PNNL

Abstract

Systems biology offers considerable promise in uncovering novel pathways by which viruses and other microbial pathogens interact with host signaling and expression networks to mediate disease severity. In this study, we have developed an unbiased modeling approach to identify new pathways and network connections mediating acute lung injury, using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model pathogen. We utilized a timecourse of matched virologic, pathologic and transcriptomic data within a novel methodological framework that can detect pathway enrichment among key highly connected network genes. This unbiased approach produced a high priority list of 4 genes in one pathway out of over 3500 genes that were differentially expressed following SARS-CoV infection. With this data we predicted that the urokinase and other wound repair pathways would regulate lethal vs. sublethal disease following SARS-CoV infection in mice. We validated the importance of the urokinase pathway on SARS-CoV disease severity using genetically defined knockout mice, proteomic correlates of pathway activation and pathologic disease severity. The results of these studies demonstrate that a fine balance exists between host coagulation and fibrinolysin pathways, regulating pathologic disease outcomes including diffuse alveolar damage and acute lung injury, following infection with highly pathogenic respiratory viruses, like SARS-CoV.