Mechanisms of Severe Acute Respiratory Syndrome Coronavirus-Induced Acute Lung Injury

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 time course of matched virologic, pathological, 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 3,500 genes that were differentially expressed following SARS-CoV infection. With these data, we predicted that the urokinase and other wound repair pathways would regulate lethal versus sublethal disease following SARS-CoV infection in mice. We validated the importance of the urokinase pathway for SARS-CoV disease severity using genetically defined knockout mice, proteomic correlates of pathway activation, and pathological disease severity. The results of these studies demonstrate that a fine balance exists between host coagulation and fibrinolysin pathways regulating pathological disease outcomes, including diffuse alveolar damage and acute lung injury, following infection with highly pathogenic respiratory viruses, such as SARS-CoV.

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

“…In a previous study, 9 Gralinski et al investigated viral pathogenesis and identified a novel host pathway involved in severe acute respiratory syndrome (SARS)‐coronavirus disease progression. Their data suggest that dysregulation of the urokinase pathway during SARS‐coronavirus infection contributes to more severe lung pathology and that plasminogen activator inhibitor‐1 plays a protective role following infection.…”

Inhibition of SERPINe1 reduces rhabdoviral infections in zebrafish

“…Although we have no evidences to favor any of these possibilities, PLASMIN, is a serine protease not only implicated in fibrinolysis but also in many other matrix protein breakdowns [25], which could include some of the rhabdoviral proteins. On this respect, serpine1 knock-out mice has shown that serpine1, tpa and plg are implicated in controlling coronavirus infections in mammals [26]. However, in coronavirus [26] and in yellow fever [27] infections, serpine1 levels were upregulated contrary to what occurred in fish rhabdoviruses.…”

“…On this respect, serpine1 knock-out mice has shown that serpine1, tpa and plg are implicated in controlling coronavirus infections in mammals [26]. However, in coronavirus [26] and in yellow fever [27] infections, serpine1 levels were upregulated contrary to what occurred in fish rhabdoviruses. We can speculate that a dramatic fighting between host and rhabdovirus could exist to control ser-pine1 transcript levels during the initial course of fish rhabdoviral infections.…”

Decoding the enigma of antiviral crisis: Does one target molecule regulate all?

“…A significant elevation of inflammatory cytokine and chemokine levels was also detected in early infection compared to the healthy control group. CD8 + T cells and neutrophils were found to migrate to the lungs during the late stage of infection [25,26].…”