R01HL162642

Balancing Epithelial Cell Resistance and Resilience to Respiratory Viral Infections - Project Summary

The COVID-19 pandemic has highlighted how one respiratory RNA virus can induce a tremendous diversity of host outcomes. While we have made progress in understanding clinical, cellular, and molecular correlates of disease severity, few studies have assessed if or how specific factors present at baseline may induce severe disease.

There is a tremendous knowledge gap in whether correlates of disease severity represent causal factors (i.e. if presence at baseline leads to more severe infection), or may actually represent generally beneficial attempts at restoring tissue function (i.e. a resilience mechanism), that are detrimental only in select host contexts.

Despite distinct biology of SARS-CoV-2 and influenza, epidemiological studies have noted that overweight and obese individuals are at greater risk for severe infection, implicating lipid metabolism, and further genetic studies have found mutations in the type I/III interferon system in severe cases.

Importantly, treating the underlying causes of severe viral respiratory diseases will require a deeper understanding of the epithelial cell states that contribute to diverse outcomes to design host-directed therapies that complement vaccination campaigns and avoid long-lasting damage to the respiratory and cardiovascular systems.

Recently through single-cell RNA-sequencing (scRNA-seq) of nasopharyngeal swabs, we have discovered that a muted interferon antiviral response combined with an increase in intracellular cholesterol biosynthesis potential in respiratory epithelial cells characterizes severe vs. mild-moderate COVID-19. In this same study, we also revealed diversified subsets of secretory and goblet cells with uncharacterized functional potential, overlapping with subsets we had previously identified in a study of seasonal influenza.

Our published data, together with that of our colleagues, mandate further investigation into how pre-existing antiviral and cholesterol biosynthetic cell states in human respiratory epithelial cells dictate host outcomes to respiratory viral infection.

In light of these findings, we hypothesize that baseline cholesterol biosynthesis in respiratory epithelial cells is a critical host resilience mechanism which becomes pathogenic in the absence of effective antiviral resistance mechanisms. This overarching hypothesis can only be tested through a shift in the conceptual and experimental approaches we traditionally deploy (new research direction).

Successfully testing our hypothesis will address (AIM 1) whether cholesterol biosynthesis dictates the maximum potential interferon response in airway epithelial cells, or whether a muted interferon response underlies enhanced cholesterol biosynthesis in mice. Furthermore, it will identify novel contributions of airway epithelial cells to local and organismal lipid metabolism.

Our work will also test (AIM 2) the stability of metabolic and antiviral cellular phenotypes in human epithelial progenitor cells. Successful completion of our plan will lead to the development of non-invasive screening approaches to better ascertain risk of susceptible populations to respiratory viruses, and of prophylactic and therapeutic strategies to achieve optimal balance of host defense strategies in the respiratory tract.

Children's Hospital Corporation

THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NHLBI) PROVIDES GLOBAL LEADERSHIP FOR A RESEARCH, TRAINING, AND EDUCATION PROGRAM TO PROMOTE THE PREVENTION AND TREATMENT OF HEART, LUNG, AND BLOOD DISEASES AND ENHANCE THE HEALTH OF ALL INDIVIDUALS SO THAT THEY CAN LIVE LONGER AND MORE FULFILLING LIVES. THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION; USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS; FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS; AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION; FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Boston, Massachusetts 021155724 United States

Single Zip Code

Stephen I. Katz Early Stage Investigator Research Project Grant (R01 Clinical Trial Not Allowed) (PAR-21-038)

Amendment Since initial award the total obligations have increased 295% from $869,852 to $3,435,939.