Flaviviruses, an expanding threat in public health: focus on dengue, West Nile, and Japanese encephalitis virus

Abstract

The flaviviruses dengue, West Nile, and Japanese encephalitis represent three major mosquito-borne viruses worldwide. These pathogens impact the lives of millions of individuals and potentially could affect non-endemic areas already colonized by mosquito vectors. Unintentional transport of infected vectors (Aedes and Culex spp.), traveling within endemic areas, rapid adaptation of the insects into new geographic locations, climate change, and lack of medical surveillance have greatly contributed to the increase in flaviviral infections worldwide. The mechanisms by which flaviviruses alter the immune and the central nervous system have only recently been examined despite the alarming number of infections, related deaths, and increasing global distribution. In this review, we will discuss the expansion of the geographic areas affected by flaviviruses, the potential threats to previously unaffected countries, the mechanisms of pathogenesis, and the potential therapeutic interventions to limit the devastating consequences of these viruses.

Figure 1

Global distribution of DENV in relation to its arthropod vectors. DENV is endemic in parts of Asia, Australia, Africa, and Latin America (area between the solid lines) and slowly expanding to other parts of the globe. Currently, DENV is located within the distribution range of A. aegypti and A. albopictus (dotted line). The presences of these mosquito vectors in non-DENV endemic areas suggest the potential for the expansion of the virus into new regions if optimal conditions are present.

Figure 2

Distribution of WNV and DENV infections have been reported United States. To date, WNV infections (green states) have been documented throughout the United States with the exception of Alaska (gray). Texas, Florida, and New York are currently the only states in which both WNV and locally acquired DENV (red states) have been reported. The dotted line designates the northernmost distribution of the WNV mosquito vector, Culex sp. while the dashed line illustrates the northern-most territory of the DENV mosquito vectors, Aedes sp, in the United States.

Figure 3

Distribution of JEV. JEV is currently endemic within South, East, and South East Asia (highlighted in blue) and its surrounding islands indicated by the red border. To date, there are no reported cases of JEV outside of this region; however, the expansion of its mosquito vector, Culex sp, to other countries worldwide make to spread of this dangerous pathogen a significant threat.

Figure 4

Flavivirus genome. The flavivirus genome consists of a single stranded positive-sense RNA encoding a polyprotein post-translationally cleaved by host proteases (sites designated by the blue arrows) and viral proteases (sites designated by green arrows). The site designated by the red arrow is cleaved by a yet to be identified protease. Processing of the polyprotein produces 3 structural (white boxes) and 7 non-structural genes (grey boxes). The prM protein is then later cleaved within the Golgi to release the M protein important for the maturation of the virus. Translation of viral RNA is controlled by the untranslated regions (UTR) located at the 5’ and 3’-ends of the RNA.

Figure 5

Flavivirus life cycle. Following attachment to the host extracellular surface (1), the virus is endocytosed (2) and encapsulated inside an endosomal vacuole. Acidification of the endosomal compartment alters the E protein causing the fusion of the virus with the endosome (3) facilitating virion release into the intracellular compartment where it is unpackaged (4). The released viral genome undergoes two different fates: the viral genome is either transported to the endoplasmic reticulum where it is translated into a polyprotein (5a) or converted into a negative-sense RNA to make positive-sense RNA copies (5b). The large polyprotein is post-translationally processed (6) producing structural and non-structural components important for virus assembly and maturation. The viral genome is packaged into a capsid and transported to the Golgi where it is coated by the E/M protein complex (7) to produce a mature virion (8).

Figure 6

Infection of CNS by flaviviruses. (1) Infection of the CNS occurs either through the adherence of the virus to molecules present on the surface of brain microvascular endothelial cells (BMVEC's) or infiltration of infected monocytes across the BBB. Viral infiltration then leads to infection of the BBB and CNS cell populations. (2) Infection of human astrocytes leads to chemokine production facilitating further recruitment of monocytes and macrophages. (3) Neurons infected by flaviviruses undergo apoptosis and activates the resident microglia population which produces an inflammatory response. Production of inflammatory cytokines (e.g. TNF-α, IL1β, INF-γ and IL-4), chemokines (e.g. CCL2, CCL5, CXCL9, CXCL10), inflammatory enzymes (COX2) and matrix-metalloproteinases (MMPs) leads to degradation of the endothelial barrier and the release of inflammatory factors (5) recruiting CD4⁺ and CD8⁺ T lymphocytes into the CNS parenchyma. Infiltration of CD4⁺/CD8⁺ T lymphocytes leads to further inflammation and eventually CNS damage.