COVID-19 Expansion for AIRe Program
Abstract
Objectives: A significant obstacle to developing prevention and treatment strategies for the novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the lack of knowledge on what cells the virus infects and how our bodies respond to infection. The severity of the disease differs based on patient age and other underlying medical conditions, such as diabetes and cardiac diseases; however, the underlying causes for these differences are unknown. COVID-19 is characterized by an initial, often asymptomatic, upper respiratory tract infection. Severe disease is defined by the development of lower respiratory tract symptoms (difficulty breathing) and pneumonia. These symptoms and signs are associated with the development of fever, muscle aches and pains, and a loss of the sense of smell. Laboratory findings also indicate that the virus can cause an exaggerated innate immune response known as a “cytokine storm” in some individuals. Why most people infected with SARS-CoV-2 have only a local response (or no detectable response) while others die of multi-organ failure is a mystery that can only be solved by better defining the cells and tissues involved in the infection and by characterizing the host response. Our program will address these gaps in knowledge by: 1) Defining the cell types that are infected by the virus in both the upper and lower respiratory tract 2) Determining what host genes affect the growth of virus by knocking them out in the relevant cell types 3) Designing a genetic approach to eliminate the virus by targeting viral and host genes Rationale: Determining the best prevention and treatment strategies for SARS-CoV-2 requires a better understanding of how the virus infects our cells and how the immune response responds and, in some instances, produces an unwanted excess immune response (i.e., a “cytokine storm”). By examining the interaction between human cells and the virus obtained patient samples, we will determine these mechanisms at the actual site of infection. Combined with our proposed novel genetic screening and validation studies, we will ultimately provide gene candidates that can be targeted to prevent and treat the disease. Relation to Outcomes of the Original Program: The work proposed in this project stems from our prior work under the DoD-funded “Anticipating Influenza Resistance and Evolution (AIRE)” program where we used single-cell RNA-Sequencing (scRNA-Seq) to examine samples from flu-infected patients and healthy controls. These studies demonstrate that scRNA-Seq can successfully determine the types of human airway cells that a virus infects, how a specific cell type responds to the virus, and how the sequence of the virus differs among the population. We are also able to determine the key differences in the expression of genes as a result of virus infection by comparing samples from infected patients to those of healthy control donors. These insights have allowed us to identify the critical pathways involved in infection and helped identify genes that can be targeted to prevent and treat infection. In addition, we used data from our AIRE project in a collaboration to investigate the cellular targets of SARS-CoV-2 in human and non-human primate tissues. Our published results demonstrate that interferon (a protein produced in response to infection) regulates ACE2, the known SARSCoV-2 receptor. Our results underscore the applicability of scRNA-Seq to provide an integrated view of both host and viral gene modulation during acute viral infection in human samples. FY20 PRMRP Topic Area(s) Addressed by the Proposed Research Project: By defining specific virus-infected human airway cells in patients with COVID-19, we can develop a strategy to minimize infection and replication. Using scRNA-Seq, we will identify host factors that can be targeted to prevent severe COVID-19, including manifestations such as acute resp
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110029
Entities
People
- Katherine A. Fitzgerald
Organizations
- United States Army
- University of Massachusetts Medical School