Orthoflavivirus at the Intersection of Science and Global Health

Posted on 2025-01-29

Flaviviridae are a family of positive-sense, single-stranded RNA viruses transmitted primarily by arthropods. These vector-borne viruses can infect a wide range of hosts and have the potential to spread unexpectedly in human populations, causing a variety of severe diseases, including hepatitis, encephalitis and congenital abnormalities ​(1). Globally, flaviviruses infect up to 400 million people annually, with most regions of the world being endemic for at least one flavivirus, placing billions at risk ​(2).  

The increasing prevalence of flaviviruses is driven by factors such as climate change, increase in population size, and global travel. Most mosquito-borne flaviviruses are associated with the Culex and Aedes genera of the Culicinae subfamily. Symptoms of infection can range from mild fever and malaise to severe encephalitis and fatal haemorrhagic fever ​(2).  

The genus now recognised as Orthoflavivirus was previously classified under the broader Flavivirus genus. It comprises over 50 species of positive-sense, single-stranded RNA viruses within the Flaviviridae family. The most prevalent and clinically relevant species include the Zika virus (O. zikaense), West Nile virus (O. nilense) and the four serotypes of dengue virus (O. denguei)​ (3). These mosquito-borne viruses have a significant global health impact (4).

Despite their prevalence, there are no clinically approved antiviral treatments for Orthoflavivirus infections. However, vaccines have been developed for some species, including Japanese encephalitis virus (Orthoflavivirus japonicum), yellow fever virus (Orthoflavivirus flavi), and tick-borne encephalitis (Orthoflavivirus encephaliticus). Challenges persist in dengue vaccine development due to the existence of four distinct serotypes, which can lead to antibody-dependent enhancement (ADE) in subsequent infections ​(5). Currently, two approved vaccines, Dengvaxia and Qdenga, are available to prevent severe dengue cases​ (6).  

Abbexa supports the research of Orthoflavivirus and other neglected tropical diseases by providing a range of key products to facilitate the advancement of research initiatives.  

• West Nile Virus (WNV)  

WNV is primarily transmitted to humans by the bite of Culex mosquitoes. First identified in Uganda in 1953, WNV initially infects keratinocytes and dendritic cells before spreading to the lymphatic system and bloodstream. The virus can cross the blood-brain barrier, leading to neuroinvasive disease by infecting neurons and causing encephalitis. The envelope (E) protein of WNV plays a crucial role in mediating cell entry by binding to cellular receptors and facilitating membrane fusion within endosomes ​(3)

Our full range of WNV products can be found here. 

• Dengue Virus (DENV) 

DENV comprises four serotypes (DENV-1 to DENV-4) and is transmitted primarily by Aedes mosquitoes ​(7). Following transmission, DENV infects various cell types, including dendritic cells, macrophages, and endothelial cells. The virus enters the cells via receptor-mediated endocytosis, with the E protein facilitating attachment and fusion ​(8). A significant aspect of DENV pathogenesis is ADE where non-neutralising antibodies from a previous infection can enhance viral entry into Fc receptor-bearing cells during subsequent infections with a different serotype, leading to increased viral replication and severe disease manifestations​ (9).  

Our full range of DENV products can be found here. 

• Yellow Fever Virus (YFV) 

YFV is transmitted to humans through the bite of infected Aedes or Haemagogus mosquitoes. After entering the host, YFV primarily targets hepatocytes in the liver, leading to apoptosis and necrosis, which manifest as jaundice – a hallmark of yellow fever ​(10). The virus utilises cellular receptors to facilitate entry via clathrin-mediated endocytosis. YFV can also infect dendritic cells and macrophages, modulating the host's immune response. The non-structural proteins of YFV play roles in evading host antiviral responses, particularly by inhibiting interferon signalling pathways, thereby enhancing viral replication and contributing to pathogenesis ​(11).  

Our full range of YFV products can be found here. 

• Japanese Encephalitis Virus (JEV) 

JEV is transmitted by Culex mosquitoes and primarily circulates in a zoonotic cycle involving pigs and wading birds ​(12). In humans, JEV infection can lead to severe neurological disease. The virus initially replicates at the site of inoculation and in regional lymph nodes before disseminating to the CNS. JEV crosses the blood-brain barrier through mechanisms that may involve infection of endothelial cells, disruption of tight junctions, and Trojan horse-like entry via infected immune cells ​(13).  

Our full range of WNV products can be found here. 

• Zika Virus (ZIKV) 

ZIKV is primarily transmitted by Aedes mosquitoes and can also be spread through sexual contact and vertical transmission. ZIKV exhibits a broad cell tropism, infecting keratinocytes, dendritic cells, and placental cells. The virus enters cells via receptor-mediated endocytosis, with the E protein facilitating attachment and fusion. A notable aspect of ZIKV pathogenesis is its ability to infect neural progenitor cells, leading to impaired neurogenesis and apoptosis, which is associated with congenital Zika syndrome ​(14).  

Our full range of ZIKV products can be found here. 

References 

​​1. Genus: Orthoflavivirus | ICTV [Internet]. [cited 2025 Jan 28]. Available from: https://ictv.global/report/chapter/flaviviridae/flaviviridae/orthoflavivirus?utm_source=chatgpt.com  

​2.  Paul S, Repository S. Flavivirus and its Threat | Flavivirus in Detail. 2021 Mar 25 [cited 2025 Jan 28]; Available from: https://www.sciencerepository.org/flavivirus-and-its-threat  

​3. Best SM. Flaviviruses. Current Biology [Internet]. 2016 Dec 19 [cited 2025 Jan 28];26(24):R1258–60. Available from: http://www.cell.com/article/S0960982216310806/fulltext 

​4. Pierson TC, Diamond MS. The continued threat of emerging flaviviruses. Nature Microbiology 2020 5:6 [Internet]. 2020 May 4 [cited 2025 Jan 28];5(6):796–812. Available from: https://www.nature.com/articles/s41564-020-0714-0 

​5. Cavina L, Bouma MJ, Gironés D, Feiters MC. Orthoflaviviral Inhibitors in Clinical Trials, Preclinical In Vivo Efficacy Targeting NS2B-NS3 and Cellular Antiviral Activity via Competitive Protease Inhibition. Molecules 2024, Vol 29, Page 4047 [Internet]. 2024 Aug 27 [cited 2025 Jan 28];29(17):4047. Available from: https://www.mdpi.com/1420-3049/29/17/4047/htm  

​6. Arkin F. Dengue vaccine fiasco leads to criminal charges for researcher in the Philippines. Science (1979). 2019 Apr 24;  

​7. Islam MT, Quispe C, Herrera-Bravo J, Sarkar C, Sharma R, Garg N, et al. Production, Transmission, Pathogenesis, and Control of Dengue Virus: A Literature-Based Undivided Perspective. Biomed Res Int [Internet]. 2021 [cited 2025 Jan 28];2021:4224816. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC8694986/ 

​8. Cruz-Oliveira C, Freire JM, Conceição TM, Higa LM, Castanho MARB, Da Poian AT. Receptors and routes of dengue virus entry into the host cells. FEMS Microbiol Rev [Internet]. 2015 Mar 1 [cited 2025 Jan 28];39(2):155–70. Available from: https://dx.doi.org/10.1093/femsre/fuu004 

​9. Teo A, Tan HD, Loy T, Chia PY, Chua CLL. Understanding antibody-dependent enhancement in dengue: Are afucosylated IgG1s a concern? PLoS Pathog [Internet]. 2023 Mar 1 [cited 2025 Jan 28];19(3):e1011223. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC10062565/ 

​10. Yellow fever [Internet]. [cited 2025 Jan 28]. Available from: https://www.who.int/news-room/fact-sheets/detail/yellow-fever?utm_source=chatgpt.com 

​11. Klitting R, Fischer C, Drexler JF, Gould EA, Roiz D, Paupy C, et al. What Does the Future Hold for Yellow Fever Virus? (II). Genes 2018, Vol 9, Page 425 [Internet]. 2018 Aug 21 [cited 2025 Jan 28];9(9):425. Available from: https://www.mdpi.com/2073-4425/9/9/425/htm 

​12. Japanese encephalitis [Internet]. [cited 2025 Jan 28]. Available from: https://www.who.int/news-room/fact-sheets/detail/japanese-encephalitis?utm_source=chatgpt.com 

​13. Hsieh JT, St John AL. Japanese encephalitis virus and its mechanisms of neuroinvasion. PLoS Pathog [Internet]. 2020 Apr 1 [cited 2025 Jan 28];16(4):e1008260. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7117652/

​14. Miner JJ, Diamond MS. Zika virus pathogenesis and tissue tropism. Cell Host Microbe [Internet]. 2017 Feb 8 [cited 2025 Jan 28];21(2):134. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC5328190/