Team:Aix-Marseille/Description

<!DOCTYPE html> Site Igem

Inspirations

Arboviruses

Arboviruses are a diverse group of vector-borne RNA viruses. Arthropod-borne viruses (arboviruses) are ecologically distinct from many other pathogens because of the involvement of arthropod vectors and animal reservoirs. Arboviruses multiply without affecting their life or fecundity; they are transmitted, by bite or sting of the infected arthropod, to receptive vertebrates, provoking an early and transitory viremia, resulting in a complex cycle between virus, arthropod vector and the vertebrate host. Depending on the ecology of the arthropod vector (ticks, mosquitoes, sandflies, Culicoides (Ceratopogonidae)), each arbovirosis occupies a specific region but can invade a previously uninfected area. Vertebrates are either disseminators and amplifiers of the virus, or accidental hosts, or epidemiological dead ends (Figure 1 and 2). (1,2)

Figure 1: Classification of arboviruses. Red point causes hemorrhagic fevers and fevers, blue point causes encephalitis.
Figure 2: Example of transmission cycle. Mosquitoes, and main mosquitoes of the genus Culex, are the vectors of WNV (West-Nile Virus). The transmission cycle of the virus mainly involves birds, which play an essential role in its dissemination as amplifying hosts. Most mammals, such as humans and horses, only constitute an epidemiological dead-end and do not allow the continuation of the transmission cycle. (3)

Three clinical pictures are described:

  • Encephalitis (CNS)

    Diseases: Tick-borne encephalitis virus, Japanese encephalitis virus, West Nile virus.

  • Eruptive fevers (Skin, muscles, and joints)

    Diseases: Dengue, Chikungunya, Zika

  • Hemorrhagic fevers (Skin and other specific organs e.g. liver)

    Diseases: Yellow fever and Dengue

Different arboviruses are responsible for identical clinical pictures; conversely, the same virus can cause several types of syndromes. (3,4)

The replication cycle in the arthropod regulates the seasonality of the disease:
  • Dry season
  • Rainy season or hot season
  • Cold season
Over the last 30 years, the emergence and/or resurgence of arboviruses have posed a considerable global health threat. The ongoing geographical expansion of the dengue virus (DENV), along with the explosive outbreaks of West Nile virus (WNV), Chikungunya virus (CHIKV), and more recently, Zika virus (ZIKV) have all served as reminders that new epidemics may emerge at any time from this diversity (Figure 3). (3)

Figure 3: Location of the main arboviruses in the world. CHIKV, chikungunya virus; DENV, dengue virus; JEV, Japanese encephalitis virus; MAYV, Mayaro virus; OROV, Oropouche virus; RVFV, Rift Valley fever virus; YFV, yellow fever virus; ZIKV, Zika virus.(3)

Chikungunya Virus

Chikungunya virus belongs to the Togaviridae family, Alphavirus genus (Figure 1). It is an enveloped positive-strand RNA virus with a 11.8kb genome (5). CHIKV is encapsulated within an icosahedral capsid, covered by a lipid layer of 65nm (6). CHIKV genome encodes 4 nonstructural proteins (nsP1 to nsP4) and the following 5 structural proteins: capsid (C), two envelope glycoproteins (E1 and E2), two small cleavage products (E3 and 6K) (5,6). CHIV is transmitted by 2 major pathways: urban and sylvatic cycles. The first cycle corresponds to the human-mosquito-human cycle, while the sylvatic cycle describes the transmission from animals to mosquitoes to humans. CHIKV mainly infects human epithelial and endothelial cells, as well as fibroblast and monocytes-derived macrophages (6). In 1952-1953, CHIKV was reported for the first time in Tanzania. Until now, West-African, Est-Central-South-African, and Asian lineages have been identified (Figure 3). In Europe, in 2007, the first CHIKV autochtone case was reported, and an outbreak of CHIKV occurred in 2017. Then, in 2010, the South of France was impacted with its first autochthonous transmission of CHIKV (7).

Zika Virus

Zika virus is a Flaviviridae belonging to the flavivirus genus (Figure 1). First isolated in Uganda forest in 1947. Zika is mainly present in Asia and Africa, and only one phenotype is reported for ZIKV (Figure 3). The first infection of ZIKV happened mainly in nonhuman primates. European Aedes genus is competent for ZIKV (7). ZIKV is a single-stranded RNA virus, with a 11kb genome, encoding for only polyprotein encoding for 10 viral proteins comprising: viral particles (capsid C, membrane M, and envelope E) and 7 other non-structural proteins needed for viral replication, use cell machinery. The genome is contained in an icosahedral capsid, protected by a glycoprotein envelope formed by E and M structural proteins. Zika is mainly transmitted through mosquitoes but human-to-human contact is also sufficient to enhance virus transmission . Human cells infected by ZIKV are neural-type cells such as neural progenitor cells (NPCs) and glial precursors. ZIKV also targets immune cells, endothelial cells, and placenta cells (Figure 4). ZIKV replication cycle is initiated with the fusion of E protein to the cell membrane of the host and is followed by the endocytosis process. Within the cytoplasm, RNA is released and translated into the polyprotein, then cleaved into 10 proteins cited previously. Maturation steps allow the release of the virions within the host extracellular matrix (8).

Figure 4: ZIKA transmission routes, target, and treatment prevention actually known (8).

Actually, there is no vaccine or any drugs approved to prevent or cure ZIKV infections (8). However, no vaccines have been developed yet.

Dengue Virus

As Zika Virus, Dengue belongs to the Flaviviridae family, flavivirus genus (Figure 1). 4 phenotypes are included in Dengue Virus: DENV-1 to DENV-4. DENV is an enveloped virus, with a positive-sense single-stranded RNA genome of 11kb, encoding for 3 structural proteins (Capsid C, Membrane prM, and envelope E) and 7 non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). As most of the Flaviviridae, DEV enters the host cell through endocytosis, releases its RNA into the cytoplasm. The latter is translated into a large polyprotein that is cleaved to generate mature proteins. Reported in more than 100 countries, it is characterized as the most widespread virus in the world(Figure 3). The first autochtone case was reported in 2010 in France (7). Actually, there is one vaccine approved against the four strains, which is recombinant tetravalent, live-attenuated known as Dengvaxia developed by Sanofi Pasteur. Other vaccine candidates are in clinical development, including two in phase III trials (9).

Mosquitoes invasion

One of the main vectors of arboviral diseases is the tiger mosquito: Aedes albopictus (figure 5). Do not confuse it with Aedes aegypti which is not considered as a tiger’s one (10).

Figure 5: Aedes albopictus, the tiger mosquito acting as a vector of arboviral diseases (11).

Mosquito’s life cycle

Before becoming a disease vector, the tiger mosquito passes through four distinct forms during his life cycle (figure 6). Eggs are laid in a water point. Then, they hatch and a larva is born. The latter goes through four larval stages by feeding organic matter. Then occurs the metamorphose period, during which the larva turns into a nymph, and the mosquito does not feed itself anymore. Finally, the nymph’s envelope opens up and lets the adult, male or female, emerge. After this cycle closes, they can reproduce. This is when the contact between mosquitoes/humans arises. Indeed, when the female is fertilized, she needs proteins needed for egg development. Blood meals are the perfect candidates for this purpose. This also explains why female mosquitoes are responsible for bites. It’s only after 3-4 days that the female laid down the eggs. This is called a gonotrophic cycle, or a bite-laying cycle. It will repeat until the mosquito's death. On the other hand, males mosquitoes only eat sweet juice such as nectar. (11)

Figure 6: Mosquito’s life cycle.

Habitats

Originally from tropical forests from southeast Asia, Aedes albopictus, one of the most known tiger mosquitoes, has invaded many places in the whole world. Indeed, many explanations can be given for the increased threat the tiger mosquito represents. First, globalization, i.e. trade and travel and human movements is one of the first causes of A. albopictus worldwide dissemination. Then, the tiger mosquito has shown a high resistance degree to climate change, this is linked to its high plasticity. Meaning that it will subsist and remain as an invasive species able to spread continuously. Moreover, A. albopictus is able to live in cold environments, which may become newly invaded areas. Finally, lack of surveillance and control are contributing to its dissemination. High plasticity is mainly due to eggs’ resistance to desiccation and diapause capacity (stopped in the development) (11).

Aedes albopictus is now listed in the 100 most invasive species (factsheet). The species is now implanted in more than 80 countries in Asia, the Indian Ocean, the Pacific, Africa, America, and Mediterranea. Indeed, in France, since 2004 a particular attention has been kept on the tiger mosquito. Nowadays, Aedes albopictus is implanted in 58 departments (figure 7). (11)

Figure 7: Map of colonization by the Aedes albopictus mosquito in metropolitan France. Red points: colonized municipalities; orange points: municipalities where Aedes albopictus is detected. (12)

Sanitary impact

The major threat carried by the tiger mosquitoes is its specificity to transport and transmit arboviral diseases such as Zika, Dengue, and Chikungunya to Humans. Up to now, those diseases mainly impact tropical areas (refer to the previous section for more details in the data). The African continent is the source of arboviruses diseases (Bruno Coutard). In France, diseases transmitted by mosquitoes represent a major threat, particularly in the PACA region and Corsica, where the main mosquito vector is the tiger mosquito, which is now omnipresent (97% of the population in the PACA region lives in a colonized area). Its seasonal activity is intense, particularly in coastal areas where it is active from the end of April to mid-November. Mosquitoes are a source of nuisance, it can at any time be the source of indigenous transmissions of arboviruses (Dengue, Chikungunya, Zika) if it bites viremic people returning from risk areas and then locally other people, thus spreading the virus from person to person. (13)

Some key points in France:

  • Chikungunya, Dengue, and Zika virus enhanced surveillance update 2019 and 2020:

    More than 100 imported cases of dengue per year; despite the decrease in airflow in 2020 due to COVID-19
    Few imported Chikungunya and Zika cases (less than 5 per year)

  • Emergences:

    2019: one Dengue emergence (seven cases) in Alpes-Maritimes and first Zika case emergence (three cases).
    2020: three dengue emergencies with no identified link between the emergencies: five cases in Nice and two cases in Saint Laurent-du-Var in the Alpes-Maritimes, four cases in Croix-Valmer in the Var.
    Origin of the emergencies: absence of adulticide treatment at the site of an imported case (dengue episode in 2019) and lack of identification of the primary imported case (Zika episode in 2019 and all three dengue episodes in 2020).

  • West-Nile:

    2019: 2 autochthonous human cases in Var (Fréjus and Les Arcs) and 13 confirmed equine cases (9 in Bouches-du-Rhône, 2 in Gard and 2 in Haute-Corse).
    2020: 5 confirmed equine cases (3 in South Corsica, 1 in Haute-Corse, and 1 in the Var)

Environmental threat

One of the main goals is to prevent arboviral transmission through mosquitoes vectors. For that, we can either target the virus with vaccines. Unfortunately, as described above, no vaccines are developed and approved yet. Actually, a lot of pesticides and insecticides are used and spread widely in the environment in order to kill and eradicate potentially infected mosquitoes. However, this solution has a severe impact. First of all, mosquitoes are becoming more and more resistant to harsh chemicals such as insecticides/DDT (6). Then, insecticides are not only toxic for mosquitoes but for the whole ecosystem, including bees, ants, and other insects, inducing a negative impact on the biodiversity and food chain.

References

  1. Wu, P., Yu, X., Wang, P., & Cheng, G. (2019). Arbovirus lifecycle in mosquito: Acquisition, propagation and transmission. Expert Reviews in Molecular Medicine, 21.
  2. Huang, Y.-J. S., Higgs, S., & Vanlandingham, D. L. (2019). Emergence and re-emergence of mosquito-borne arboviruses. Current Opinion in Virology, 34, 104–109.
  3. Weaver, S. C., Charlier, C., Vasilakis, N., & Lecuit, M. (2018). Zika, Chikungunya, and Other Emerging Vector-Borne Viral Diseases. Annual Review of Medicine, 69, 395–408.
  4. Gubler, D. J. (1998). Resurgent vector-borne diseases as a global health problem. Emerging Infectious Diseases, 4(3), 442–450.
  5. Simon, F., Javelle, E., Oliver, M., Leparc-Goffart, I., & Marimoutou, C. (2011). Chikungunya virus infection. Current Infectious Disease Reports, 13(3), 218–228.
  6. Ganesan, V. K., Duan, B., & Reid, S. P. (2017). Chikungunya Virus: Pathophysiology, Mechanism, and Modeling. Viruses, 9(12), E368.
  7. Martinet, J.-P., Ferté, H., Failloux, A.-B., Schaffner, F., & Depaquit, J. (2019). Mosquitoes of North-Western Europe as Potential Vectors of Arboviruses: A Review. Viruses, 11(11), E1059.
  8. Gasco, S., & Muñoz-Fernández, M. Á. (2021). A Review on the Current Knowledge on ZIKV Infection and the Interest of Organoids and Nanotechnology on Development of Effective Therapies against Zika Infection. International Journal of Molecular Sciences, 22(1), 35.
  9. Vaccines and immunization: Dengue (who.int) Retrieved October 21, 2021.
  10. Aedes albopictus - Factsheet for experts (europa.eu) European Centre for Disease Prevention and Control. Retrieved October 21, 2021.
  11. Signalement A. albopictus. S’informer. (anses.fr) Retrieved October 21, 2021.
  12. http://www.cnr-arbovirus.fr/www/ (anses.fr) Retrieved October 21, 2021.
  13. Santé Publique France. Bulletin de santé publique arboviroses en Paca et Corse. Mai 2021. Retrieved October 21, 2021.

IGEM Aix-Marseille 2021