Dengue fever pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Alonso Alvarado, M.D. [2]

## Overview

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Aedes aegypti is the principal mosquito vector of dengue fever viruses and is closely associated with humans and their dwellings. The Dengue fever virus also inhibits the human immune response.

## The Vector is the Aedes aegypti Mosquito

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* Aedes aegypti, the principal mosquito vector of dengue viruses, is an insect closely associated with humans and their dwellings. People not only provide the mosquitoes with blood meals but also water-holding containers in and around the home needed to complete their development.
* The mosquito lays her eggs on the sides of containers with water and eggs hatch into larvae after a rain or flooding.
* A larva changes into a pupa in about a week and into a mosquito in two days.

## The Pathogen is Dengue fever virus

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Dengue fever virus (DENV) is an RNA virus of the family Flaviviridae; genus Flavivirus. Other members of the same genus include yellow fever virus, West Nile virus, St. Louis encephalitis virus, japanese encephalitis virus, tick-borne encephalitis, Kyasanur Forest disease virus, and Omsk hemorrhagic fever virus. Most are transmitted by arthropods (mosquitoes or ticks), and are therefore also referred to as arboviruses (arthropod-borne viruses).

The dengue virus genome contains about 11,000 nucleotide bases, which code for the three different types of protein molecules (C, prM and E) that form the virus particle and seven other types of protein molecules (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5) that are only found in infected host cells and are required for replication of the virus. There are five strains of the virus, of which the first four are referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The distinctions between the serotypes is based on the their antigenicity.

## Transmission

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Dengue virus is primarily transmitted by Aedes mosquitoes, particularly A. aegypti. These mosquitoes typically bite during the day, particularly in the early morning and in the evening, but they are able to bite and thus spread infection at any time of day through all the year. Other Aedes species that transmit the disease include A. albopictus, A. polynesiensis and A. scutellaris. Humans are the primary host of the virus, but it also circulates in nonhuman primates. An infection can be acquired via a single bite. A female mosquito that takes a blood meal from a person infected with dengue fever, during the initial 2 to 10 day febrile period, becomes itself infected with the virus in the cells lining its gut. About 8 to 10 days later, the virus spreads to other tissues including the mosquito's salivary glands and is subsequently released into its saliva. The virus seems to have no detrimental effect on the mosquito, which remains infected for life. Aedes aegypti prefers to lay its eggs in artificial water containers, to live in close proximity to humans, and to feed on people rather than other vertebrates.

Dengue can also be transmitted via infected blood products and through organ donation and through Vertical transmission. Other person-to-person modes of transmission have also been reported, but are very unusual. The genetic variation in dengue viruses is region specific, suggestive that establishment into new territories is relatively infrequent, despite dengue emerging in new regions in recent decades.

## Inhibition of the Human Immune System by the Dengue Fever Virus

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Dengue virus inhibits the innate immune response in serval ways as discussed below.[1][2]

### Inhibition of interferon signaling by blocking signal transducer [3][4]

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* NS4B: Is a protein associated with the endoplasmic reticulum. It may block the phosphorylation of STAT 1 after induction by interferons type I alpha and beta. The activity of Tyk2 kinase decreases with the dengue virus; then the STAT 1 phosphorylation also decreases. Therefore, the innate immune system response may be blocked. Thus there is no production of ISG. NS2A and NS4A cofactor may also take part in the STAT 1 inhibition.[5]
* NS5 : Is a protein associated with the inactivation of STAT2 (via the signal transduction of the response to interferon) when it is expressed alone. When NS5 is cleaved with NS4B by a protease (NS2B3) it can degrade STAT2. In fact, after the cleavage of NS5 by the protease, there is an E3 ligase association with STAT2, and the E3 ligase targets STAT2 for the degradation.

### Inhibition of the type I interferon response

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NS2B3 protease complex is a proteolytic core consisting of the last 40 amino acids of NS2B and the first 180 amino acids of NS3. Cleavage of the NS2B3 precursor activates the protease complex. This protease complex allows the inhibition of the production of type I interferon by reducing the activity of IFN-β promoter: studies have shown that NS2B3 protease complex is involved in inhibiting the phosphorylation of IRF3.[6] A recent study shows that the NS2B3 protease complex inhibits (by cleaving) protein MITA which allows the IRF3 activation.

## References

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1. ↑ Diamond MS (2009). "Mechanisms of evasion of the type I interferon antiviral response by flaviviruses". J Interferon Cytokine Res. 29 (9): 521–30. doi:10.1089/jir.2009.0069. PMID 19694536.
2. ↑ Jones M, Davidson A, Hibbert L, Gruenwald P, Schlaak J, Ball S; et al. (2005). "Dengue virus inhibits alpha interferon signaling by reducing STAT2 expression". J Virol. 79 (9): 5414–20. doi:10.1128/JVI.79.9.5414-5420.2005. PMC 1082737. PMID 15827155.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
3. ↑ Ho LJ, Hung LF, Weng CY, Wu WL, Chou P, Lin YL; et al. (2005). "Dengue virus type 2 antagonizes IFN-alpha but not IFN-gamma antiviral effect via down-regulating Tyk2-STAT signaling in the human dendritic cell". J Immunol. 174 (12): 8163–72. PMID 15944325.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
4. ↑ Ashour J, Laurent-Rolle M, Shi PY, García-Sastre A (2009). "NS5 of dengue virus mediates STAT2 binding and degradation". J Virol. 83 (11): 5408–18. doi:10.1128/JVI.02188-08. PMC 2681973. PMID 19279106.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
5. ↑ Muñoz-Jordan JL, Sánchez-Burgos GG, Laurent-Rolle M, García-Sastre A (2003). "Inhibition of interferon signaling by dengue virus". Proc Natl Acad Sci U S A. 100 (24): 14333–8. doi:10.1073/pnas.2335168100. PMC 283592. PMID 14612562.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
6. ↑ Rodriguez-Madoz JR, Belicha-Villanueva A, Bernal-Rubio D, Ashour J, Ayllon J, Fernandez-Sesma A (2010). "Inhibition of the type I interferon response in human dendritic cells by dengue virus infection requires a catalytically active NS2B3 complex". J Virol. 84 (19): 9760–74. doi:10.1128/JVI.01051-10. PMC 2937777. PMID 20660196.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)