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.IMPORTANCESevere acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and 2003, and infected patients developed an atypical pneumonia, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) leading to pulmonary fibrosis and death. We identified sets of differentially expressed genes that contribute to ALI and ARDS using lethal and sublethal SARS-CoV infection models. Mathematical prioritization of our gene sets identified the urokinase and extracellular matrix remodeling pathways as the most enriched pathways. By infecting Serpine1-knockout mice, we showed that the urokinase pathway had a significant effect on both lung pathology and overall SARS-CoV pathogenesis. These results demonstrate the effective use of unbiased modeling techniques for identification of high-priority host targets that regulate disease outcomes. Similar transcriptional signatures were noted in 1918 and 2009 H1N1 influenza virus-infected mice, suggesting a common, potentially treatable mechanism in development of virus-induced ALI

A comprehensive collection of systems biology data characterizing the host response to viral infection

The Systems Biology for Infectious Diseases Research program was established by the U.S. National Institute of Allergy and Infectious Diseases to investigate host-pathogen interactions at a systems level. This program generated 47 transcriptomic and proteomic datasets from 30 studies that investigate in vivo and in vitro host responses to viral infections. Human pathogens in the Orthomyxoviridae and Coronaviridae families, especially pandemic H1N1 and avian H5N1 influenza A viruses and severe acute respiratory syndrome coronavirus (SARS-CoV), were investigated. Study validation was demonstrated via experimental quality control measures and meta-analysis of independent experiments performed under similar conditions. Primary assay results are archived at the GEO and PeptideAtlas public repositories, while processed statistical results together with standardized metadata are publically available at the Influenza Research Database (www.fludb.org) and the Virus Pathogen Resource (www.viprbrc.org). By comparing data from mutant versus wild-type virus and host strains, RNA versus protein differential expression, and infection with genetically similar strains, these data can be used to further investigate genetic and physiological determinants of host responses to viral infection

Decolonizing anthropology

Thirty-two years after the publication of Faye V. Harrison's edited volume, Decolonizing Anthropology: Moving Further toward an Anthropology of Liberation, I take stock of the book's origins and its impact on the discipline. Despite intellectual barriers and postmodernist critiques, Decolonizing Anthropology has influenced a generation of anthropologists who carry forward the book's original spirit. Focusing on the third edition, I show that Decolonizing has both reflected and incited changes in the discipline. Finally, I turn to some recent work in which scholars continue to push the boundaries of what decolonizing anthropology can mean. Throughout, I emphasize the importance of decolonization as a practice in anthropology and highlight the ongoing struggles and successes of scholars working in this tradition.https://doi.org/10.1111/amet.1319

Anthropological Theory for the Twenty-First Century: A Critical Approach

Anthropological Theory for the Twenty-First Century presents a critical approach to the study of anthropological theory for the next generation of aspiring anthropologists. Through a carefully curated selection of readings, this collection reflects the diversity of scholars who have long contributed to the development of anthropological theory, incorporating writings by scholars of color, non-Western scholars, and others whose contributions have historically been under-acknowledged. The volume puts writings from established canonical thinkers, such as Marx, Boas, and Foucault, into productive conversations with Du Bois, Ortiz, Medicine, Trouillot, Said, and many others. The editors also engage in critical conversations surrounding the canon itself, including its colonial history and decolonial potential. Updating the canon with late twentieth-century and early twenty-first-century scholarship, this reader includes discussions of contemporary theories such as queer theory, decolonial theory, ontology, and anti-racism. Each section is framed by clear and concise editorial introductions that place the readings in context and conversation with each other, as well as questions and glossaries to guide reader comprehension. A dynamic companion website features additional resources, including links to videos, podcasts, articles, and more.https://ecommons.luc.edu/facultybooks/1198/thumbnail.jp