Dengue and Zika Viruses: Epidemiological History, Potential Therapies, and Promising Vaccines

Abstract

Dengue virus (DENV), which can lead to fatal hemorrhagic fever, affects 390 million people worldwide. The closely related Zika virus (ZIKV) causes microcephaly in newborns and Guillain-Barré syndrome in adults. Both viruses are mostly transmitted by Aedes albopictus and Aedes aegypti mosquitoes, which, due to globalization of trade and travel alongside climate change, are spreading worldwide, paving the way to DENV and ZIKV transmission and the occurrence of new epidemics. Local outbreaks have already occurred in temperate climates, even in Europe. As there are no specific treatments, these viruses are an international public health concern. Here, we analyze and discuss DENV and ZIKV outbreaks history, clinical and pathogenesis features, and modes of transmission, supplementing with information on advances on potential therapies and restraining measures. Taking advantage of the knowledge of the structure and biological function of the capsid (C) protein, a relatively conserved protein among flaviviruses, within a genus that includes DENV and ZIKV, we designed and patented a new drug lead, pep14-23 (WO2008/028939A1). It was demonstrated that it inhibits the interaction of DENV C protein with the host lipid system, a process essential for viral replication. Such an approach can be used to develop new therapies for related viruses, such as ZIKV.

Keywords: Aedes; Flavivirus; Zika; dengue; epidemiology.

Figure 1

Timeline of dengue and Zika cases in Europe. Dengue has been present in Europe and is considered an emerging threat by the European Center for Disease Control and by the European Union (EU) public health authorities. The mosquito is found in the region, leading to recent outbreaks. Thus, it must be accounted for in terms of public health policies across the EU.

Figure 2

Flavivirus life cycle, highlighting the capsid protein role. (a) Flavivirus life cycle. The virion enters the host cell by clathrin-mediated endocytosis (1). Fusion of the viral envelope and the cell membrane is promoted by acidification of the endosome (2), followed by the viral genome release into the cytoplasm (3). The viral genome is translated into a polyprotein that is cleaved into 10 proteins: three structural and seven non-structural (4). Next, replication occurs surrounding the ER and LDs (5). This process is followed by virus packaging and assembly, to form new infectious viral particles (6) that follow a secretory pathway, being released through exocytosis (7). (b) The C protein interacts with host LDs and the viral genome, interactions that are crucial for DENV replication and genome packaging, respectively. Those interactions might be targeted in future therapeutic strategies. Adapted from [69,76].

Figure 3

Flavivirus polyprotein disorder propensity. (a) The Flavivirus proteome is rich in structurally disordered regions (values scored above 0.5 in the graph). (b) Flaviviruses use disordered protein regions to extract more function out of a small genome. One such proteins is the C protein, which amino acid residues sequence variability (left) is representative of that of the polyprotein (right). The same clades within mosquito-borne flaviviruses are observed. Abbreviations: SPOV—Spondweni virus; KEDV—Kedougou virus; ILHV—Ilheus virus; ROCV—Rocio virus; AROAV—Aroa virus; SLEV—Saint Louis encephalitis virus; WNV-K—WNV serotype Kunjin; ALFV—Alfuy virus; MVEV—Murray Valley encephalitis virus; USUV—Usutu virus; BAGV—Bagaza virus; IGUV—Iguape virus; KOKV—Kokobera virus. Adapted with permission from [76,77,78].

Figure 4

Dengue and Zika viruses tissue tropism. Representative target-organs of (a) DENV and (b) ZIKV are highlighted. This image has been designed using resources from Freepik.com.

Figure 5

Dengue infection clinical symptoms. The typical clinical manifestations of dengue include flu-like symptoms, namely headache, fever, and fatigue, plus a number of more specific symptoms such as rash and severe myalgia and arthralgia. When it evolves to severe cases, it can induce bleeding, organ impairment, and loss of fluids, all of which may lead to death. This image has been designed using resources from Freepik.com.

Figure 6

Zika infection clinical symptoms. The typical clinical manifestations of Zika include flu-like symptoms, namely headache, fever, and fatigue. Myalgia, arthralgia, and conjunctivitis are also commonly observed symptoms. However, the most serious complications are the development of Guillain-Barré syndrome in adults and microcephalia in newborn babies, which are devastating consequences of Zika infection. This image has been designed using resources from Freepik.com.

Figure 7

Modes of transmission of DENV and ZIKV. The main mode of transmission for both viruses is horizontal transmission (from infected mosquito to human). However, other modes have been suggested or reported, as well as vertical transmission (from an infected female mosquito to its progeny). This image has been designed using resources from Freepik.com.

Figure 8

Potential distribution of Aedes aegypti and Aedes albopictus. This distribution is based on present climatic conditions. Blue shaded areas are projected as suitable and grey shaded regions are unfavorable. Adapted from [205].

Figure 9

Expansion of Aedes spp. mosquitoes in Europe. Geographical distributions of Aedes albopictus in (a) March 2013 and (b) May 2020, and of Aedes aegypti in (c) March 2013 and (d) May 2020. Adapted from [219,220,221].