Exuberant fibroblast activity compromises lung function via ADAMTS4

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes—in particular the ECM protease ADAMTS4—and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections

Publisher Correction: Exuberant fibroblast activity compromises lung function via ADAMTS4 (Nature, (2020), 587, 7834, (466-471), 10.1038/s41586-020-2877-5)

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. An amendment to this paper has been published and can be accessed via a link at the top of the paper

Role of microRNAs in Cancer

MicroRNAs are well known for their role in translational inhibition or mRNA degradation by base pairing to the 3\u27 untranslated region (3\u27UTR) of the target mRNAs. Till date thousands of microRNAs have been reported, and the function of most microRNAs is yet to be determined. MicroRNAs have been described as OncomiRs or Tumor suppressors as some microRNAs are reported to be up-regulated whereas some are down-regulated in different types of tumors. To better understand the role of microRNAs in cancer, we were involved in two different projects. In our first project, the main objective was to identify the functionally important microRNA species that play role in the activation of Akt and study the mechanism through which these microRNAs mediate Akt activation. An extensive screening against LY294002 (PI3K inhibitor) was performed on the microRNA-library consisting of more than 600 microRNA precursors. LY29 concentration was optimized such that the drug killed most of the vector control MCF7 cells. Presence of some microRNAs assists in cell survival even in the presence of PI3K inhibitor due to their involvement in Akt activation. Based on this screening, we were able to identify 14 different microRNAs that helped cell survive the LY29 treatment. Western blots demonstrated that miR-9 and miR-943 consistently activated Akt which was further confirmed with cytotoxic assay that demonstrated increased cell survival in presence of miR-9 and miR-943. Online prediction tools identified PTEN as one of the potential target and luciferase reporter assay with 3\u27UTR of PTEN showed decreased luciferase intensity in presence of miR-9 and miR-943. Therefore, miR-9 and miR-943 were identified as Akt activators and a better understanding on their mechanism of action could help indicate their significance as a novel biomarker in tumorigenesis. In our second project, the major aim was to study the post transcriptional regulation of microRNAs by ADARs (Adenosine deaminases acting on RNA). The processing of microRNAs has been shown to be affected through A-to-I editing presumably because the stem-loop structure of the microRNA precursors makes them ideal targets for ADARs. Several microRNAs are known to be subject to ADAR mediated editing. However, the role of microRNA editing in cancer has not yet been studied. We performed IHC in breast tissue microarray which indicated that the level of ADAR1 is significantly higher in breast tumor tissue as compared to the normal breast tissue. Also, the expression of ADAR1 was tissue specific as there was not much difference in ADAR1 expression between the colon tumor vs. normal colon specimen. The increased expression of ADAR1 in breast tumor possibly alters microRNA editing and this deregulation in microRNA editing might be one of the potential causative of tumor. Although, due to some technical difficulty in amplifying pre-microRNAs we were unable to relate altered ADAR1 expression in breast tumor to deregulation in microRNA editing, none the less we were able to demonstrate a differential cell growth when ADAR was over-expressed and a significant increase of ADAR1 expression in breast tumor

Exuberant fibroblast activity compromises lung function via ADAMTS4

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS) . There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS . Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes-in particular the ECM protease ADAMTS4-and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections