Major Areas of Research
- Pathogenesis of emerging viruses that cause severe respiratory disease
- Develop in vitro and in vivo model systems to integrate analyses of pathogen, single cell, and host to identify common pathways involved in disease progression
- Use our knowledge of the pathogenesis of respiratory tract infections to aid development of effective, broad-acting therapeutics
The goal of the Molecular Pathogenesis Unit (MPU) is to increase our understanding of the pathogenesis of emerging respiratory viruses on every level from host to molecule. The emergence of SARS-CoV-2 in late 2019 and the resulting COVID-19 pandemic have made clear how little we understand about the pathogenesis of viral infections of the respiratory tract and how inadequate existing therapeutics are.
It is important to note that even before the COVID-19 pandemic, lower respiratory tract infections were the leading cause of infectious disease deaths worldwide, and the eighth most important cause of death in the US. Besides this continuous burden of endemic respiratory viruses, emerging respiratory viruses remain an important threat to global health. Novel respiratory viruses keep emerging from animal reservoirs: in the last decade alone Middle East Respiratory Syndrome-coronavirus (MERS-CoV), enterovirus D68, Nipah virus, several avian influenza viruses, and SARS-CoV-2 emerged or re-emerged.
Although great progress has been made in the field of direct-acting antivirals, especially for the treatment of COVID-19, therapeutics to treat severe lower respiratory tract disease have lagged behind. A key problem in the development of treatments for severe respiratory virus disease is that virus replication often peaks ahead of disease severity. Rather than virus-induced lung damage alone, the proinflammatory immune response also contributes to severe respiratory disease. Although increasing attention is given to the host processes involved in severe respiratory infections, these studies are often hampered by a focus on in vivo pathogenesis in lethal disease models, or on mechanistic studies of single molecules or signaling pathways in vitro. In MPU, we aim to combine pathogenesis studies with detailed molecular analyses to identify molecular determinants of severe respiratory tract disease within the virus and the host. Ultimately, the identification of common pathways involved in lower respiratory tract disease progression and druggable targets within those pathways will be used to develop broad-acting, syndrome-based therapeutics.
Dr. de Wit received her Ph.D. in virology from Erasmus University Rotterdam, the Netherlands. Her research there focused on the replication, pathogenesis and transmission of influenza A virus. Dr. de Wit then moved to the Laboratory of Virology of NIAID in Hamilton, Montana to work in the biosafety level 4 laboratory there. Here, she focused on the pathogenesis of and countermeasures against Nipah virus, the Middle East Respiratory Syndrome Coronavirus and the 1918 H1N1 influenza A virus (Spanish flu). In 2014-2015, Dr. de Wit spent 4 months in a field lab in Monrovia, Liberia in charge of patient diagnostics for several Ebola Treatment Units in the area, to help contain the devastating Ebola epidemic in Liberia. In 2019, Dr. de Wit became the Chief of the Molecular Pathogenesis Unit. When SARS-CoV-2 emerged in late 2019, Dr. de Wit focused her research on SARS-CoV-2, developing animal models and using those for testing of medical countermeasures and gaining a better understanding of SARS-CoV-2 pathogenesis. Amongst other accomplishments, the data generated in Dr. de Wit’s lab contributed to the licensing of remdesivir as an antiviral treatment for COVID-19 patients.
Kerry Goldin, DVM, Graduate Student
Brandi Williamson, MPH, Microbiologist
Lizzette Perez-Perez, MS, Postbac IRTA
Manmeet Singh, Ph.D., Postdoctoral IRTA
Meaghan Flagg, Ph.D., Postdoctoral IRTA
Beniah Brumbaugh, Postbac IRTA
Reinaldo Mercado-Hernandez, Postbac IRTA
Singh M, de Wit E. Antiviral agents for the treatment of COVID-19: Progress and challenges. Cell Rep Med. 2022 Mar 15;3(3):100549.
Speranza E, Purushotham JN, Port JR, Schwarz B, Flagg M, Williamson BN, Feldmann F, Singh M, Pérez-Pérez L, Sturdevant GL, Roberts LM, Carmody A, Schulz JE, van Doremalen N, Okumura A, Lovaglio J, Hanley PW, Shaia C, Germain RN, Best SM, Munster VJ, Bosio CM, de Wit E. Age-related differences in immune dynamics during SARS-CoV-2 infection in rhesus macaques. Life Sci Alliance. 2022 Jan 17;5(4):e202101314.
Munster VJ, Flagg M, Singh M, Williamson BN, Feldmann F, Pérez-Pérez L, Brumbaugh B, Holbrook MG, Adney DR, Okumura A, Hanley PW, Smith BJ, Lovaglio J, Anzick SL, Martens C, van Doremalen N, Saturday G, de Wit E. Subtle differences in the pathogenicity of SARS-CoV-2 variants of concern B.1.1.7 and B.1.351 in rhesus macaques. bioRxiv [Preprint]. 2021 May 7:2021.05.07.443115.
Speranza E, Williamson BN, Feldmann F, Sturdevant GL, Pérez-Pérez L, Meade-White K, Smith BJ, Lovaglio J, Martens C, Munster VJ, Okumura A, Shaia C, Feldmann H, Best.
SM, de Wit E. Single-cell RNA sequencing reveals SARS-CoV-2 infection dynamics in lungs of African green monkeys. Sci Transl Med. 2021 Jan 27;13(578):eabe8146.
Williamson BN, Feldmann F, Schwarz B, Meade-White K, Porter DP, Schulz J, van Doremalen N, Leighton I, Yinda CK, Pérez-Pérez L, Okumura A, Lovaglio J, Hanley PW, Saturday G, Bosio CM, Anzick S, Barbian K, Cihlar T, Martens C, Scott DP, Munster VJ, de Wit E. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature. 2020 Sep;585(7824):273-276.
Munster VJ, Koopmans M, van Doremalen N, van Riel D, de Wit E. A Novel Coronavirus Emerging in China - Key Questions for Impact Assessment. N Engl J Med. 2020 Feb 20;382(8):692-694.