Pericytes are critical gatekeepers of the vascular barrier, contributing to viral haemorrhagic diseases pathogenesis

Viruses aim at disrupting the vascular barrier to enable transmission or within-host dissemination, often resulting in severe symptoms such as haemorrhage and oedema. The effect of viruses and viral proteins on the endothelium is well documented, however maintenance of the vascular barrier requires the close association of endothelial cells and pericytes.
 
Flaviviruses such as Dengue virus (DENV) cause widespread morbidity and mortality, especially in low- and mid-income countries. Several emerging haemorrhagic viruses are also part of this family, including Alkhumra haemorrhagic fever virus (AHFV) and Kyanasur forest disease virus (KFDV).

Flavivirus-secreted non-structural protein-1 (NS1) has been associated with disease severity and haemorrhage. Here we will investigate how NS1-mediated pericyte dysfunction contribute to flaviviruses’ haemorrhagic symptoms.

Our results in 2D and 3D in vitro co-culture models of microvascular cells indicate that pericytes are highly dysfunctional in haemorrhagic diseases, losing their perivascular characteristics and regulatory properties and therefore failing to support the endothelium. The pericyte failure further escalates the hyper-permeability of the vasculature by triggering the release of a secreted mediator (Protein X) which negatively regulates endothelial barrier function by destabilising the cell-cell junctions and stimulating pro-inflammatory responses.

Our work indicates the importance of the endothelial-pericyte interactions in determining the severe pathogenesis of known and emerging flaviviruses. Furthermore, establishing the molecular mechanisms will help developing diagnostic markers and novel treatments.