Examining Mechanisms of Synergy between Asthma Exacerbations and RV Infection - PROJECT SUMMARY/ABSTRACT
Dr. Kennedy is an Allergist/Immunologist at the University of Arkansas for Medical Sciences Departments
of Pediatrics and Internal Medicine and a young investigator at Arkansas Children's Hospital Research
Institute. A three-pronged mission to perform cutting-edge research, provide outstanding clinical care, and
pursue educational excellence summarizes his overarching academic career objectives. His training and
experience have enabled him to develop the skills and insight necessary to provide high-quality care to
patients with asthma and allergic disorders, as well as providing a foundation for human subjects research.
The primary objective for this mentored career development award proposal is to further Dr. Kennedy's
knowledge and abilities in basic and translational investigation. This objective will specifically enable him to
achieve my long-term research goals, including: 1) understanding the immune responses accounting for
synergy between asthma exacerbations and infection with RV, 2) developing biomarkers of asthma
disease severity and exacerbation following RV infection, and 3) translating this research into clinically
relevant prevention and intervention strategies for patients with asthma.
Asthma is prevalent in ~12% of the US population, and RV is recognized as the most important virus
producing the common cold syndrome worldwide. Unlike patients without asthma who generally develop upper
respiratory symptoms during colds, asthmatics with an RV infection may exhibit lower respiratory symptoms
(e.g., cough, wheeze, shortness of breath). In fact, RV is associated with 60% to 80% of asthma exacerbations
in children requiring treatment in the emergency department9-11. Despite such strong relationships, a significant
knowledge gap exists with regards to the mechanisms whereby RV exacerbates asthma symptoms. Recent
developments in cytokine biology have increasingly emphasized the importance of respiratory epithelial-
derived cytokines in creating the milieu that promotes the evolution of allergic immune responses. The overall
goal of this proposal is to understand the association between RV infection and the epithelial immune
responses that bridge the allergic response to infection in asthmatics. We hypothesize that RV infection
modulates epithelial cytokine expression [Interleukin (IL)-25 and thymic stromal lymphopoietin (TSLP)]
in asthmatics with bias towards an allergic inflammatory response, and this underlies infection-
mediated increases airway hyper-responsiveness (AHR). To address this hypothesis, we have a unique
approach that brings together an in vivo study of epithelial-derived cytokines from subjects with asthma
exacerbations, primary epithelial cell cultures, and a novel precision cut lung slice (PCLS) explant system
allowing comparison of RV infections in asthmatic and non-asthmatic tissues. Using a cross-sectional design in
a pediatric emergency department, we will compare cytokine signatures within nasal washes of asthmatics with
RV-induced exacerbations and controls with cold symptoms and compare these levels with asthma symptoms.
In ex vivo approaches, we will study mechanisms driving the production of IL-25 and TSLP by Toll-like receptor
(TLR)-3 and Retinoic Acid Inducible Gene-I (RIG-I)-like receptors (RLR), both important in recognition of RV
within epithelial cells. Finally, we will use the human airways PCLS to evaluate the effects of IL-25 and TSLP
on AHR to carbachol and compare these responses between tissue derived from donors with and without
asthma. By evaluating mechanisms of synergy that bridge the role of epithelial-derived cytokines to RV
infection and asthma exacerbations, we will elucidate cytokine signatures and delineate pathways involved that
will provide insight into the inflammatory environment produced by RV leading to exacerbations of asthma.
Further, the studies within this proposal provide a firm foundation for research independence, allowing
progression through further investigation of cellular targets (e.g., innate lymphoid type 2 cells (ILC2), mast
cells) for these cytokines in RV-induced asthma exacerbations.
To accomplish his research and academic goals, Dr. Kennedy has assembled a multi-tiered mentoring
group with a wide breadth of experience. Interactions with his primary scientific co-mentors (Drs. Richard
Kurten, Usha Ponnappan, and Reynold Panettieri) and his Scientific Advisory Committee (SAC) will enhance
his understanding of the basic mechanisms of RV immunopathogenesis, develop research design skills, and
expand his knowledge of advanced statistical techniques. Interactions with Dr. Stacie Jones, Chief of Pediatric
Allergy and Immunology and primary career development mentor, will serve to improve his translational
research acumen and enhance career development opportunities. Further, a Departmental Clinician Scientist
Mentoring Committee composed of successful researchers at his institution has been in place since the
beginning of his faculty appointment. This multi-tiered mentoring system will provide scientific and career
development guidance that will enable Dr. Kennedy to become an independent researcher and an experienced
clinician scientist specializing in RV-induced exacerbations of asthma.
