Emerging respiratory viruses - pathogenesis and countermeasures

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

In any given year, lower respiratory tract infections are the leading cause of infectious disease deaths worldwide, and the fifth most important cause of death overall. Respiratory viruses keep emerging at a steady pace (e.g. MERS-CoV, enterovirus D68, avian influenza viruses), adding to the burden of respiratory tract infections on global health. In 2019-2021, the emergence of SARS-CoV-2 and the resulting COVID-19 pandemic highlighted how devastating the effect of emerging respiratory viruses on global public health and economies can be. The COVID-19 pandemic also showed once again the difficulty of effectively treating severe viral lower respiratory tract infections. Major advances have been made in our knowledge of the pathogenic processes involved in severe respiratory disease over the past decade; however, few successful treatments have made their way into the clinic. Although many clinical trials have been performed and are ongoing in COVID-19 patients, very few of those have generated promising results. Thus, it is clear that our current understanding of the pathogenesis of viral lower respiratory tract infections is insufficient to drive the development of effective treatments. The main goal of the Molecular Pathogenesis Unit is to contribute to our understanding of the pathogenesis of lower respiratory tract infections caused by emerging viruses such as Nipah virus, influenza A virus and coronaviruses on the level of the host and individual cell. Ultimately, this will lead to the identification of common pathways involved in lower respiratory tract disease progression and druggable targets within those pathways. In FY2020, our research efforts were mainly aimed at responding to the COVID-19 pandemic. We continued our search for a nonhuman primate model that better recapitulates severe COVID-19 in humans by inoculating African green monkeys with SARS-CoV-2. Unfortunately, the animals did not develop more severe disease than rhesus macaques; however, this study did provide important insights into the pathogenesis of SARS-CoV-2 and the role of individual cell types in the lungs through single-cell RNA sequencing analyses. Through detection of reads to the SARS-CoV-2 genome, we were able to determine that SARS-CoV-2 replication in the lungs occurs mainly in pneumocytes, while macrophages drive the inflammatory response. Interestingly, monocyte-derived macrophages recruited to the lungs rather than tissue resident macrophages were most likely to be responsible for phagocytosis of infected cells and cellular debris early in infection, with their roles switching as the infection is cleared. Additional pathogenesis studies investigating the role of age in COVID-19 disease are underway in rhesus macaques. We have started the development of organoids of the human respiratory tract, with the purpose of using these organoids to bridge between traditional in vitro studies, animal studies, and human clinical data. Organoids would allow us to study specific aspects of viral respiratory tract disease, such as breakdown of the epithelial barrier function that is a major cause of acute respiratory distress, as well as the host response to infection in the most relevant, functional cell types and in a host that can be rarely studied in sufficient detail, humans. We started by establishing organoids from mouse lungs to work out some isolation and culture conditions before moving on to more complicated organisms (from an organoid establishment perspective) such as nonhuman primates and humans. We have successfully established mouse organoids representing airway epithelium, containing club cells and ciliated epithelial cells, as well as organoids representing the alveoli, containing type II pneumocytes. We have started to establish human airway and alveolar organoids from resectioned human lung tissue and are hoping to start implementing these in our pathogenesis studies soon.