Endothelial leak and knowledge gaps: yellow fever virus non-structural protein 1 and the antibodies that bind it

Yellow fever virus, family Orthoflaviviridae, is the causative agent of yellow fever - a lethal mosquito-borne disease endemic to South America and Africa. Recent advances in understanding the mechanism of orthoflavivirus pathogenesis, particularly for dengue (DENV), demonstrate a role for the secreted viral non-structural protein 1 (NS1) in both animal and human models. The NS1 protein's most well described pathogenic mechanism is its ability to induce vascular endothelial permeability in a tissue organ specific manner, contributing to orthoflavivirus disease severity. Surprisingly, there is minimal research published on the role of NS1 in YFV pathogenesis, despite the clear and present danger of YFV outbreaks in endemic countries. Understanding the role of NS1 in YFV pathogenesis is critical for the development of therapeutic interventions. Notably, while vaccination efforts for orthoflaviviruses have been historically difficult, the live attenuated vaccine (YFV-17D) against YFV has been hailed as not only the most successful orthoflavivirus vaccine but is among the most successful live virus vaccines ever created. Despite YFV-17D's widespread use since its introduction in the 1930's, the best described mechanism of protection is the vaccine's potent neutralizing antibodies. Our knowledge of NS1 pathogenic mechanisms has expanded since the development of YFV-17D, but how vaccine mediated immunity may interact with NS1 during natural YFV infection is not well described. In this review we describe the current knowledge of YFV NS1 mediated pathogenesis and adaptive immunity directed against YFV NS1 in a variety of animal and human models.