Extracellular vesicles in arbovirus infections: from basic biology to potential clinical applications

Abstract

Arthropod-borne viruses, or arboviruses, are currently considered a global health threat responsible for potentially severe human diseases. The increased population density, changes in land use and climate change are some of the factors that are contributing to the spread of these infections over the last years. The pathogenesis of these diseases and the mechanisms of interaction with the host, especially those leading to the development of severe forms, are yet to be fully understood. In recent years extracellular vesicles (EVs) have emerged as important players in the inter-cellular and host-pathogen interaction arising a lot of interest also in the field of vector-borne viruses. In this context, EVs seem to play a dual role, by either promoting, thus facilitating, or preventing infection. Many studies are showing how viruses can hijack the vesiculation machinery to escape the host immune response and exploit EVs to sustain their replication and propagation, even though EVs shed by immune cells seem essential to promote antiviral responses. In this manuscript we reviewed the current knowledge regarding the association between EVs and vector-borne viruses, paying particular attention to their possible role in disease transmission and dissemination, as well as to their potential as novel tools for clinical applications, spanning from biomarkers of clinical utility to novel therapeutic options.

Keywords: arboviruses; biomarkers; extracellular vesicles; host-pathogen interaction; pathogenesis.

Figure 1

Schematic representation of the size distribution of extracellular vesicles and arboviruses. The upper part of the figure depicts small and medium/large EVs together with plasma lipoproteins (high, low and very low density lipoproteins - HDL, LDL, VLDL), which represent the main contaminants when enriching EVs from human plasma or serum. Small EVs are generally characterized by the presence of tetraspanins on their surface (i.e., CD63, CD9, CD81) while medium/large EVs by the exposure of phosphatidyl serine. Both types of vesicles enclose nucleic acids (small RNAs, mRNAs), proteins and lipids and carry on their surface different types of transmembrane proteins and receptors. The lower part of the chart represents the size of the different viral particles described in this review to highlight the important overlap in size with EVs. This overlap might represent an important issue when enriching EVs, since viral particles might be co-enriched. The numbers in the arrow represent the size range of the different particles in nm. Figure created in https://BioRender.com.

Figure 2

Summary of the main effects mediated by EVs during arboviral infections. EVs derived from cells infected in vitro or from biological samples from infected patients display functional effects on host cells or tissues. These effects can either promote the infectivity of target cells or prevent the infection. NET, neutrophil extracellular trap; PBMC, peripheral blood mononuclear cells; CNS, central nervous system; IFN, interferon; ADE, antibody dependent enhancement; IFITM3, interferon-inducible transmembrane protein 3. Figure created in https://BioRender.com.