As the causative agents in a majority of recurrent respiratory virus infections and the most common trigger of lung disease exacerbations, rhinoviruses are a major threat to public health and a significant economic burden. There are no vaccines or direct-activating antiviral therapies available to prevent rhinovirus infection or mitigate disease. Relative to other strains, rhinoviruses species C (RV-C) are associated with more severe disease, especially in individuals with asthma. In addition, a single nucleotide polymorphism (SNP) in the gene encoding CDHR3, a receptor for RV-C, was recently identified as a risk factor for severe asthma exacerbations. However, as a recently identified pathogen, many aspects of RV-C biology, such as details of the host response and the effects of CDHR3 genetic variation on infection dynamics remain undefined. Thus, the overall goals of this application are to (i) define the host response to RV-C infection in both normal and asthmatic human airway epithelium (HAE) and (ii) determine the impact of the CDHR3 rs6967330 SNP on virus?host dynamics in physiological context. Our central hypotheses are that the innate immune response to RV-C will be altered in asthmatic HAE compared to normal HAE, and that the CDHR3 rs6967330[A] risk allele modifies this response by altering viral infectivity of ciliated cells. We will test these hypotheses by pursuing two Specific Aims:
Aim 1 will define the host response to RV-C in normal and asthmatic HAE at single cell resolution;
Aim 2 will determine the contribution of the CDHR3 asthma risk allele to RV-C infection and host response. Our research plan builds upon an ongoing collaboration between the Scull and Rosenberg laboratories and is both conceptually and technically innovative in its integration of HAE culture models and single cell RNA-Seq to explore the physiologically-relevant host response to RV-C at unprecedented resolution. Furthermore, we propose novel gene editing experiments that will directly determine how CDHR3 genetic variation affects RV-C infection in primary HAE on an isogenic background. This work is significant as our results will have broad implications for understanding the roles of specific airway epithelial cell types in the antiviral response and specifically address how underlying disease status and host genotype impact susceptibility to RV-C.

Public Health Relevance

Human rhinoviruses are a frequent cause of the ?common cold? and the recently identified rhinovirus species C (RV-C) is associated with more severe illness and exacerbations of lung disease in people with asthma. Our proposed research will reveal how the innate response to RV-C differs between normal and asthmatic airway epithelial cells at unprecedented, single cell resolution and define effects of asthma-associated genetic variation in the RV-C receptor gene on infection susceptibility and corresponding host response. This work will not only yield novel insight into the roles of specific airway epithelial cell types in!antiviral defense but may also identify potential therapeutic targets for managing RV-C infection, particularly in the context of asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI149180-01A1
Application #
9979166
Study Section
Virology - B Study Section (VIRB)
Program Officer
Stemmy, Erik J
Project Start
2020-01-24
Project End
2021-12-31
Budget Start
2020-01-24
Budget End
2020-12-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Maryland College Park
Department
Anatomy/Cell Biology
Type
Earth Sciences/Resources
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742