first time that a human virus had been isolated. Unfortunately, Stokes contracted the virus during his experiments and died within four days [20]. In 1937, the live-attenuated 17D vaccine was obtained by passaging the Asibi strain of YFV a total of 176 times, initially in live monkeys and murine embryonic tissues, followed by chicken embryos and eventually chicken embryos lacking neurological tissue; this work earned Max Theiler the 1951 Nobel Prize in medicine [21].
Due to the devastating outbreaks, in 1942 the Pan American Health Organization (PAHO) started an ambitious vector-control program with the goal of completely eradicating Ae. aegypti mosquitoes utilizing insecticides such as DDT and source reduction to remove artificial containers that usually serve as larval habitats [22,23]. By 1962, Ae. aegypti was eradicated in almost 20 Latin American countries, including Brazil [22,24]. However, urbanization, transportation, insecticide resistance, concerns over off-target effects of DDT, lack of funds and political will resulted in the reinfestation of these mosquitoes throughout the Americas [25].

3. Animal Models

3.1. Mice (Mus Musculus)

Laboratory rodents display varying degrees of susceptibility to YF with multiple factors playing important roles such as the virus strain, animal age and immune status, and route of and dose of infection. While model development with wild-type strains of YFV has been limited, partially due to biosafety requirements, numerous efforts have been made in developing a mouse model using the vaccine strain 17D and its sub-strains. Table 1 summarizes the attempts for mouse model development using wild-type (WT) and vaccine strains at different doses and routes of inoculation in immunocompetent and immunocompromised mice. Efforts to generate a lethal, viscerotropic model in immunocompetent mice have thus far proven unsuccessful. In contrast, several models exist using mice that lack key component(s) of the innate immune response. Mice lacking both the IFN-α/β receptor and the IFN-γ receptor are susceptible to the 17D-204 vaccine, developing a lethal infection in a dose-dependent fashion with high viral titers in the brain and liver [26]. Three- to four-week-old mice lacking either the IFN-α/β receptor (A129) or the STAT1 signaling molecule (STAT129) are susceptible to wild-type strains of YFV such as Asibi and Angola73, succumbing to illness within six to seven days [27]. Elevated MCP-1 and IL-6 levels in these mice suggest the development of a cytokine storm, and histopathological examination of the liver revealed extensive damage including fatty acid steatosis, apoptotic and necrotic lesions, and immune cell infiltrate [27]. All these factors are consistent with the viscerotropic, hepatic YF disease seen in severe human illness. Similar observations are reported in adult C57BL/6 IFNAR−/− mice (lacking type 1 interferon receptor on C57BL/6 background) [28]. Studies in STAT2 −/− (lacking signal transducer and activator of transcription 2) mice have shown efficient replication of YFV Asibi stain emphasizing the role of murine STAT2 in restricting replication [29]. In contrast to observations in other flaviviruses such as DENV and ZIKV. hSTAT2 incorporated in murine cells does not bind to YFV NS5, indicating the role of other human factors [29]. Additional examples of the disease outcome in immunocompromised mice are summarized in Table 1. Thus, immunocompromised mouse models are a useful tool for examining YFV pathogenesis and testing vaccine and therapeutic candidates, provided that the early, innate immune response is not critical to the scientific question under examination.
Another strategy for the development of a YF mouse model has been chimerization. The FRG (fumarylacetoacetate) mice have three genetic lesions (Fah−/−, Rag−/−, Il2rg−/−) on a C57BL/6 background. They are immune-deficient Fah knockout mice, and they lack the genes for Rag-2 and the common gamma chain of the interleukin receptor [30]. These mice can then be modified to replace murine with human hepatocytes (hFRG) [31]. Intravenous inoculation of hFRG mice with 2 × 105 focus-forming units (ffu) of a highly pathogenic YFV-Dakar strain resulted in 10–25% weight loss and a viscerotropic disease in conjunction with high viral titers in the liver [31]. Histopathological analysis of YFV-infected hFRG livers showed apoptotic and steatotic hepatocytes, areas of necrosis, and inflammatory infiltration, all of which are classic YF manifestations in humans [31]. Despite the shortcomings of current YF mouse models, all of which require either dysregulation of the animals’ immune response or chimerization, they represent an important resource due to the cost-effectiveness, availability of both animals and reagents, and simplicity of working with mice in contrast to hamsters or NHPs. Efforts toward the development of an immune-intact, adult mouse model capable of mimicking human illness would be of substantial benefit to YFV research.
Table
Table 1. Mouse models of YFV infection.
Table 1. Mouse models of YFV infection.
MouseAgeVirus StrainRoute of Inoculation/DoseDisease OutcomeReference
Immunocompetent
C57BL/63–4-week-old17D *1 IM; 104, 107 4 PFUNo signs of disease up to 30 days[32]
2 IP; 104 PFUNo signs of disease up to 30 days[32]
WT1293–4-week-old17D-204 #3 SQ (both footpad); 106 PFUNo signs of disease[27]
Asibi; # Angola73 #SQ (both footpad); 106 PFUNo signs of disease[27]
Immunocompromised
C57BL/6 (IFNAR−/−)3–4-week-old17D *SQ; 104 PFUNo signs of disease[32]
Footpad; 104 PFUTransient swelling at site of inoc; fully recovered by 6 DPI[32]
IM; 104 PFU32% of mice had neurotropic or viscerotropic disease[32]
IM; 107 PFU42% of mice had neurotropic or viscerotropic[32]
6–7-week-old17D *IM; 107 PFUNo signs of disease[32]
Independent of ageAngola71 #SQ (both rear footpads); 2 × 104 PFU100% lethal by 6–9 DPI[28]
A1293–4-week-old17D-204 #SQ (both footpad); 106 PFUNo signs of disease[27]
Asibi; # Angola 73 #SQ (both footpad); 104 PFUClinical signs such as lethargy, hunched posture, swelling at inoculation site; weight loss; lethal by 7–8 DPI[27]
AG1293–4-week-old17D-204 #SQ (both footpad); 106 PFUWeight loss; lethal by 10–11 DPI[27]
6–7-week-old17D-204 † IP; 104 PFUNeurotropic; lethal; 5 AST (days): 17.2 ± 1.1[26]
IP; 105 PFUNeurotropic; lethal; AST (days): 15.2 ± 3.3[26]
IP; 106 PFUNeurotropic; lethal; AST (days): 12.0 ± 3.6[26]
SQ; 104 PFUNeurotropic; 70% mortality; AST (days): 20.8 ± 4.6[26]
SQ; 105 PFUNeurotropic; lethal; AST (days): 16.8 ± 2.1[26]
3–4-week-oldAsibi; # Angola73 #SQ (both footpad); 104 PFUClinical signs such as lethargy, hunched posture, swelling at inoculation site; weight loss; lethal by 6–7 DPI[27]
G1293–4-week-old17D-204 #SQ (both footpad); 106 PFUNo signs of disease[27]
Asibi; # Angola73 #SQ (both footpad); 104 PFUNo signs of disease[27]
STAT1293–4-week-old17D-204 #SQ (both footpad); 106 PFUNo signs of disease[27]
Asibi #SQ (both footpad); 104 PFULethal by 7–8 DPI[27]
STAT2−/−UnknownAsibiHock; 104 PFUViral burden and histopathological abormalities in spleen, liver; viremia on day 3 PI[29]
1 IM, intramuscular; 2 IP, intraperitoneal; 3 SQ, subcutaneous; 4 PFU, plaque-forming unit; 5 AST, average survival time. * Virus infectivity determined in Baby Hamster Kidney (BHK) cells; # Virus infectivity determined in human hepatoma derived cells (Huh7); † Virus infectivity determined in African green monkey epithelial cells (Vero E6).

3.2. Hamsters (Mesocricetus Auratus)

Mesocricetus auratus, commonly known as the Syrian golden hamster, offers an alternative small animal model for the study of YF. In contrast to mouse models, which rely on modification of the host but permit infection with wild-type strains of YFV, the hamster models utilize wild-type animals with hamster-adapted strains of YFV. The Jiménez strain of YFV was hamster adapted by ten passages in hamster livers, and the resulting Jiménez p10 strain induced lethargy, loss of appetite, and ruffled fur, as well as generated a higher viremia than the parental p0 Jimenez strain [33]. Histopathologic analyses showed acidophil bodies compatible with the apoptotic bodies frequently observed in the livers of experimentally infected rhesus macaques and fatal human cases [34]. Other findings in the livers of YFV Jimenez-infected hamsters were massive hepatocyte necrosis in conjunction with elevated levels of serum aspartate and alanine amino transaminase and microvesicular steatosis, all of which are consistent with human disease [34]. Molecular characterization of the Jimenez p10 strain revealed five nucleotide changes encoding two amino acid substitutions within the non-structural proteins NS3 and NS5 [35]. A hamster-adapted Asibi strain of YFV was also developed by seven passages in hamster livers, resulting in Asibi/hamster p7 virus that caused robust viremia, severe illness, viscerotropic disease, and death in subadult hamsters by 8 days post-infection (DPI) [36]. In comparison to the parental Asibi strain, the genome of the Asibi/hamster p7 virus had 14 nucleotide changes encoding seven amino acid substitutions (five of which were in the envelope protein) [36]. The above findings suggest that there are multiple molecular mechanisms responsible for the viscerotropism in hamsters. Nevertheless, the hamster model can be utilized for several applications, especially for vector competence experiments that require high levels of viremia [37].
The hamster model has been used extensively for the evaluation of antiviral drugs and vaccine candidates, applications for which the intact immune system of the hamster model is particularly important [38,39,40,41]. T-705, a small molecule therapeutic shown to be active against influenza virus, and T-1106, a chemical analog of T-705, were effective in the treatment of YFV Jimenez-infected hamsters with improved survival, reduced viremia, and reduced serum levels of liver enzymes [38,39]. The early treatment of YFV Jimenez-infected hamsters with ribavirin also resulted in reduced liver damage and increased survival [40]. The YFV Jimenez hamster model was also used to determine the efficacy and immune correlates of protection of XRX-001, an inactivated whole virion YFV vaccine candidate adjuvanted with aluminum hydroxide [41,42].

3.3. Non-Human Primates

Historically, NHPs have been used as models to recapitulate human disease. In addition to serving as models of human infection, NHP infection with YFV is worthy of study in and of itself due to its role as a natural reservoir in sylvatic and intermediate transmission cycles. Neotropical NHPs such as Alouotta spp. (howler monkeys), Callithrix spp. (marmoset) and Callicebus spp. (titis) are susceptible to YFV infection [43], and fatal epizootics often precede human infections [9]. Despite the efforts in surveillance and vaccinations, the 2016–2019 YFV outbreak in Brazil is considered the most significant New World YF activity in the last 70 years, resulting in 2251 human cases and 772 deaths as well as 2590 confirmed NHP infections [9,43]. Alternatively, African NHPs such as the Cercopithecus spp. (genons)., Cercocebus spp. (mangabey), Colobus spp. (colobus) are susceptible to YFV infection but are mostly resistant to disease making, it difficult to isolate the virus and use these NHPs as sentinels [44,45]. Various attempts at experimental infection of NHPs are summarized in Table 2.
The first documented experiments with NHPs and YFV date to 1928 when Stokes and colleagues discovered that monkeys from Asia (rhesus macaques) were susceptible to infection with almost identical clinical and post-mortem reports as those from humans [46]. Thereafter, rhesus and cynomolgus macaques have commonly been used to study the clinical, biochemical, immunological, and pathophysiologic aspects of YF [47,48]. Histological observations in rhesus macaques (infected with doses ranging from 25 to 5 × 104 TCID50 of YFV strain DakH1279) showed a classic viscerotropic disease with significant injury to the liver and kidney [47]. Infected livers were discolored with signs of hemorrhagic foci, extensive hepatocyte necrosis, and councilman bodies (eosinophilic degeneration of liver cells), and all the kidney sections showed evidence of tubular necrosis and protein deposits. Consistent with these gross pathological findings, key indicators of liver and kidney damage such as lymphopenia, elevated cytokines, and elevated liver enzymes were often observed only a few hours before humane euthanasia of moribund animals [47,48].
Experimental infection of African NHPs with YFV produces an inapparent infection and only mild disease. In contrast, many African NHPs have high, intense, and prolonged viremia, making them good amplifying hosts for the virus. Since epizootic NHP deaths associated with YFV in Africa are not as common as in South America, surveillance is of utmost importance, especially since multiple species of NHPs are often found to be seropositive [49].
YFV antibodies have been detected in chimpanzees (Pan troglodytes) and baboons (Papio cynocephalus, Papio anubis) during surveillance in Africa. Experimental infection of chimpanzees with an African YFV strain showed relatively low viremia that lasted for a duration of 3 days [50]. Inoculation of African pottos (Perodicticus potto) with YFV resulted in 4–8 days of viremia high enough to infect mosquitoes; however, no clinical signs were observed up to 10 DPI [49].
In the New World, many species of NHPs are impacted during epizootics in terms of severity of disease and fatality with the most common ones being marmosets (Callithrix spp.), howler monkeys (Alouatta spp.), night monkeys (Aotus spp.), spider monkeys (Ateles spp.), woolly monkeys (Lagothrix spp.), squirrel monkeys (Saimiri spp.), and capuchin monkeys (Cebus spp.), [44]. Susceptibility and tolerance to infection with YFV varies greatly among these groups and even among species of these groups. Howler monkeys are generally considered the most susceptible species to minimal doses of experimental YFV infection [51]. In contrast, the capuchin monkeys are relatively refractory to infection [52]. Animals that survive infection typically develop lifelong humoral immunity against YFV, which allows for serological analysis.
Table
Table 2. NHP models of YFV Infection.
Table 2. NHP models of YFV Infection.
NHP SpeciesYFV StrainDose/Route of InoculationOutcomeReference
Old World NHPs
Macaca mullata (Rhesus macaque)DakH129 *25 1 TCID50; 2 SQ75% lethal (3/4) by 5–7 DPI; 39–79% hepatocellular damage in animals with lethal outcome[47]
102 TCID50; SQ75% lethal (3/4) by 5–7 DPI; 36–57% hepatocellular damage in animals with lethal outcome[47]
103 TCID50; SQ84% lethal (5/6) by 4–6 DPI; 33–77% hepatocellular damage in animals with lethal outcome[47]
104 TCID50; SQ50% lethal (1/2) by 4–5 DPI; 68% hepatocellular damage in the animal with lethal outcome[47]
5 × 104 TCID50; SQ75% lethal (3/4) by 4–5 DPI; 70–81% hepatocellular damage in animals with lethal outcome[47]
Asibi800 adult mouse 3 ic LD50; 4 IP100% lethal (3/3) by 5–6 DPI[53]
French Viscerotropic8000 baby mouse ic LD50; 5 ID100% lethal (2/2) by 5–6 DPI[53]
JSS (South American)3 baby mouse ic LD50; SQ0% lethal (0/2)[53]
Macaca fascicularis
(Cynomolgus macaque)		Asibi #900 6 PFU; SQ100% lethal (1/1) by Day 7 PI; Peak viremia 9 log10 PFU/mL; elevated levels of 7 AST and 8 ALT[54]
Asibi #104 TCID50; SQ100% lethal (6/6) by 6 DPI; liver swelling, jaundice, pathological abnormalities in liver, spleen, lymph node, kidney; peak viremia 3 × 109 genome copies/mL; increased ALT, AST, AP, Bilirubin[55]
17D #104 TCID50; SQNo clinical signs of disease[55]
Galago crassicaudatus
(Bush baby)		UnknownUnknown50% lethal; viremia duration 4–8 days[44]
Cercopithecus spp. (various species)UnknownUnknownIntense viremia for 3–4 days followed by immunity[44]
Colobus abyssinicusEast African strain2–6000 mouse LD50No apparent signs of disease; Viremia duration 6–9 days[45]
Cercocebus spp.UnknownUnknownViremia duration 2 days (Only C. torquatus develops high enough viremia to infect mosquitoes)[44]
Pan troglodytes (Chimpanzee)African400 mouse LD50Viremia duration 3 days[50]
Perodicticus potto (African potto) Intense viremia, high enough to infect mosquitoes; viremia duration 4–8 days; no clinical signs of disease[49]
New World NHPs
Saimiri spp. (Squirrel monkey)BeH655417 * (South American)1 × 106 PFU/mL; IDViscerotropic disease; pathological abnormalities and viral burden in liver, spleen, kidney, lymph node, heart, lung, brain, stomach[56]
Callithrix albicollis (Marmoset)AsibiUnknown (blood transferred from other NHPs or via mosquito bites)33% lethal (2/6); febrile, pathological abnormalities in liver and kidney[57]
S.R.Unknown (blood transferred from other NHPs or via mosquito bites)80% lethal (4/5); febrile, pathological abnormalities in liver, kidney, spleen[57]
Leontocebus ursulus (Tamarin)AsibiUnknown (blood transferred from other NHPs or via mosquito bites)100% lethal (5/5); febrile, pathological abnormalities in liver and kidney[57]
Cebus spp. (Capuchin)Asibi; S.R.Unknown (blood transferred from other NHPs or via mosquito bites)Very low mortality, viremia may or may not be high enough to infect mosquitoes[58]
1 TCID50, tissue culture infectious dose 50; 2 SQ, subcutaneous; 3 IC LD50, inoculum titrated by intracerebral inoculation of mice with serial tenfold dilutions of the virus; 4 IP, intraperitoneal; 5 ID, intradermal; 6 PFU, plaque-forming units; 7 AST: aspartate aminotransferase; 8 ALT: alanine aminotransferase; * Virus infectivity determined in Aedes albopictus cell line (C6/36); # Virus infectivity determined in African green monkey epithelial cells (Vero E6).

3.4. Other Animal Models

Attempts to experimentally infect other animal models with YFV have been unsuccessful. Guinea pigs inoculated by the intraperitoneal route with an infectious dose of 106 TCID50 of the YFV strains Asibi, Jimenez as well as the hamster adapted strains Asibi/hamster p7 and Jimenez/hamster p10, showed no clinical signs of illness, no detectable viremia and 100% survival [35]. Histopathological observation of liver, spleen and brain showed no abnormalities [35]. Historic experiments have shown that rabbits are non-susceptible to YF disease with no apparent clinical signs and detectable viremia, but they develop immunity [59]. Other attempts to evaluate the immune response and determine the level of circulating virus in blood in experimentally YFV-exposed wild animals displayed varied results [60]. Akodon spp. (South American grass mice), Oryzomys spp. (North American semiaquatic rodent), and Didelphis paraguayensis (Brazilian opossum) were completely negative with an absence of detectable viremia and neutralizing antibody response, suggesting that these animals play no role in epidemic emergence [60]. Metachirops opossum (South American opossum) had inconsistent and low viremia, although neutralizing antibodies were detected in the majority of the animals exposed, suggesting that they could be dead-end hosts [60]. In contrast, Metachirus nudicaudatus (brown four-eyed opossum) were found to be susceptible with viremia high enough to infect mosquitoes and short-term neutralizing antibody response [60]. Trinomys dimidiatus (soft-spined Atlantic spiny rat) and armadillos had inconsistent and low viremia and unreliable neutralizing antibodies, indicating no epidemiological significance [60].
Based on the purpose of the experiment, one animal model may be preferred over the other. The advantages and disadvantages of common laboratory animal models are listed in Table 3.

4. Arthropod Vectors

4.1. The Urban Cycle of Transmission

Aedes aegypti, also known as the “yellow fever mosquito”, was most likely introduced into the New World approximately 400–500 years ago from West Africa via the European slave trade [61]. Despite its limited flight range, Ae. aegypti has expanded its geographic range rapidly due to international trade and globalization [61]. The eggs are resistant to desiccation, which enables their survival during long-distance travel [62]. Although Ae. aegypti are found throughout tropical and sub-tropical regions, their populations vary in their ability to transmit arboviruses. Outside of Africa, Ae. aegypti populations are anthropophilic, which contributes to their vectorial capacity for human pathogens [63]. In contrast, Ae. aegypti populations across sub-Saharan Africa vary strongly in their ecology, behavior, and appearance [62]. Some populations are tree dwelling and are found in forests feeding on other mammals [64,65], whereas the more “domesticated” forms are found around homes feeding on humans [64,65]. Aedes aegypti females lay eggs in multiple, small batches, and the domestic form Ae. aegypti aegypti is typically found in human settlements and oviposits in man-made containers [63,64,65]. These daytime feeders are competent vectors for several medically relevant arboviruses such as dengue, chikungunya, Zika, and YFV.
Although urban, human-amplified YF outbreaks occurred frequently in the Americas for centuries, major urban outbreaks had not been documented since 1942. The 2016–2019 Brazilian outbreak was due to spillover infections from the sylvatic cycle, with no detection of human-amplified transmission [6]. However, the presence of Ae. aegypti in nearly all of the affected regions has raised major concerns over the specter of an urban cycle establishing itself in South America [9]. This fear was driven by various studies (summarized below and in Table 4) that have shown Brazilian Ae. aegypti mosquito colonies to be highly susceptible to YFV infection [66,67,68].
Vector competence is defined as the intrinsic ability of a mosquito to acquire and transmit a pathogen [69]. Vector competence studies were conducted with three Brazilian Ae. aegypti colonies (Manaus, Goiania, and Rio) experimentally infected with two Brazilian and one Senegalese YFV strain at an infectious dose of 106 PFU via artificial bloodmeal. At 14 DPI, the three mosquito colonies exhibited a significant difference in infection rates for the three YFV strains ranging from 30–85% [66]. Vector competence studies with Ae. aegypti collected at eight different locations across Senegal and infected with two West African YFV strains had great variation in the midgut infection rate (11–100%) and dissemination rate (0–59%) across all locations as well as between the two YFV strains [70]. Another study to evaluate the vector competence of Australian Ae. aegypti from two different locations (Cairns and Townsville) showed that mosquitoes exposed to an artificial bloodmeal with a titer of 6.7 Log10 TCID50/mL of a South American YFV strain had 24% and 36% infection rates, whereas the mosquitoes exposed to 7 Log10 TCID50/mL of a Nigerian YFV strain had 80% and 72% infection rates, respectively [71]. All these results further support the variability in results and complexity in vector competence studies. A summary of various vector competence studies in Ae. aegypti from different locations has been listed in Table 4. Increased knowledge of vector competence and transmission of viruses will improve our ability to predict and respond to emerging arboviruses through better surveillance and vector control methods.
Table
Table 4. Vector competence studies in Ae. aegypti mosquitoes.
Table 4. Vector competence studies in Ae. aegypti mosquitoes.
ColonyInfectious Dose/RouteYFV StrainResultsReference
Santos, Brazil7–7.8 Log10 1 PFU/mL;
2 ABM		Brazilian (MG2001)4 IR: 35%, 6 TR: 28%
at 11–14 3 DPF		[72]
6.3 Log10 PFU/mL;
ABM		Brazilian (MG2001)TR: 23%
at 21 DPF		[72]
Respublic of Vanuatu7–7.8 Log10 PFU/mL;
ABM		Brazilian (MG2001)IR: 18%, TR: 12%
at 11–14 DPF		[72]
6.3 Log10 PFU/mL;
ABM		Brazilian (MG2001)TR: 17%
at 21 DPF		[72]
Goias, Brazil6 Log10 PFU/mL; ABMBrazilian
(4408-1E)		IR: 0, ~30, ~70, ~10 % at 3, 7, 14 and 21 DPF
5 DR: 0, ~25, ~70, 100% at 3, 7, 14 and 21 DPF
TR: 0, 0, ~20, ~50% at 3, 7, 14 and 21 DPF		[66]
Brazilian
(74018-1D)		IR: 0, ~30, ~80, ~65% at 3, 7, 14 and 21 DPF
DR: 0, ~35, ~65, ~90% at 3, 7, 14 and 21 DPF
TR: 0, 0, ~20, 0% at 3, 7, 14 and 21 DPF		[66]
Senegalese
(S-79)		IR: 0, ~30, ~80, 0% at 3, 7, 14 and 21 DPF
DR: 0, ~35, ~75,0% at 3, 7, 14 and 21 DPF
TR: 0% at 3, 7, 14 and 21 DPF		[66]
Manaus, Brazil6 Log10 PFU/mL; ABMBrazilian
(4408-1E)		IR: ~55%, DR:~85%, TR: ~25% at 14–21 DPF[66]
Brazilian
(74018-1D)		IR: ~55%, DR: ~60%, TR: ~15% at 14–21 DPF[66]
Senegalese
(S-79)		IR: ~30%, DR: ~50%, TR: ~35% at 14–21 DPF[66]
Rio, Brazil6 Log10 PFU/mL; ABMBrazilian
(4408-1E)		IR: ~85%, DR: ~60%, TR: ~60% at 14–21 DPF[66]
Brazilian
(74018-1D)		IR: ~45%, DR: ~60%, TR: ~35% at 14–21 DPF[66]
Senegalese
(S-79)		IR: ~50%, DR: ~65%, TR: ~40% at 14–21 DPF[66]
Fatick, Senegal6.22 Log10 PFU/mL;
ABM		Nigerian
(BA-55)		7 MIR: 100%, 8 DIR:59%
at 14 DPF		[70]
5.9 Log10 PFU/mL;
ABM		Nigerian
(DAK 1279)		MIR: 17%, DIR: 0%
at 14 DPF		[70]
Bignona, Senegal6.22 Log10 PFU/mL;
ABM		Nigerian
(BA-55)		MIR: 83%, DIR: 13%
at 14 DPF		[70]
7.79 Log10 PFU/mL;
ABM		Nigerian
(DAK 1279)		MIR: 33%, DIR:0%
at 14 DPF		[70]
Richard Toll, Senegal6.32 Log10 PFU/mL;
ABM		Nigerian
(BA-55)		MIR: 57%, DIR: 10%
at 14 DPF		[70]
7.79 Log10 PFU/mL;
ABM		Nigerian
(DAK 1279)		MIR: 57%, DIR: 17%
at 14 DPF		[70]
Goudiry, Senegal6.04 Log10 PFU/mL;
ABM		Nigerian
(BA-55)		MIR: 53%, DIR: 0%
at 14 DPF		[70]
5.9 Log10 PFU/mL;
ABM		Nigerian
(DAK 1279)		MIR: 10%, DIR: 0%
at 14 DPF		[70]
Kedougou, Senegal5.34 Log10 PFU/mL;
ABM		Nigerian
(BA-55)		MIR: 35%, DIR: 0%
at 14 DPF		[70]
5.9 Log10 PFU/mL;
ABM		Nigerian
(DAK 1279)		MIR: 10%, DIR: 0%
at 14 DPF		[70]
PK10, Senegal6.04 Log10 PFU/mL;
ABM		Nigerian
(BA-55)		MIR: 27%, DIR: 3%
at 14 DPF		[70]
5.9 Log10 PFU/mL;
ABM		Nigerian
(DAK 1279)		MIR: 22%, DIR: 0%
at 14 DPF		[70]
Mont Rolland, Senegal6.2 Log10 PFU/mL;
ABM		Nigerian
(BA-55)		MIR: 27%, DIR: 0%
at 14 DPF		[70]
5.9 Log10 PFU/mL;
ABM		Nigerian
(DAK 1279)		MIR: 20%, DIR: 3%
at 14 DPF		[70]
Rufisque, Senegal6.13 Log10 PFU/mL;
ABM		Nigerian
(BA-55)		MIR: 17%, DIR: 0%
at 14 DPF		[70]
5.9 Log10 PFU/mL;
ABM		Nigerian
(DAK 1279)		MIR: 11%, DIR: 0%[70]
Cairns, Australia7.2 Log10 TCID50/mL;
ABM		Nigerian
(BA-55)		IR: 80%, DIR: 72%, 9 TIR: 52%
at 14 DPF		[71]
6.7 Log10 TCID50/mL;
ABM		Bolivian
(Cinetrop 28)		IR: 24%, DIR: 24%, TIR: 24%
at 15 DPF		[71]
8 Log10 TCID50/mL;
ABM		African (Asibi)IR: 92%, DIR: 80%
At 14 DPF		[71]
Townsville, Australia7.2 Log10 TCID50/mL;
ABM		Nigerian
(BA-55)		IR: 72%, DIR: 60%, TIR: 60%
at 14 DPF		[71]
6.7 Log10 TCID50/mL;
ABM		Bolivian
(Cinetrop 28)		IR: 36%, DIR: 32%, TIR: 28%
at 14 DPF		[71]
8 Log10 TCID50/mL
ABM		African (Asibi)IR: 96%, DIR: 100%[71]
Cambodia, Asia7 Log10 PFU/mL;
ABM		Senegalese
(S-79)		IR: 40%, DR: 60%, TR: 0% at 14 DPF
IR: 40%, DR: 90%, TR: 35% at 21 DPF		[73]
Vietnam, Asia7 Log10 PFU/mL;
ABM		Senegalese
(S-79)		IR: 60%, DR: 70%, TR: 0% at 14 DPF
IR: 70%, DR: 55%, TR: 5% at 21 DPF		[73]
Trung, Asia7 Log10 PFU/mL;
ABM		Senegalese
(S-79)		IR: 95%, DR: 75%, TR: 0% at 14 DPF
IR: 90%, DR: 90%, TR: 30% at 21 DPF		[73]
Laos, Asia7 Log10 PFU/mL;
ABM		Senegalese
(S-79)		IR: 75%, DR: 62%, TR: 0% at 14 DPF
IR: 100%, DR: 90%, TR: 40% at 21 DPF		[73]
Thailand, Asia7 Log10 PFU/mL;
ABM		Senegalese
(S-79)		IR: 100%, DR: 85%, TR: 45% at 14 DPF
IR: 100%, DR: 100%, TR: 58% at 21 DPF		[73]
Singapore, Asia7 Log10 PFU/mL;
ABM		Senegalese
(S-79)		IR: 80%, DR: 80%, TR: 10% at 14 DPF
IR: 100%, DR: 50%, TR: 5% at 21 DPF		[73]
New Caledonia, Asia7 Log10 PFU/mL;
ABM		Senegalese
(S-79)		IR: 100%, DR: 100%, TR: 10% at 14 DPF
IR: 100%, DR: 75%, TR: 25% at 21 DPF		[73]
Taiwan, Asia7 Log10 PFU/mL;
ABM		Senegalese
(S-79)		IR: 65%, DR: 55%, TR: 0% at 14 DPF
IR: 85%, DR: 50%, TR: 50% at 21 DPF		[73]
1 PFU, plaque-forming units; 2 ABM, artificial bloodmeal; 3 DPF, days post-feeding; 4 IR, infection rate (number of positive mosquitoes/total mosquitoes); 5 DR, dissemination rate (number of positive heads or legs/total infected mosquitoes); 6 TR, transmission rate (number of positive saliva or salivary glands/total infected mosquitoes); 7 MIR, midgut infection rate (number of positive midguts/total engorged mosquitoes); 8 DIR, disseminated infection rate (number of positive legs/total engorged mosquitoes); 9 TIR, transmitted infection rate (number of positive saliva or salivary glands/total engorged mosquitoes).

4.2. The Sylvatic Cycle of Transmission

YFV is maintained in the sylvatic/enzootic cycle in South America and sub-Saharan Africa between non-human primates and arboreal mosquitoes. The principal sylvatic vector in some regions of tropical Africa is Ae. africanus; however, other mosquito species such as Ae. furcifer- taylori, Ae. vittatus, Ae. simpsoni, etc., have also been implicated [3]. These mosquitoes are primatophilic and usually use treeholes filled with rainwater as oviposition sites and larval habitats [74]. The occurrence of YFV in East Africa has solely been attributed to sylvatic vectors [75]. Unlike Africa, the sylvatic vectors in South America belong to the genera Haemogogus spp. (Hg. janthinomys, Hg. spegazzinni, Hg. leucocelaenus) and Sabethes spp. (Sa. chloropterus, Sa. albipivus, Sa. soperi, Sa. cyaneus) [3]. Haemogogus leucocelaenus and Sa. albipivirus experimentally infected using artificial bloodmeals at a titer of 106 PFU/mL were competent for West African and Brazilian strains of YFV with approximately 48% infection [66].
YFV has been isolated from various sylvatic mosquito vectors in East and West Africa and South America [5,76,77]. However, these sylvatic mosquitoes are generally difficult to rear in the laboratory; hence, the knowledge of their biology is often restricted to the study of field-collected mosquitoes. Unfortunately, this limits our understanding of vector competence, transmission, and susceptibility of these enzootic vectors.
Eighty-nine species of mosquitoes collected from 44 municipalities of five Brazilian states during the 2016–2019 YF outbreak revealed that five sylvatic species were positive in 42% of municipalities [6]. Haemogogus janthinomys and Hg. leucocelaenus were found to be the primary vectors due to high numbers of YFV-positive pools and the extensive distribution of the mosquito population [6]. Despite the wide distribution of the urban vector, Ae. aegypti, YFV was not detected in the mosquito pools of this species.

5. Discussion and Conclusions

There have been excellent advances in our understanding of YF; however, there is much about the virus that we do not know. Fatal outcome in YFV-infected patients has been associated with elevated cytokines and chemokines such as interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, interferon-inducible protein (IP)-10, tumor necrosis factor (TNF)-α, and IL1 receptor antagonist (IL1-RA) [78]. Severe liver damage accompanied by elevated levels of ALT and AST, coagulopathy, kidney failure, and rapid deterioration has been observed in severe clinical cases [75]. Histopathology studies of YF-infected patient livers have demonstrated high prevalence of apoptosis over necrosis, steatosis, and councilman bodies corresponding to hepatocyte damage from apoptosis [79,80]. Most of these observations have been studied in all three animal models showing characteristic viscerotropic disease and molecular abnormalities, especially in the NHP model. Unfortunately, the NHP model being the most relevant to represent human disease is also more difficult, expensive, and ethically challenging to obtain. Mice and hamsters are easily available; however, they each have their restrictions with respect to using immunodeficient mice or hamster-adapted strains.
There is great variability in the susceptibility of Ae. aegypti mosquitoes to YFV infection across geographic vector populations as well as viral genotypes, strains, and dose [66,67,68,69,70,81]. Despite numerous efforts, it is difficult to standardize vector competence studies due to differences in laboratory conditions, mosquito rearing, food and water, microbiome, insectary environment, and colonization history [82]. Importantly, more studies are required to bridge the gap between results from laboratory studies and data from epidemic emergence. The lack of YFV in the urban vector, Ae. aegypti, along with the lack of human cases distant from infected NHPs, have demonstrated that the virus failed to establish itself in the urban, human-amplified cycle during the 2016 Brazilian outbreak. This was surprising considering the detection of NHP and human cases in major cities with little human immunity due to the lack of vaccination during many years without outbreaks. Moreover, the wide presence of competent Ae. aegypti throughout Asia [73,83] yet complete absence of YFV is a similar mystery yet to be solved [84]. Multiple theories to explain the lack of YFV have been posited, which include the failure of virus introductions into Asia (although other viruses with similar origins in Africa such as Zika and chikungunya have extensive histories of movement to Asia), competition or interference with other flaviviruses such as dengue within the vector (although vector infection rates are low even during epidemics) and cross-protection provided by other flaviviruses such as dengue, which are hyperendemic in much of Asia and Latin America [84,85]. The two major outbreaks of YFV in Angola and Brazil during the 2015–2019 period as well as the more recent epizootics reported in Brazil [86] underscore the need to reassess the epidemic emergence potential of the virus. Additionally, we need to continue our attempts to develop better animal models for antiviral and vaccine development as well as standardize the vector competence studies across laboratories to minimize variability in results and improve interpretation of results from different research groups.

Author Contributions

Conceptualization, D.P.S., J.A.P., K.S.P. and S.C.W.; literature review, D.P.S.; writing—original draft preparation, D.P.S.; writing—review and editing, D.P.S., J.A.P., K.S.P. and S.C.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by NIH grant numbers R24AI120942 and U01AI151801, and Divya P. Shinde was funded by the UTMB Center for Vector-borne and Zoonotic Diseases.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Simmonds, P.; Becher, P.; Bukh, J.; Gould, E.A.; Meyers, G.; Monath, T.; Muerhoff, S.; Pletnev, A.; Rico-Hesse, R.; Smith, D.B.; et al. ICTV Virus Taxonomy Profile: Flaviviridae. J. Gen. Virol. 2017, 98, 2–3. [Google Scholar] [CrossRef] [PubMed]
  2. Rice, C.M.; Lenches, E.M.; Eddy, S.R.; Shin, S.J.; Sheets, R.L.; Strauss, J.H. Nucleotide sequence of yellow yever virus: Implications for flavivirus gene expression and evolution. Science 1985, 229, 726–733. [Google Scholar] [CrossRef] [PubMed]
  3. Hanley, K.A.; Monath, T.P.; Weaver, S.C.; Rossi, S.L.; Richman, R.L.; Vasilakis, N. Fever versus Fever: The role of host and vector susceptibility and interspecific competition in shaping the current and future distributions of the sylvatic cycles of dengue virus and yellow fever virus. Infect. Genet. Evol. J. Mol. Epidemiol. Evol. Genet. Infect. Dis. 2013, 19, 292–311. [Google Scholar] [CrossRef] [PubMed]
  4. Angola: Epidemic (Yellow Fever) Emergency Plan of Action Preliminary Final Report (MDRAO006)—Angola|ReliefWeb. Available online: https://reliefweb.int/report/angola/angola-epidemic-yellow-fever-emergency-plan-action-preliminary-final-report-mdrao006 (accessed on 30 June 2022).
  5. Germain, M.; Cornet, M.; Mouchet, J.; Monath, T.P.; Hervé, J.P.; Salaun, J.J.; Cordellier, R.; Saluzzo, J.F.; Camicas, J.L.; Hervy, J.P.; et al. Recent advances in research regarding sylvatic yellow fever in West and Central Africa. Bull. De L’institut Pasteur 1982, 80, 315–330. Available online: https://horizon.documentation.ird.fr/exl-doc/pleins_textes/pleins_textes_5/b_fdi_04-05/03774.pdf (accessed on 21 July 2022).
  6. Abreu, F.V.S.D.; Ribeiro, I.P.; Ferreira-de-Brito, A.; Santos, A.A.C.D.; Miranda, R.M.D.; Bonelly, I.D.S.; Neves, M.S.A.S.; Bersot, M.I.; Santos, T.P.D.; Gomes, M.Q.; et al. Haemagogus leucocelaenus and Haemagogus janthinomys are the primary vectors in the major yellow fever outbreak in Brazil, 2016–2018. Emerg. Microbes Infect. 2019, 8, 218–231. [Google Scholar] [CrossRef]
  7. Mutebi, J.-P.; Barrett, A.D.T. The epidemiology of yellow fever in Africa. Microbes Infect. 2002, 4, 1459–1468. [Google Scholar] [CrossRef]
  8. Yellow Fever. Available online: https://www.who.int/news-room/fact-sheets/detail/yellow-fever (accessed on 18 May 2022).
  9. Silva, N.I.O.; Sacchetto, L.; de Rezende, I.M.; Trindade, G.D.S.; LaBeaud, A.D. Recent sylvatic yellow fever virus transmission in Brazil: The news from an old disease. Virol. J. 2020, 17, 9. [Google Scholar] [CrossRef]
  10. Gershman, M.D. Addressing a yellow fever vaccine shortage—United States, 2016–2017. MMWR Morb. Mortal Wkly. Rep. 2017, 66, 457. [Google Scholar] [CrossRef]
  11. Monath, T.P.; Cetron, M.S.; McCarthy, K.; Nichols, R.; Archambault, W.T.; Weld, L.; Bedford, P. Yellow fever 17D vaccine safety and immunogenicity in the elderly. Hum. Vaccines 2005, 1, 207–214. [Google Scholar] [CrossRef]
  12. Monath, T.P.; Barrett, A.D.T. Pathogenesis and Pathophysiology of Yellow Fever. In Advances in Virus Research; Elsevier: Amsterdam, The Netherlands, 2003; Volume 60, pp. 343–395. [Google Scholar] [CrossRef]
  13. Symptoms, Diagnosis, & Treatment 26 February 2020. Available online: https://www.cdc.gov/yellowfever/symptoms/index.html (accessed on 18 May 2022).
  14. Bryant, J.E.; Holmes, E.C.; Barrett, A.D.T. Out of Africa: A molecular perspective on the introduction of yellow fever virus into the Americas. PLoS Pathog. 2007, 3, e75. [Google Scholar] [CrossRef]
  15. To, K.K.; Yuen, K.-Y. In memory of Patrick Manson, founding father of tropical medicine and the discovery of vector-borne infections. Emerg. Microbes Infect. 2012, 1, 1–7. [Google Scholar] [CrossRef]
  16. Clements, A.N.; Harbach, R.E. History of the discovery of the mode of transmission of yellow fever virus. J. Vector Ecol. J. Soc. Vector Ecol. 2017, 42, 208–222. [Google Scholar] [CrossRef]
  17. Finlay, C. The mosquito hypothetically considered as an agent in the transmission of yellow fever poison. Yale J. Biol. Med. 1973, 9, 589–604. [Google Scholar]
  18. Reed, W.; Carroll, J.; Agramonte, A.; Lazear, J.W. The etiology of yellow fever—A preliminary note. Public Health Pap. Rep. 1900, 26, 37–53. [Google Scholar]
  19. Sanitation in Panama/by William Crawford Gorgas. Wellcome Collection. Available online: https://wellcomecollection.org/works/f97wdqvn/items (accessed on 18 May 2022).
  20. Hudson, N.P. Adrian stokes and yellow fever research: A tribute. Trans. R. Soc. Trop. Med. Hyg. 1966, 60, 170–174. [Google Scholar] [CrossRef]
  21. Norrby, E. Yellow fever and Max Theiler: The only Nobel Prize for a virus vaccine. J. Exp. Med. 2007, 204, 2779–2784. [Google Scholar] [CrossRef] [PubMed]
  22. Camargo, S. History of Aedes aegypti eradication in the Americas. Bull. World Health Organ. 1967, 36, 602–603. [Google Scholar] [PubMed]
  23. Aedes Aegypti Eradication Program; Communicable Disease Center: Atlanta, GA, USA, 1966.
  24. Soper, F.L. The elimination of urban yellow fever in the Americas through the eradication of Aedes aegypti. Am. J. Public Health Natl. Health 1963, 53, 7–16. [Google Scholar] [CrossRef]
  25. Status of Aedes aegypti eradication in Americas. Pan American Health Organization Meeting, August 1967. Available online: https://iris.paho.org/bitstream/handle/10665.2/5757/48939.pdf?sequence=1&isAllowed=y (accessed on 17 May 2022).
  26. Thibodeaux, B.A.; Garbino, N.C.; Liss, N.M.; Piper, J.; Blair, C.D.; Roehrig, J.T. A small animal peripheral challenge model of yellow fever using interferon-receptor deficient mice and the 17D-204 vaccine strain. Vaccine 2012, 30, 3180–3187. [Google Scholar] [CrossRef]
  27. Meier, K.C.; Gardner, C.L.; Khoretonenko, M.V.; Klimstra, W.B.; Ryman, K.D. A mouse model for studying viscerotropic disease caused by yellow fever virus infection. PLoS Pathog. 2009, 5, e1000614. [Google Scholar] [CrossRef]
  28. Watson, A.M.; Lam, L.K.M.; Klimstra, W.B.; Ryman, K.D. The 17D-204 vaccine strain-induced protection against virulent yellow fever virus is mediated by humoral immunity and CD4+ but not CD8+ T Cells. PLoS Pathog. 2016, 12, e1005786. [Google Scholar] [CrossRef]
  29. Miorin, L.; Laurent-Rolle, M.; Pisanelli, G.; Co, P.H.; Albrecht, R.A.; García-Sastre, A.; Morrison, J. Host-Specific NS5 Ubiquitination Determines Yellow Fever Virus Tropism. J. Virol. 2019, 93, e00151-19. [Google Scholar] [CrossRef]
  30. Strom, S.C.; Davila, J.; Grompe, M. Chimeric mice with humanized liver: Tools for the study of drug metabolism, excretion, and toxicity. Methods Mol. Biol. 2010, 640, 491–509. [Google Scholar] [CrossRef]
  31. Bailey, A.L.; Kang, L.I.; De Assis Barros, D. Consumptive coagulopathy of severe yellow fever occurs independently of hepatocellular tropism and massive hepatic injury. Proc. Natl. Acad. Soc. USA 2020, 117, 32648–32656. [Google Scholar] [CrossRef]
  32. Erickson, A.K.; Pfeiffer, J.K. Spectrum of disease outcomes in mice infected with YFV-17D. J. Gen. Virol. 2015, 96, 1328–1339. [Google Scholar] [CrossRef]
  33. Tesh, R.B.; Guzman, H.; da Rosa, A.P.; Vasconcelos, P.F.; Dias, L.B.; Bunnell, J.E.; Zhang, H.; Xiao, S.Y. Experimental yellow fever virus infection in the Golden Hamster (Mesocricetus auratus). I. Virologic, biochemical, and immunologic studies. J. Infect. Dis. 2001, 183, 1431–1436. [Google Scholar] [CrossRef]
  34. Xiao, S.; Zhang, H.; Guzman, H.; Tesh, R.B. Experimental yellow fever virus infection in the Golden Hamster (Mesocricetus auratus). II. Pathology. J. Infect. Dis. 2001, 183, 1437–1444. [Google Scholar] [CrossRef]
  35. McArthur, M.A.; Zhang, S.L.; Li, L.; Tesh, R.B.; Barrett, A.D.T. Molecular characterization of hamster-adapted yellow fever virus. Vector Borne Zoonotic Dis. 2020, 20, 222–227. [Google Scholar] [CrossRef]
  36. McArthur, M.A.; Suderman, M.T.; Mutebi, J.-P.; Xiao, S.-Y.; Barrett, A.D.T. Molecular characterization of a hamster viscerotropic strain of yellow fever virus. J. Virol. 2003, 77, 1462–1468. [Google Scholar] [CrossRef]
  37. Kumm, H.W.; Laemmert, H.W., Jr. A study of the concentration of yellow fever virus which will infect certain species of Aedes mosquitoes. Am. J. Trop. Med. 1950, 30, 1950. Available online: https://www.cabdirect.org/cabdirect/abstract/19531000394 (accessed on 14 July 2021). [CrossRef]
  38. Julander, J.G.; Furuta, Y.; Shafer, K.; Sidwell, R.W. Activity of T-1106 in a hamster model of yellow fever virus Infection. Antimicrob. Agents Chemother. 2007, 51, 1962–1966. [Google Scholar] [CrossRef]
  39. Julander, J.G.; Shafer, K.; Smee, D.F.; Morrey, J.D.; Furuta, Y. Activity of T-705 in a hamster model of yellow fever virus infection in comparison with that of a chemically related compound, T-1106. Antimicrob. Agents Chemother. 2009, 53, 202–209. [Google Scholar] [CrossRef]
  40. Sbrana, E.; Xiao, S.; Guzman, H.; Ye, M.; Tesh, R.B. Efficacy of post-exposure treatment of yellow fever with ribavirin in a hamster model of the disease. Am. J. Trop. Med. Hyg. 2004, 71, 306–312. [Google Scholar] [CrossRef]
  41. Monath, T.P.; Lee, C.K.; Julander, J.G.; Brown, A.; Beasley, D.W.; Watts, D.M.; Hayman, E.; Guertin, P.; Makowiecki, J.; Crowell, J.; et al. Inactivated yellow fever 17D vaccine: Development and nonclinical safety, immunogenicity and protective activity. Vaccine 2010, 28, 3827–3840. [Google Scholar] [CrossRef]
  42. Julander, J.G.; Trent, D.W.; Monath, T.P. Immune correlates of protection against yellow fever determined by passive immunization and challenge in the hamster model. Vaccine 2011, 29, 6008–6016. [Google Scholar] [CrossRef]
  43. Sacchetto, L.; Silva, N.I.O.; Rezende, I.M.D.; Arruda, M.S.; Costa, T.A.; de Mello, E.M.; Oliveira, G.F.G.; Alves, P.A.; de Mendonca, V.E.; Stumpp, R.G.A.V.; et al. Neighbor danger: Yellow fever virus epizootics in urban and urban-rural transition areas of Minas Gerais state, during 2017-2018 yellow fever outbreaks in Brazil. PLoS Negl. Trop. Dis. 2020, 14, e0008658. [Google Scholar] [CrossRef]
  44. Rodhain, F. The role of monkeys in the biology of dengue and yellow fever. Comp. Immunol. Microbiol. Infect. Dis. 1991, 1, 9–19. [Google Scholar] [CrossRef]
  45. Woodall, J.P.; Dykes, J.R.W.; Williams, M.C. The reaction of a species of colobus monkey to inoculation with yellow fever virus. Ann. Trop. Med. Parasitol. 1968, 62, 528–535. [Google Scholar] [CrossRef]
  46. Stokes, A.; Bauer, J.H.; Hudson, N.P.; Mortimer, R.B.P.P. The transmission of yellow fever to Macacus Rhesus. Rev. Med. Virol. 2001, 11, 141–148. [Google Scholar] [CrossRef]
  47. Engelmann, F.; Josset, L.; Girke, T.; Park, B.; Barron, A.; Dewane, J.; Hammarlund, E.; Lewis, A.; Axthelm, M.K.; Slifka, M.K.; et al. Pathophysiologic and transcriptomic analyses of viscerotropic yellow fever in a rhesus macaque model. PLoS Negl. Trop. Dis. 2014, 8, e3295. [Google Scholar] [CrossRef]
  48. Monath, T.P.; Brinker, K.R.; Cropp, C.B.; Chandler, F.W.; Kemp, G.E. Pathophysiologic correlations in a rhesus monkey model of yellow fever: With special observations on the acute necrosis of B cell areas of lymphoid tissues*. Am. J. Trop. Med. Hyg. 1981, 30, 431–443. [Google Scholar] [CrossRef]
  49. Risk assessment on yellow fever virus circulation in endemic countries. Available online: https://apps.who.int/iris/bitstream/handle/10665/112751/WHO_HSE_PED_CED_2014.2_eng.pdf?sequence=1 (accessed on 15 February 2022).
  50. Smithburn, K.C.; Haddow, A.J. The susceptibility of African wild animals to yellow fever: I. Monkeys. Am. J. Trop. Med. Hyg. 1949, s1–s29, 389–423. [Google Scholar] [CrossRef]
  51. Galindo, P. Monkeys and Yellow Fever. In Non-Human Primates and Medical Research; Academic Press, Inc.: New York, NY, USA; London, UK, 1973; Available online: http://www.gorgas.gob.pa/BiblioGorgas/pdf/monkey%20and%20yellow%20fever.%20pedro%20galindo.pdf (accessed on 5 June 2022).
  52. da Vasconcelos, P.F.C. Febre amarela. Rev. Soc. Bras. Med. Trop. 2003, 36, 275–293. [Google Scholar] [CrossRef]
  53. Theiler, M.; Anderson, C.R. The relative resistance of dengue-immune monkeys to yellow fever virus. Am. J. Trop. Med. Hyg. 1975, 24, 115–117. [Google Scholar] [CrossRef]
  54. Barrett, A.D.T.; Monath, T.P.; Cropp, C.B.; Adkins, J.A.; Ledger, T.N.; Gould, E.A.; Schlesinger, J.J.; Kinney, R.M.; Trent, D.W. Attenuation of wild-type yellow fever virus by passage in HeLa cells. J. Gen. Virol. 1990, 71, 2301–2306. [Google Scholar] [CrossRef]
  55. McGee, C. Evaluation of arthropod-Borne Virus Recombination Potential and Phenotype: In Vitro and In Vivo Analysis of Flavivirus and Alphavirus Model Systems; University of Texas Medical Branch: Galveston, TX, USA, 2010; Available online: https://utmb-ir.tdl.org/bitstream/handle/2152.3/117/CEMcGeeDissertationFinalFinal.pdf?sequence=1&isAllowed=y (accessed on 1 June 2022).
  56. Ferreira, M.S.; Júnior, P.S.B.; Cerqueira, V.D.; Rivero, G.R.C.; Júnior, C.A.O.; Castro, P.H.G.; Silva, G.A.D.; Silva, W.B.D.; Imbeloni, A.A.; Sousa, J.R.; et al. Experimental yellow fever virus infection in the squirrel monkey (Saimiri spp.) I: Gross anatomical and histopathological findings in organs at necropsy. Memórias Do Inst. Oswaldo Cruz 2020, 115, e190501. [Google Scholar] [CrossRef]
  57. Davis, N.C. The susceptibility of marmosets to yellow fever virus. J. Exp. Med. 1930, 52, 405–416. [Google Scholar] [CrossRef]
  58. Davis, N.C. Susceptibility of capuchin (Cebus) monkeys to yellow fever virus. Am. J. Epidemiol. 1930, 11, 321–334. [Google Scholar] [CrossRef]
  59. Whitman, L. The response to yellow fever virus in the nonsusceptible rabbit. J. Immunol. 1935, 29, 12. [Google Scholar]
  60. Hughes, T.P.; Perlowagora, A. The application of immunological tests of sera from captured wild animals to the study of yellow fever epidemiology. Am. J. Trop. Med. Hyg. 1950, s1-30, 835–853. [Google Scholar] [CrossRef]
  61. Powell, J.R.; Gloria-Soria, A.; Kotsakiozi, P. Recent History of Aedes aegypti: Vector Genomics and Epidemiology Records. Bioscience 2018, 68, 854–860. [Google Scholar] [CrossRef]
  62. Christophers, S.R. Aedes Aegypti: The Yellow Fever Mosquito. In Aedes Aegypti: The Yellow Fever Mosquito. Its Life History, Binomics and Structure; The Syndics of The Cambridge University Press: London, UK, 1960. [Google Scholar]
  63. Crawford, J.E.; Alves, J.M.; Palmer, W.J.; Day, J.P.; Sylla, M.; Ramasamy, R.; Surendran, S.N.; Black, W.C.; Pain, A.; Jiggins, F.M.; et al. Population genomics reveals that an anthropophilic population of Aedes aegypti mosquitoes in West Africa recently gave rise to American and Asian populations of this major disease vector. BMC Biol. 2017, 15, 16. [Google Scholar] [CrossRef]
  64. Tabachnick, W.J.; Powell, J.R. A world-wide survey of genetic variation in the yellow fever mosquito, Aedes aegypti*. Genet. Res. 1979, 34, 215–229. [Google Scholar] [CrossRef]
  65. Failloux, A.-B.; Vazeille, M.; Rodhain, F. Geographic Genetic Variation in Populations of the Dengue Virus Vector Aedes aegypti. J. Mol. Evol. 2002, 55, 653–663. [Google Scholar] [CrossRef]
  66. Couto-Lima, D.; Madec, Y.; Bersot, M.I.; Campos, S.S.; Motta, M.D.A.; Santos, F.B.D.; Vazeille, M.; Vasconcelos, P.F.D.C.; Lourenço-de-Oliveira, R.; Failloux, A.B. Potential risk of re-emergence of urban transmission of Yellow Fever virus in Brazil facilitated by competent Aedes populations. Sci. Rep. 2017, 7, 4848. [Google Scholar] [CrossRef]
  67. Mutebi, J.-P.; Gianella, A.; da Rosa, A.T.; Tesh, R.B.; Barrett, A.D.T.; Higgs, S. Yellow fever virus infectivity for Bolivian Aedes aegypti mosquitoes. Emerg. Infect. Dis. 2004, 10, 1657–1660. [Google Scholar] [CrossRef]
  68. Lourenço-de-Oliveira, R.; Vazeille, M.; de Filippis, A.M.B.; Failloux, A.-B. Oral susceptibility to yellow fever virus of Aedes aegypti from Brazil. Memórias Do Inst. Oswaldo Cruz 2002, 97, 437–439. [Google Scholar] [CrossRef]
  69. Souza-Neto, J.A.; Powell, J.R.; Bonizzoni, M. Aedes aegypti vector competence studies: A review. Infect. Genet. Evol. J. Mol. Epidemiol. Evol. Genet. Infect. Dis. 2019, 67, 191–209. [Google Scholar] [CrossRef]
  70. Dickson, L.B.; Sanchez-Vargas, I.; Sylla, M.; Fleming, K.; Iv, W.C.B. Vector competence in West African Aedes aegypti Is flavivirus species and genotype dependent. PLoS Negl. Trop. Dis. 2014, 8, e3153. [Google Scholar] [CrossRef]
  71. Van Den Hurk, A.F.; McElroy, K.; Pyke, A.T.; McGee, C.E.; Hall-Mendelin, S.; Day, A.; Ryan, P.A.; Ritchie, S.A.; Vanlandingham, D.L.; Higgs, S. Vector competence of Australian mosquitoes for yellow fever virus. Am. J. Trop. Med. Hyg. 2011, 85, 446–451. [Google Scholar] [CrossRef]
  72. Johnson, B.W.; Chambers, T.V.; Crabtree, M.B.; Filippis, A.M.; Vilarinhos, P.T.; Resende, M.C.; Macoris, M.D.L.G.; Miller, B.R. Vector competence of Brazilian Aedes aegypti and Ae. albopictus for a Brazilian yellow fever virus isolate. Trans. R. Soc. Trop. Med. Hyg. 2002, 96, 611–613. [Google Scholar] [CrossRef]
  73. Lataillade, L.D.G.D.; Vazeille, M.; Obadia, T.; Madec, Y.; Mousson, L.; Kamgang, B.; Chen, C.H.; Failloux, A.B.; Yen, P.S. Risk of yellow fever virus transmission in the Asia-Pacific region. Nat. Commun. 2020, 11, 5801. [Google Scholar] [CrossRef] [PubMed]
  74. Diallo, D.; Diagne, C.T.; Hanley, K.A.; Sall, A.A.; Buenemann, M.; Ba, Y.; Dia, I.; Weaver, S.C.; Diallo, M. Larval ecology of mosquitoes in sylvatic arbovirus foci in southeastern Senegal. Parasites Vectors 2012, 5, 286. [Google Scholar] [CrossRef]
  75. Monath, T.P.; Vasconcelos, P.F.C. Yellow fever. J. Clin. Virol. 2015, 64, 160–173. [Google Scholar] [CrossRef] [PubMed]
  76. de Rodaniche, E.; Galindo, P. Isolation of yellow fever virus from Haemagogus mesodentatus, H. equinus and Sabethes chloropterus captured in Guatemala in 1956. Am. J. Trop. Med. Hyg. 1957, 6, 232–237. [Google Scholar] [CrossRef]
  77. Mondet, B.; Vasconcelos, P.F.C.; Travassos da Rosa, A.P.A.; Travassos da Rosa, E.S.; Rodrigues, S.G.; Travassos da Rosa, J.F.S.; Bicout, D.J. Isolation of yellow fever virus from nulliparous Haemagogusjanthinomys in Eastern Amazonia. Vector-Borne Zoonotic Dis. 2002, 2, 47–50. [Google Scholar] [CrossRef] [PubMed]
  78. ter Meulen, J.; Sakho, M.; Koulemou, K.; Magassouba, N.F.; Bah, A.; Preiser, W.; Daffis, S.; Klewitz, C.; Bae, H.G.; Niedrig, M.; et al. Activation of the cytokine network and unfavorable outcome in patients with yellow fever. J. Infect. Dis. 2004, 190, 1821–1827. [Google Scholar] [CrossRef]
  79. Quaresma, J.A.; Barros, V.L.; Pagliari, C.; Fernandes, E.R.; Guedes, F.; Takakura, C.F.; Andrade, H.F., Jr.; Vasconcelos, P.F.; Duarte, M.I. Revisiting the liver in human yellow fever: Virus-induced apoptosis in hepatocytes associated with TGF-β, TNF-α and NK cells activity. Virology 2006, 345, 22–30. [Google Scholar] [CrossRef]
  80. Quaresma, J.A.S.; Barros, V.L.R.S.; Fernandes, E.R.; Pagliari, C.; Takakura, C.; da Costa Vasconcelos, P.F.; de Andrade, H.F., Jr.; Duarte, M.I.S. Reconsideration of histopathology and ultrastructural aspects of the human liver in yellow fever. Acta Trop. 2005, 94, 116–127. [Google Scholar] [CrossRef]
  81. Tabachnick, W.J.; Wallis, G.P.; Aitken, T.H.; Miller, B.R.; Amato, G.D.; Lorenz, L.; Powell, J.R.; Beaty, B.J. Oral infection of Aedes aegypti with yellow fever virus: Geographic variation and genetic consideration. Am. J. Trop. Med. Hyg. 1985, 34, 1219–1224. [Google Scholar] [CrossRef]
  82. Lorenz, L.; Beaty, B.J.; Aitken, T.H.G.; Wallis, G.P.; Tabachnick, W.J. The effect of colonization upon Aedes aegypti susceptibility to oral infection with yellow fever virus*. Am. J. Trop. Med. Hyg. 1984, 33, 690–694. [Google Scholar] [CrossRef]
  83. Miot, E.F.; Aubry, F.; Dabo, S.; Mendenhall, I.H.; Marcombe, S.; Tan, C.H.; Ng, L.C.; Failloux, A.B.; Pompon, J.; Brey, P.T.; et al. A peridomestic Aedes malayensis population in Singapore can transmit yellow fever virus. PLoS Negl. Trop. Dis. 2019, 13, e0007783. [Google Scholar] [CrossRef] [PubMed]
  84. Kuno, G. The absence of yellow fever in Asia: History, hypotheses, vector dispersal, possibility of YF in Asia, and other enigmas. Viruses 2020, 12, 1349. [Google Scholar] [CrossRef] [PubMed]
  85. Agampodi, S.B.; Wickramage, K. Is there a risk of yellow fever virus transmission in South Asian countries with hyperendemic dengue? BioMed. Res. Int. 2013, 2013, e905043. [Google Scholar] [CrossRef] [PubMed]
  86. Home—ProMED. ProMED-Mail. Available online: https://promedmail.org/ (accessed on 8 June 2022).
Microorganisms 10 01578 g001 550
Figure 1. The three cycles for YFV transmission involve various mosquito species and hosts. In the sylvatic cycle, the YFV is maintained between sylvatic mosquito species and NHPs as host. In the urban cycle, the virus is primarily maintained between Ae. aegypti mosquitoes and humans as host. The intermediate cycle occurs in Africa only in moist savannah regions with small human settlements. The virus can be transmitted from semi-domestic mosquitoes to humans or NHPs as host. Adapted from CDC (created with Biorender.com, accessed on 1 July 2022).
Figure 1. The three cycles for YFV transmission involve various mosquito species and hosts. In the sylvatic cycle, the YFV is maintained between sylvatic mosquito species and NHPs as host. In the urban cycle, the virus is primarily maintained between Ae. aegypti mosquitoes and humans as host. The intermediate cycle occurs in Africa only in moist savannah regions with small human settlements. The virus can be transmitted from semi-domestic mosquitoes to humans or NHPs as host. Adapted from CDC (created with Biorender.com, accessed on 1 July 2022).
Microorganisms 10 01578 g001
Microorganisms 10 01578 g002 550
Figure 2. The three phases of severe yellow fever disease: period of infection characterized by non-specific symptoms, period of remission, where most individuals recover, and period of intoxication that occurs in extreme cases where individuals progress to a more severe form of the disease [12]. (Created with Biorender.com, accessed on 1 July 2022).
Figure 2. The three phases of severe yellow fever disease: period of infection characterized by non-specific symptoms, period of remission, where most individuals recover, and period of intoxication that occurs in extreme cases where individuals progress to a more severe form of the disease [12]. (Created with Biorender.com, accessed on 1 July 2022).
Microorganisms 10 01578 g002
Table
Table 3. Advantages and disadvantage of animal models of YF.
Table 3. Advantages and disadvantage of animal models of YF.
Animal modelAdvantagesDisadvantages
MiceSmall, easy to handle, cost-effective; reagents available; can conduct studies involving large number of animals; can use wild-type strains of YFVNeed to use immunocompromised mice; generally, viremia is not high enough to conduct mosquito experiments; disease outcome not similar to humans
HamsterViscerotropic disease outcome typical of YFV; can use immune-intact animals; generates high enough viremia for mosquito experimentsNeed to use hamster-adapted strains; reagents are limited
Non-human primatesDisease outcome similar to humans; intact immunity; best representative model for vaccine and therapeutic studies; generally required in the past prior to clinical trialsExpensive; require specialized facilities, training; cannot use large groups due to ethical restrictions
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Shinde, D.P.; Plante, J.A.; Plante, K.S.; Weaver, S.C. Yellow Fever: Roles of Animal Models and Arthropod Vector Studies in Understanding Epidemic Emergence. Microorganisms 2022, 10, 1578. https://doi.org/10.3390/microorganisms10081578

AMA Style

Shinde DP, Plante JA, Plante KS, Weaver SC. Yellow Fever: Roles of Animal Models and Arthropod Vector Studies in Understanding Epidemic Emergence. Microorganisms. 2022; 10(8):1578. https://doi.org/10.3390/microorganisms10081578

Chicago/Turabian Style

Shinde, Divya P., Jessica A. Plante, Kenneth S. Plante, and Scott C. Weaver. 2022. "Yellow Fever: Roles of Animal Models and Arthropod Vector Studies in Understanding Epidemic Emergence" Microorganisms 10, no. 8: 1578. https://doi.org/10.3390/microorganisms10081578

APA Style

Shinde, D. P., Plante, J. A., Plante, K. S., & Weaver, S. C. (2022). Yellow Fever: Roles of Animal Models and Arthropod Vector Studies in Understanding Epidemic Emergence. Microorganisms, 10(8), 1578. https://doi.org/10.3390/microorganisms10081578

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop