Summary
Viral infection is a major contributor to the global burden of infectious diseases. Virus-related glomerular diseases
are seen in increasing frequency in clinical practice but are still underrecognized, thus miss opportunities for
timely treatment. Viral exposure can alter host immunity in subtle ways, leaving an indelible footprint on the
immune system. While there have been many studies indicating the association of viral infection with glomerular
disease, a direct involvement of virus in kidney barrier dysfunction is unknown in most cases. Among remarkable
research obstacles, lacking of a convenient and relevant animal model can be the most alarming one. We have
recently established a novel mouse model whereby viral proteins drive glomerular disease in concert with a
unique immune molecule, soluble urokinase receptor (suPAR). Intranasal injection of SARS-Cov-2 spike S1
protein (2019-nCov) caused proteinuria and podocyte injury specifically in mice with high levels of suPAR.
Treatment with anti-suPAR antibody in mice or anti- v 3 integrin antibody on human podocytes blocked
proteinuria and protected the glomerular filtration apparatus respectively. Notably, we found this unique synergy
between viral protein and host suPAR in causing glomerular disease applies to other integrin binding viruses as
well, including HIV-1 and Epstein-Barr virus (EBV). Clinically, suPAR is associated with kidney function loss in
patients with HIV-1 infection, and in those with moderate to severe Covid-19. Based on these intriguing new
insights, we hypothesize that viral-host suPAR interplay induces glomerular integrin activation and plays an
essential role in some virus-associated glomerular disease. We propose to test this hypothesis by
comprehensively evaluating the implication of viral protein-suPAR-integrin triad in both mouse models (Aim 1)
and virus-associated human glomerular diseases (Aim 2), utilizing state of the art tools, and unique combinations
of top-down and bottom-up approaches. Additionally, we will test therapeutic modalities targeting the vicious viral
protein-suPAR-integrin cycle with relevant small molecule inhibitors and antibodies (Aim 3).