The emergence of the Severe Acute Respiratory Syndrome (SARS) in 2002-3 and the Middle East Respiratory Syndrome (MERS) in 2012 demonstrates that zoonotic coronaviruses (CoV) have and will likely continue to spread from zoonotic sources to infect human populations. MERS-CoV continues to circulate in camels and to spread to susceptible humans, highlighting the need to better understand the pathogenesis of diseases mediated by pathogenic human respiratory CoV. In this PPG, investigators with experience in coronavirus pathogenesis, molecular biology, immunology and vaccinology will work together to understand how virus factors and dysregulated innate and adaptive immune responses contribute to MERS and SARS disease in young and aged animals and in animals with co-morbidities. All of the projects will utilize newly developed mice expressing human MERS receptor (DPP4) in lieu of the mouse receptor (hDPP4-KI) and a mouse-virulent MERS-CoV, selected in these mice (MERSMA). Project 1 will use MERSMA to investigate the role of aging in infected mice. Project 1 is also based on published data showing that specific eiconsanoids with anti-inflammatory properites and their upstream phopholipases increase during aging, contributing to a delayed immune response after SARS-CoV (and by extension, perhaps MERSMA) infection. Project 2 is based on preliminary data showing that MERS-CoV has a greater dependence on host cell proteases for virus entry than does SARS-CoV. This project will investigate unique mutations found in the surface (S) glycoprotein of MERSMA that appear to affect protease function. Project 3 will investigate how MERSMA causes more severe disease than the initial human EMC/2012 strain, with focus on the ORF4b accessory protein. This project will also investigate how hDPP4 contributes to disease severity. Project 4 is based on published data showing that the CoV E protein has ion channel activity, is a virulence factor and contains a PDZ binding domain (PBM), which is critical for virus viability. This project will focus on how the E protein causes edema in lungs and on the role of the PBM in pathogenesis. A novel PBM in the C terminal of E arose in MERSMA during mouse passage and its role will be studied. This project will also continue to develop safe, live attenuated MERS and SARS vaccines. All of the projects will use the Animal/Virology Core, which will provide nonrecombinant and recombinant MERS-CoV and SARS-CoVs and will monitor and analyze infected mice. Using the Core for these purposes will maximize experimental quality control and effective use of our resources. These projects are all interrelated and collaborative, will take advantage of the unique skills and expertise of the project directors and provide new information about MERS and SARS pathogenesis that is essential to vaccine development.

Public Health Relevance

OVERVIEW-NARRATIVE The overarching goal of this Program Project Grant is to increase understanding of severe pulmonary infections caused by MERS-CoV, SARS-CoV, and by extension, other respiratory viral pathogens in young and aged animals. Results will facilitate the development of novel vaccines and anti-viral therapies, which is critical since MERS-CoV continues to infect camels and other zoonotic CoV circulate in the wild.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI060699-12
Application #
9545638
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Stemmy, Erik J
Project Start
2004-07-01
Project End
2022-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Iowa
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Canton, Javier; Fehr, Anthony R; Fernandez-Delgado, Raúl et al. (2018) MERS-CoV 4b protein interferes with the NF-?B-dependent innate immune response during infection. PLoS Pathog 14:e1006838
Fehr, Anthony R; Jankevicius, Gytis; Ahel, Ivan et al. (2018) Viral Macrodomains: Unique Mediators of Viral Replication and Pathogenesis. Trends Microbiol 26:598-610
Alshukairi, Abeer N; Zheng, Jian; Zhao, Jingxian et al. (2018) High Prevalence of MERS-CoV Infection in Camel Workers in Saudi Arabia. MBio 9:
Sodhi, Chhinder P; Wohlford-Lenane, Christine; Yamaguchi, Yukihiro et al. (2018) Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. Am J Physiol Lung Cell Mol Physiol 314:L17-L31
Castaño-Rodriguez, Carlos; Honrubia, Jose M; Gutiérrez-Álvarez, Javier et al. (2018) Role of Severe Acute Respiratory Syndrome Coronavirus Viroporins E, 3a, and 8a in Replication and Pathogenesis. MBio 9:
Zheng, Jian; Perlman, Stanley (2018) Immune responses in influenza A virus and human coronavirus infections: an ongoing battle between the virus and host. Curr Opin Virol 28:43-52
Chu, Daniel K W; Hui, Kenrie P Y; Perera, Ranawaka A P M et al. (2018) MERS coronaviruses from camels in Africa exhibit region-dependent genetic diversity. Proc Natl Acad Sci U S A 115:3144-3149
Galasiti Kankanamalage, Anushka C; Kim, Yunjeong; Damalanka, Vishnu C et al. (2018) Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element. Eur J Med Chem 150:334-346
Grunewald, Matthew E; Fehr, Anthony R; Athmer, Jeremiah et al. (2018) The coronavirus nucleocapsid protein is ADP-ribosylated. Virology 517:62-68
Tai, Wanbo; Wang, Yufei; Fett, Craig A et al. (2017) Recombinant Receptor-Binding Domains of Multiple Middle East Respiratory Syndrome Coronaviruses (MERS-CoVs) Induce Cross-Neutralizing Antibodies against Divergent Human and Camel MERS-CoVs and Antibody Escape Mutants. J Virol 91:

Showing the most recent 10 out of 111 publications