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)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI104317-02
Application #
8790527
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
DUNS #
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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