Recent studies utilizing PCR-based diagnostics have demonstrated that rhinovirus (HRV) is an important cause of lower respiratory illness including bronchiolitis, influenza-like illness, and exacerbations of chronic lung diseases such as asthma, cystic fibrosis, and chronic obstructive lung disease (COPD). In addition, HRV wheezing illnesses in the first three years of life are among the strongest risk factors for subsequent asthma. The lack of specific treatments and preventive strategies for more severe HRV illnesses and exacerbations of asthma is a major unmet medical need. To address this therapeutic gap, we propose a novel program of three interrelated projects to identify risk factors and pathogenic mechanisms related to the virus, host immune response, and environment that determine the severity of HRV illnesses. The clinical centerpiece of the program is the proposed Wisconsin Infant Immune &Illness Surveillance Cohort (""""""""WISC"""""""", Project 1), which will define how a naturally-occurring intervention, farm exposure in early childhood, enhances immune maturation and antiviral responses, and reduces morbidity from viral respiratory illnesses. Defining distinct farm-related patterns of immune maturation that mediate protection from viral illnesses will provide a road map for new preventive approaches intended to minimize respiratory morbidity for children growing up in other environments. In Project 2, Dr. Ann Palmenberg and colleagues propose to use novel tissue culture systems and molecular approaches to define the pathogenesis of the newly described HRV-C species, focusing on identification of the cellular receptor and clinical consequences of unique 2Apro structure and biochemistry. Finally, in Project 3, Dr. John Yin will use novel techniques (fluorescent-tagged HRVs and indicator cell lines, real-time fluorescent microscopy) to reveal how HRV replication in single cells stimulates immune responses and define mechanisms of spread to neighboring cells. Collectively, these three projects will extensively share clinical samples, expertise and conceptual advances to identify new targets for the treatment and prevention of HRV infections.

Public Health Relevance

Rhinoviruses, originally known as common cold viruses, also cause lower respiratory illnesses such as childhood wheezing, influenza-like illness, and exacerbations of asthma and COPD. Unfortunately, no treatments or vaccines are available for HRV infections. We propose to identify new environmental and molecular determinants of HRV illness severity that will serve as a basis for new treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI104317-02
Application #
8605840
Study Section
Special Emphasis Panel (ZAI1-PA-I (J1))
Program Officer
Minnicozzi, Michael
Project Start
2013-02-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$1,425,264
Indirect Cost
$354,123
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Voigt, Emily A; Swick, Adam; Yin, John (2016) Rapid induction and persistence of paracrine-induced cellular antiviral states arrest viral infection spread in A549 cells. Virology 496:59-66
Palmenberg, Ann C (2016) The Language of Life. Annu Rev Virol 3:1-28
Akpinar, Fulya; Timm, Andrea; Yin, John (2016) High-Throughput Single-Cell Kinetics of Virus Infections in the Presence of Defective Interfering Particles. J Virol 90:1599-612
Liu, Yue; Hill, Marchel G; Klose, Thomas et al. (2016) Atomic structure of a rhinovirus C, a virus species linked to severe childhood asthma. Proc Natl Acad Sci U S A 113:8997-9002
Turunen, Riitta; Jartti, Tuomas; Bochkov, Yury A et al. (2016) Rhinovirus species and clinical characteristics in the first wheezing episode in children. J Med Virol 88:2059-2068
Lindsay, Stephen M; Yin, John (2016) Temperature gradients drive radial fluid flow in Petri dishes and multiwell plates. AIChE J 62:2227-2233
Bochkov, Yury A; Watters, Kelly; Basnet, Sarmila et al. (2016) Mutations in VP1 and 3A proteins improve binding and replication of rhinovirus C15 in HeLa-E8 cells. Virology 499:350-360
Fawkner-Corbett, David W; Khoo, Siew Kim; Duarte, Carminha M et al. (2016) Rhinovirus-C detection in children presenting with acute respiratory infection to hospital in Brazil. J Med Virol 88:58-63
Bochkov, Yury A; Gern, James E (2016) Rhinoviruses and Their Receptors: Implications for Allergic Disease. Curr Allergy Asthma Rep 16:30
Warrick, Jay W; Timm, Andrea; Swick, Adam et al. (2016) Tools for Single-Cell Kinetic Analysis of Virus-Host Interactions. PLoS One 11:e0145081

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