This project will compare and contrast the molecular biology of human rhinovirus C (HRV-C) to viruses in the better known HRV-A and HRV-B species. HRV are canonically linked to the common cold, but more recent studies have clearly established that these viruses, and especially HRV-C, are closely linked to lower respiratory infections and wheezing illnesses. It's the job of the first viral proteins produced in the first 2-3 hrs of infection, in the first infected cells, to shutoff essential sentinel host response systems. Evolution has superbly refined HRV proteases (2Apro and 3Cpro) with species and strain-specific preferences for key cellular substrates. We hypothesize that the magnitude of the immunological alarms set off by any individual HRV have at their origin, the efficacy with which 2Apro does its jobs in the first round(s) of infection. The proposed experiments will document for the first time, the 2Apro genotype diversity within and among the 3 HRV species, and the consequences of that diversity at the biochemical and cellular levels. It will exploit our unique, new-found ability to grow HRV-Cs to identify the cellular receptor for these viruses and expose their comparative molecular secrets. Given that many natural isolates of the HRV-C are mapped recombinants (with the HRV-A) in the 2Apro region, it is paramount to understand what, how and why this protein contributes to individual virus-host interfaces. Specifically, this project proposes three aims: 1) to identify the HRV-C cellular receptor and the natural cell type(s) infected by this virus;2) to determine the biochemical consequences of virus-specific 2Apro sequence variation by studying the activities of comparable recombinant 2Apro towards cell proteins crucial for virus-induced shutoff of host nucleocytoplasmic trafficking;and 3) using full-length recombinant, chimeric viruses derived from HRV-A, HRV-B, and HRV-C cDNAs, test whether species- and strain-specific 2Apro genes and/or 5'untranslated regions (UTR) influence viral replication and immune responses. These experiments will utilize epithelial cells and clinical HRV isolates collected in Project I, and there will be extensive intellectual and experimental interactions with Project 3 to determine the role of 2Apro on HRV growth in single cells and cell-to-cell transmission.

Public Health Relevance

In addition to causing common colds, HRV frequently cause lower respiratory illnesses in children, the elderly, and in patients with chronic lung diseases (e.g. asthma, COPD). Recently, an entire new HRV species (HRV-C) was discovered that is closely linked to wheezing illnesses and LRI. These experiments will provide new insights into HRV-C biology, and set the stage for the development of specific treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI104317-01
Application #
8469998
Study Section
Special Emphasis Panel (ZAI1-PA-I (J1))
Project Start
2013-02-01
Project End
2018-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$213,834
Indirect Cost
$56,100
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Scully, Erik J; Basnet, Sarmi; Wrangham, Richard W et al. (2018) Lethal Respiratory Disease Associated with Human Rhinovirus C in Wild Chimpanzees, Uganda, 2013. Emerg Infect Dis 24:267-274
Ludka-Gaulke, Tiffany; Ghera, Princy; Waring, Stephen C et al. (2018) Farm exposure in early childhood is associated with a lower risk of severe respiratory illnesses. J Allergy Clin Immunol 141:454-456.e4
Teo, Shu Mei; Tang, Howard H F; Mok, Danny et al. (2018) Airway Microbiota Dynamics Uncover a Critical Window for Interplay of Pathogenic Bacteria and Allergy in Childhood Respiratory Disease. Cell Host Microbe 24:341-352.e5
Bashir, Hiba; Grindle, Kristine; Vrtis, Rose et al. (2018) Association of rhinovirus species with common cold and asthma symptoms and bacterial pathogens. J Allergy Clin Immunol 141:822-824.e9
Kim, Chang Keun; Callaway, Zak; Gern, James E (2018) Viral Infections and Associated Factors That Promote Acute Exacerbations of Asthma. Allergy Asthma Immunol Res 10:12-17
Gern, James E; Lee, Wai Ming; Swenson, Cheri A et al. (2018) Development of a Rhinovirus Inoculum using a Reverse Genetics Approach. J Infect Dis :
Leino, Annamari; Lukkarinen, Minna; Turunen, Riitta et al. (2018) Pulmonary function and bronchial reactivity 4 years after the first virus-induced wheezing. Allergy :
Cox, Desmond W; Khoo, Siew-Kim; Zhang, Guicheng et al. (2018) Rhinovirus is the most common virus and rhinovirus-C is the most common species in paediatric intensive care respiratory admissions. Eur Respir J 52:
Shen, Zhong-Jian; Hu, Jie; Kashi, Venkatesh et al. (2018) TLR-7 Stress Signaling in Differentiating and Mature Eosinophils Is Mediated by the Prolyl Isomerase Pin1. J Immunol 201:3503-3513
Yang, Zhonghui; Bochkov, Yury A; Voelker, Dennis R et al. (2018) Identification of a Novel Inhibitor of HRV Replication and Inflammation in Airway Epithelial Cells. Am J Respir Cell Mol Biol :

Showing the most recent 10 out of 61 publications