A decade of colonization: the spread of the Asian tiger mosquito in Pennsylvania and implications for disease risk

In recent decades, the Asian tiger mosquito expanded its geographic range throughout the northeastern United States, including Pennsylvania. The establishment of Aedes albopictus in novel areas raises significant public health concerns, since this species is a highly competent vector of several arboviruses, including chikungunya, West Nile, and dengue. In this study, we used geographic information systems (GIS) to examine a decade of colonization by Ae. albopictus throughout Pennsylvania between 2001 and 2010. We examined the spatial and temporal distribution of Ae. albopictus using spatial statistical analysis and examined the risk of dengue virus transmission using a model that captures the probability of transmission. Our findings show that since 2001, the Ae. albopictus population in Pennsylvania has increased, becoming established and expanding in range throughout much of the state. Since 2010, imported cases of dengue fever have been recorded in Pennsylvania. Imported cases of dengue, in combination with summer temperatures conducive for virus transmission, raise the risk of local disease transmission.     

The climatic factors affecting dengue fever outbreaks in southern Taiwan: an application of symbolic data analysis

Background

Dengue fever is a leading cause of severe illness and hospitalization in Taiwan. This study sought to elucidate the linkage between dengue fever incidence and climate factors.

Results

The result indicated that temperature, accumulated rainfall, and sunshine play an important role in the transmission cycles of dengue fever. A predictive model equation plots dengue fever incidence versus temperature, rainfall, and sunshine, and it suggests that temperature, rainfall, and sunshine are significantly correlated with dengue fever incidence.

Conclusions

The data suggests that climate factors are important determinants of dengue fever in southern Taiwan. Dengue fever viruses and the mosquito vectors are sensitive to their environment. Temperature, rainfall and sunshine have well-defined roles in the transmission cycle. This finding suggests that control of mosquito by climatic factor during high temperature seasons may be an important strategy for containing the burden of dengue fever.

     

Dengue Outbreak in Mombasa City,Kenya, 2013–2014: Entomologic Investigations

Dengue outbreaks were first reported in East Africa in the late 1970s to early 1980s including the 1982 outbreak on the Kenyan coast. In 2011, dengue outbreaks occurred in Mandera in northern Kenya and subsequently in Mombasa city along the Kenyan coast in 2013–2014. Following laboratory confirmation of dengue fever cases, an entomologic investigation was conducted to establish the mosquito species, and densities, causing the outbreak. Affected parts of the city were identified with the help of public health officials. Adult Ae. aegypti mosquitoes were collected using various tools, processed and screened for dengue virus (DENV) by cell culture and RT-PCR. All containers in every accessible house and compound within affected suburbs were inspected for immatures. A total of 2,065 Ae. aegypti adults were collected and 192 houses and 1,676 containers inspected. An overall house index of 22%, container index, 31.0% (indoor = 19; outdoor = 43) and Breteau index, 270.1, were observed, suggesting that the risk of dengue transmission was high. Overall, jerry cans were the most productive containers (18%), followed by drums (17%), buckets (16%), tires (14%) and tanks (10%). However, each site had specific most-productive container-types such as tanks (17%) in Kizingo; Drums in Nyali (30%) and Changamwe (33%), plastic basins (35%) in Nyali-B and plastic buckets (81%) in Ganjoni. We recommend that for effective control of the dengue vector in Mombasa city, all container types would be targeted. Measures would include proper covering of water storage containers and eliminating discarded containers outdoors through a public participatory environmental clean-up exercise. Providing reliable piped water to all households would minimize the need for water storage and reduce aquatic habitats. Isolation of DENV from male Ae. aegypti mosquitoes is a first observation in Kenya and provides further evidence that transovarial transmission may have a role in DENV circulation and/or maintenance in the environment.     

Present and future projections of habitat suitability of the Asian tiger mosquito,a vector of viral pathogens,from global climate simulation

Climate change can influence the transmission of vector-borne diseases (VBDs) through altering the habitat suitability of insect vectors. Here we present global climate model simulations and evaluate the associated uncertainties in view of the main meteorological factors that may affect the distribution of the Asian tiger mosquito (Aedes albopictus), which can transmit pathogens that cause chikungunya, dengue fever, yellow fever and various encephalitides. Using a general circulation model at 50 km horizontal resolution to simulate mosquito survival variables including temperature, precipitation and relative humidity, we present both global and regional projections of the habitat suitability up to the middle of the twenty-first century. The model resolution of 50 km allows evaluation against previous projections for Europe and provides a basis for comparative analyses with other regions. Model uncertainties and performance are addressed in light of the recent CMIP5 ensemble climate model simulations for the RCP8.5 concentration pathway and using meteorological re-analysis data (ERA-Interim/ECMWF) for the recent past. Uncertainty ranges associated with the thresholds of meteorological variables that may affect the distribution of Ae. albopictus are diagnosed using fuzzy-logic methodology, notably to assess the influence of selected meteorological criteria and combinations of criteria that influence mosquito habitat suitability. From the climate projections for 2050, and adopting a habitat suitability index larger than 70%, we estimate that approximately 2.4 billion individuals in a land area of nearly 20 million km² will potentially be exposed to Ae. albopictus. The synthesis of fuzzy-logic based on mosquito biology and climate change analysis provides new insights into the regional and global spreading of VBDs to support disease control and policy making.     

Modeling the dynamic transmission of dengue fever: investigating disease persistence

Background

Dengue is a disease of great complexity, due to interactions between humans, mosquitoes and various virus serotypes as well as efficient vector survival strategies. Thus, understanding the factors influencing the persistence of the disease has been a challenge for scientists and policy makers. The aim of this study is to investigate the influence of various factors related to humans and vectors in the maintenance of viral transmission during extended periods.

Methodology/Principal Findings

We developed a stochastic cellular automata model to simulate the spread of dengue fever in a dense community. Each cell can correspond to a built area, and human and mosquito populations are individually monitored during the simulations. Human mobility and renewal, as well as vector infestation, are taken into consideration. To investigate the factors influencing the maintenance of viral circulation, two sets of simulations were performed: (1^st) varying human renewal rates and human population sizes and (2^nd) varying the house index (fraction of infested buildings) and vector per human ratio. We found that viral transmission is inhibited with the combination of small human populations with low renewal rates. It is also shown that maintenance of viral circulation for extended periods is possible at low values of house index. Based on the results of the model and on a study conducted in the city of Recife, Brazil, which associates vector infestation with Aedes aegytpi egg counts, we question the current methodology used in calculating the house index, based on larval survey.

Conclusions/Significance

This study contributed to a better understanding of the dynamics of dengue subsistence. Using basic concepts of metapopulations, we concluded that low infestation rates in a few neighborhoods ensure the persistence of dengue in large cities and suggested that better strategies should be implemented to obtain measures of house index values, in order to improve the dengue monitoring and control system.     

Humanized Mice Show Clinical Signs of Dengue Fever according to Infecting Virus Genotype

We demonstrated that the infection of humanized NOD-scid IL2rγ ^null mice with different strains (representing the four genotypes) of dengue virus serotype 2 (DEN-2) can induce the development of human-like disease, including fever, viremia, erythema, and thrombocytopenia. Newborn mice were irradiated and received transplants by intrahepatic inoculation of human cord blood-derived hematopoietic progenitor cells (CD34⁺). After 6 weeks, mouse peripheral blood was tested by flow cytometry to determine levels of human lymphocytes (CD45⁺ cells); rates of reconstitution ranged from 16 to 80% (median, 52%). Infection (with approximately 10⁶ PFU, the equivalent of a mosquito bite) of these humanized mice with eight low-passage-number strains produced a high viremia extending to days 12 to 18 postinfection. We observed a significant decrease in platelets at day 10 in most of the mice and an increase in body temperature (fever) and erythema (rash) in comparison with humanized mice inoculated with cell culture medium only. Comparison of Southeast (SE) Asian and other genotype viruses (American, Indian, and West African) in this model showed significant differences in magnitude and duration of viremia and rash, with the SE Asian viruses always being highest. Indian genotype viruses produced lower viremias and less thrombocytopenia than the others, and West African (sylvatic) viruses produced the shortest periods of viremia and the lowest rash measurements. These results correlate with virulence and transmission differences described previously for primary human target cells and whole mosquitoes and may correlate with epidemiologic observations around the world. These characteristics make this mouse model ideal for the study of dengue pathogenesis and the evaluation of vaccine attenuation and antivirals.Dengue viruses, which cause the disease dengue fever (DF) and its more severe form, dengue hemorrhagic fever (DHF), in humans, have been spreading to more areas of the world along with their mosquito (Aedes aegypti and Aedes albopictus) vectors. Now over 100 countries are affected, including some areas of the United States (Texas and Hawaii) (5, 26). Due to the fact that only humans show clinical signs and symptoms of disease, it has been difficult to directly test the mechanisms of pathogenesis of these viruses (4). Through decades of research, including clinical, epidemiologic, and laboratory studies, the factors involved in producing disease, whether it be DF or DHF, have remained unproved. However, there are many indications that both the virus and the host contribute to the occurrence and severity of disease: there are genetic differences in the virus and host immune response that can be measured in vitro, and these factors seem to lead to immunopathology in addition to the damage done by virus replication. Because there are four antigenically distinct dengue viruses (serotypes 1 to 4), humans can theoretically have dengue virus infections leading to clinical disease up to four times, and the immunity to the first virus enhances the probability of developing severe dengue after a subsequent infection. Thus, the development of vaccines has been hampered by the unknown effects of inoculating with a tetravalent preparation that might cause immunopathology or severe disease, and there are no appropriate animal models in which to test vaccine attenuation and efficacy for human applications.In 2005 we reported the development of humanized NOD/SCID (nonobese diabetic/severe combined immunodeficient) mice that produced signs of DF upon infection with one strain of dengue virus (3). The mice were humanized by giving them transplants of purified hematopoietic stem cells from human umbilical cord blood (CB) samples taken from normal births. After subcutaneous infection with a low dose of a Southeast (SE) Asian virus, the viremia, rash, and thrombocytopenia were significantly higher, longer lasting, and more like human disease than in any other animal model described at the time. We concluded that this model could be used to test antiviral treatments, since these mice did not produce measurable human antibodies. Since then, many other immunodeficient mouse strains have been produced that can have enhanced human engraftment levels, and they develop functional human immune system cells, including some level of adaptive immunity (20). It has been reported that some of these mouse strains develop immunoglobulins specific for human immunodeficiency virus and dengue virus, albeit at low levels (14, 25).Here we present results of dengue virus pathogenesis studies in a new mouse strain, NOD-scid IL2rγ ^null, that has a much higher degree of human lymphocyte development (median of 52%, versus 14% previously). The comparison of viruses from different genetic subgroups of dengue serotype 2 has led us to conclude that this model is reflective of actual human dengue pathogenesis, and this development might bring us to a new era in testing the factors that contribute to dengue disease.     

Modelling the Use of Wolbachia to Control Dengue Fever Transmission

Experiments and field trials have shown that the intracellular bacterium Wolbachia may be introduced into populations of the mosquito Aedes aegypti, the primary vector for dengue fever. In the absence of Wolbachia, a mosquito acquiring the dengue virus from an infected human enters an exposed (infected but not infectious) period before becoming infectious itself. A Wolbachia-infected mosquito that acquires dengue (i) may have a reduced lifespan, so that it is less likely to survive the exposed period and become infectious, and (ii) may have a reduced ability to transmit dengue, even if it has survived the exposed period. Wolbachia introduction has therefore been suggested as a potential dengue control measure. We set up a mathematical model for the system to investigate this suggestion and to evaluate the desirable properties of the Wolbachia strain to be introduced. We show that Wolbachia has excellent potential for dengue control in areas where R ₀ is not too large. However, if R ₀ is large, Wolbachia strains that reduce but do not eliminate dengue transmission have little effect on endemic steady states or epidemic sizes. Unless control measures to reduce R ₀ by reducing mosquito populations are also put in place, it may be worth the extra effort in such cases to introduce Wolbachia strains that eliminate dengue transmission completely.     

Selection for virulent dengue viruses occurs in humans and mosquitoes

Dengue is the most common mosquito-borne viral disease in humans. The spread of both mosquito vectors and viruses has led to the resurgence of epidemic dengue fever (a self-limited flu-like syndrome) and the emergence of dengue hemorrhagic fever (severe dengue with bleeding abnormalities) in urban centers of the tropics. There are no animal or laboratory models of dengue disease; indirect evidence suggests that dengue viruses differ in virulence, including their pathogenicities for humans and epidemic potential. We developed two assay systems (using human dendritic cells and Aedes aegypti mosquitoes) for measuring differences in virus replication that correlate with the potential to cause hemorrhagic dengue and increased virus transmission. Infection and growth experiments showed that dengue serotype 2 viruses causing dengue hemorrhagic fever epidemics (Southeast Asian genotype) can outcompete viruses that cause dengue fever only (American genotype). This fact implies that Southeast Asian genotype viruses will continue to displace other viruses, causing more hemorrhagic dengue epidemics.     

Assessing the suitability for Aedes albopictus and dengue transmission risk in China with a delay differential equation model

Dengue is considered non-endemic to mainland China. However, travellers frequently import the virus from overseas and local mosquito species can then spread the disease in the population. As a consequence, mainland China still experiences large dengue outbreaks. Temperature plays a key role in these outbreaks: it affects the development and survival of the vector and the replication rate of the virus. To better understand its implication in the transmission risk of dengue, we developed a delay differential equation model that explicitly simulates temperature-dependent development periods and tested it with collected field data for the Asian tiger mosquito, Aedes albopictus. The model predicts mosquito occurrence locations with a high accuracy (Cohen’s κ of 0.78) and realistically replicates mosquito population dynamics. Analysing the infection dynamics during the 2014 dengue outbreak that occurred in Guangzhou showed that the outbreak could have lasted for another four weeks if mosquito control interventions had not been undertaken. Finally, we analyse the dengue transmission risk in mainland China. We find that southern China, including Guangzhou, can have more than seven months of dengue transmission per year while even Beijing, in the temperate north, can have dengue transmission during hot summer months. The results demonstrate the importance of using detailed vector and infection ecology, especially when vector-borne disease transmission risk is modelled over a broad range of climatic zones.     

Dengue and dengue haemorrhagic fever: Indian perspective

The relationship of this country with dengue has been long and intense. The first recorded epidemic of clinically dengue-like illness occurred at Madras in 1780 and the dengue virus was isolated for the first time almost simultaneously in Japan and Calcutta in 1943–1944. After the first virologically proved epidemic of dengue fever along the East Coast of India in 1963–1964, it spread to allover the country. The first full-blown epidemic of the severe form of the illness, the dengue haemorrhagic fever/dengue shock syndrome occurred in North India in 1996. Aedes aegypti is the vector for transmission of the disease. Vaccines or antiviral drugs are not available for dengue viruses; the only effective way to prevent epidemic degure fever/dengue haemorrhagic fever (DF/DHF) is to control the mosquito vector, Aedes aegypti and prevent its bite. This country has few virus laboratories and some of them have done excellent work in the area of molecular epidemiology, immunopathology and vaccine development. Selected work done in this country on the problems of dengue is presented here.     

The Effects of Climate Change and Globalization on Mosquito Vectors: Evidence from Jeju Island,South Korea on the Potential for Asian Tiger Mosquito (Aedes albopictus) Influxes and Survival from Vietnam Rather Than Japan

Background

Climate change affects the survival and transmission of arthropod vectors as well as the development rates of vector-borne pathogens. Increased international travel is also an important factor in the spread of vector-borne diseases (VBDs) such as dengue, West Nile, yellow fever, chikungunya, and malaria. Dengue is the most important vector-borne viral disease. An estimated 2.5 billion people are at risk of infection in the world and there are approximately 50 million dengue infections and an estimated 500,000 individuals are hospitalized with dengue haemorrhagic fever annually. The Asian tiger mosquito (Aedes albopictus) is one of the vectors of dengue virus, and populations already exist on Jeju Island, South Korea. Currently, colder winter temperatures kill off Asian tiger mosquito populations and there is no evidence of the mosquitos being vectors for the dengue virus in this location. However, dengue virus-bearing mosquito vectors can inflow to Jeju Island from endemic area such as Vietnam by increased international travel, and this mosquito vector''s survival during colder winter months will likely occur due to the effects of climate change.

Methods and Results

In this section, we show the geographical distribution of medically important mosquito vectors such as Ae. albopictus, a vector of both dengue and chikungunya viruses; Culex pipiens, a vector of West Nile virus; and Anopheles sinensis, a vector of Plasmodium vivax, within Jeju Island, South Korea. We found a significant association between the mean temperature, amount of precipitation, and density of mosquitoes. The phylogenetic analyses show that an Ae. albopictus, collected in southern area of Jeju Island, was identical to specimens found in Ho Chi Minh, Vietnam, and not Nagasaki, Japan.

Conclusion

Our results suggest that mosquito vectors or virus-bearing vectors can transmit from epidemic regions of Southeast Asia to Jeju Island and can survive during colder winter months. Therefore, Jeju Island is no longer safe from vector borne diseases (VBDs) due to the effects of globalization and climate change, and we should immediately monitor regional climate change to identify newly emerging VBDs.     

Why dengue and yellow fever coexist in some areas of the world and not in others?

Urban yellow fever and dengue coexist in Africa but not in Asia and South America. In this paper, we examine four hypotheses (and various combinations thereof) to explain the absence of yellow fever in urban areas of Asia and South America. In addition, we examine an additional hypothesis that offers an explanation of the coexistence of the infections in Africa while at the same time explaining their lack of coexistence in Asia. The hypotheses we tested to explain the nonexistence of yellow fever in Asia are the following: (1) the Asian Aedes aegypti is relatively incompetent to transmit yellow fever; (2) there would exist a competition between dengue and yellow fever viruses within the mosquitoes, as suggested by in vitro studies in which the dengue virus always wins; (3) when an A. aegypti mosquito that is infected by or latent for yellow fever acquires dengue, it becomes latent for dengue due to internal competition within the mosquito between the two viruses; (4) there is an important cross-immunity between yellow fever and other flaviviruses, dengue in particular, such that a person recovered from a bout of dengue exhibits a diminished susceptibility to yellow fever. This latter hypothesis is referred to below as the "Asian hypothesis." Finally, we hypothesize that: (5) the coexistence of the infections in Africa is due to the low prevalence of the mosquito Aedes albopictus in Africa, as it competes with A. aegypti. We will refer to this latter hypothesis as the "African hypothesis." We construct a model of transmission that allows all of the above hypotheses to be tested. We conclude that the Asian and the African hypotheses can explain the observed phenomena, whereas other hypotheses fail to do so.     

Threshold Dynamics of a Temperature-Dependent Stage-Structured Mosquito Population Model with Nested Delays

Mosquito-borne diseases remain a significant threat to public health and economics. Since mosquitoes are quite sensitive to temperature, global warming may not only worsen the disease transmission case in current endemic areas but also facilitate mosquito population together with pathogens to establish in new regions. Therefore, understanding mosquito population dynamics under the impact of temperature is considerably important for making disease control policies. In this paper, we develop a stage-structured mosquito population model in the environment of a temperature-controlled experiment. The model turns out to be a system of periodic delay differential equations with periodic delays. We show that the basic reproduction number is a threshold parameter which determines whether the mosquito population goes to extinction or remains persistent. We then estimate the parameter values for Aedes aegypti, the mosquito that transmits dengue virus. We verify the analytic result by numerical simulations with the temperature data of Colombo, Sri Lanka where a dengue outbreak occurred in 2017.     

Comparing vector–host and SIR models for dengue transmission

Various simple mathematical models have been used to investigate dengue transmission. Some of these models explicitly model the mosquito population, while others model the mosquitoes implicitly in the transmission term. We study the impact of modeling assumptions on the dynamics of dengue in Thailand by fitting dengue hemorrhagic fever (DHF) data to simple vector–host and SIR models using Bayesian Markov chain Monte Carlo estimation. The parameter estimates obtained for both models were consistent with previous studies. Most importantly, model selection found that the SIR model was substantially better than the vector–host model for the DHF data from Thailand. Therefore, explicitly incorporating the mosquito population may not be necessary in modeling dengue transmission for some populations.     

Fitting the Incidence Data from the City of Campinas,Brazil, Based on Dengue Transmission Modellings Considering Time-Dependent Entomological Parameters

Four time-dependent dengue transmission models are considered in order to fit the incidence data from the City of Campinas, Brazil, recorded from October 1^st 1995 to September 30^th 2012. The entomological parameters are allowed to depend on temperature and precipitation, while the carrying capacity and the hatching of eggs depend only on precipitation. The whole period of incidence of dengue is split into four periods, due to the fact that the model is formulated considering the circulation of only one serotype. Dengue transmission parameters from human to mosquito and mosquito to human are fitted for each one of the periods. The time varying partial and overall effective reproduction numbers are obtained to explain the incidence of dengue provided by the models.     

The enzyme 3-hydroxykynurenine transaminase as potential target for 1,2,4-oxadiazoles with larvicide activity against the dengue vector Aedes aegypti

The mosquito Aedes aegypti is the vector agent responsible for the transmission of yellow fever and dengue fever viruses to over 80 million people in tropical and subtropical regions of the world. Exhaustive efforts have lead to a vaccine candidate with only 30% effectiveness against the dengue virus and failure to protect patients against the serotype 2. Hence, vector control remains the most viable route to dengue fever control programs. We have synthesized a class of 1,2,4-oxadiazole derivatives whose most biologically active compounds exhibit potent activity against Aedes aegypti larvae (ca. of 15 ppm) and low toxicity in mammals. Exposure to these larvicides results in larvae pigmentation in a manner correlated with the LC₅₀ measurements. Structural comparisons of the 1,2,4-oxadiazole nucleus against known inhibitors of insect enzymes allowed the identification of 3-hydroxykynurenine transaminase as a potential target for these synthetic larvicides. Molecular docking calculations indicate that 1,2,4-oxadiazole compounds can bind to 3-hydroxykynurenine transaminase with similar conformation and binding energies as its crystallographic inhibitor 4-(2-aminophenyl)-4-oxobutanoic acid.