Arboviruses: The Hidden Path of an Imminent Threat

Abstract

Arboviruses are a grade of viruses carried by arthropods, which have been in the headlines due to recent epidemics. Members of this grade are the families Flaviviridae which includes Zika (ZIKV), Dengue (DENV), Yellow Fever (YFV), among other viruses and Togaviridae, which includes Chikungunya (CHIKV). Research on some arboviruses has been strong over the past couple of decades. Other arboviruses have not garnered much attention until lately. For example, ZIKV has been understudied until 2015. Since the 1950s ZIKV was considered to cause only a benign infection in humans. ZIKV became well studied only after the recent outbreaks of the virus in the Pacific, Americas, and South-East Asia, was found to be related to severe neuropathology, which includes the development of neurological defects such as microcephaly on the fetus and Guillain Barré Syndrome in adults. CHIKV is another arbovirus that although been circulating for a long time in Africa and Asia, has been recently introduced into the Americas in 2013, causing recurring outbreaks in South and Central American naïve populations. YFV, which been known to be endemic and thought to be controlled in South America, has re-emerged in Brazil beginning in December 2016. This outbreak, although restricted to transmission by the sylvatic mosquito Haemagogus leococelaenus, raised questions among researchers regarding the potential for spread to the United States due to the presence of the urban vectors Aedes aegypti and Aedes albopictus} and a naïve, largely unvaccinated population. Another question that still remains is whether YFV will ever reach the Asian continent? Today, the time it takes for awareness of the health organizations, to convince the funding agencies, and to work on vaccine development is much more than the time needed for the disease to change from a local outbreak to a global epidemic. The overall objective of this work is to provide the grounds for a viral surveillance system based on evolution, utilizing the current ZIKV and CHIKV outbreaks and other arboviruses as case studies. Utilizing phylogenetic and molecular sequence alignment tools I developed a pipeline to evaluate the genomic changes of viruses on CHIKV and ZIKV. I also created a pipeline to generate pathogen transmission networks and compare different disease networks utilizing different network centrality metrics. CHIKV, DENV, YFV and ZIKV were utilized as case studies. The strategies utilized in this work will enable better abatement and management strategies of viral outbreaks. My findings indicate that changes in the coding sequence does not seem to be the main reason why ZIKV has changed its behavior in terms of pathogenicity. In CHIKV there is an insertion on the UTR region of a group of sequences and change of virulence has been associated with UTR sizes in different CHIKV strains. Upon analyzing viral 3' and 5' UTRs, a trinuncleotide motif, known as Musashi Binding Element was identified in both CHIKV and ZIKV, its presence and availability on ZIKV may explain a preference to human cells, in CHIKV the motif is present but not available. Although both CHIKV and ZIKV coexist and have spread in the same regions in a short period of time, their spread seems to be from independent events. When looking at transmission networks, there is a high correlation between the different centrality metrics utilized to measure all four DENV serotypes transmission networks, CHIKV, YFV and ZIKV have lower correlation, thus, distinct patterns