Severe Acute Respiratory Syndrome (SARS) is a coronavirus-induced human respiratory disease with a 10% mortality. Mortality is especially high in aged populations. Using a mouse-adapted version of SARSCoV (MAI 5 virus) that causes severe disease in BALB/c mice, we previously showed that the initial immune response is activated suboptimally in infected mice and this resulted, in turn, in a delayed anti-virus T cell response. We also found that depletion of lung inhibitory macrophages, important for maintaining homeostasis in the uninfected lung, or adoptive transfer of activated dendritic cells resulted in activation of the pulmonary immune response, an enhanced anti-virus T cell response and complete protection from severe clinical disease. The central objectives of this proposal are to determine whether enhancement of the anti-virus T cell response, in the absence of other interventions, is sufficient to protect young BALB/c mice from severe disease and to investigate whether quantitiative and qualitative defects also contribute to disease in aged mice, which like older humans, are more susceptible to infection than young animals. These objectives will be approached in the following specific aims:
Specific aim 1. To determine if enhancing the T cell response is sufficient for optimal virus clearance and protection from disease in young BALB/c mice. Dendritic cell (DC) vaccination and transfer of virus-specific T cells into infected BALB/c and immunodeficient mice (SCID-severe combined immunodeficiency) will be used in this aim.
Specific aim 2. To determine if an inefficient T cell response is also the basis for severe disease in aged mice. The goal of this specific aim will be compare the quality and quantity of the T cell response in young and aged B6 mice and determine whether enhancement of the response in aged mice affords protection.
Specific aim 3. To determine the basis of the poor activation of the innate, and ultimately, the T cell response in aged B6 mice. The role of TLR signaling will be investigated in this aim. Previous work in the SARS field has emphasized the importance of the innate immune response in protection. Our results suggest that while the innate response is poorly activated in young and aged mice prone to severe disease, the anti-virus T cell response may be most critical for improved outcomes. At the completion of the proposal, we will better understand the relative importance of the two arms of the immune response in SARS.

Public Health Relevance

Severe Acute Respiratory Syndrome (SARS), caused by a coronavirus, is a useful model for understanding severe respiratory disease caused by pathogens in general, especially in aged populations. This project is based on new information showing a critical role for the anti-virus T cell response in protection from severe disease. Understanding the role of this response is critical for understanding SARS-CoV pathogenesis and in the development of safe and effective SARS-coronavirus vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI060699-09
Application #
8686709
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
DUNS #
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
Chi, Hang; Zheng, Xuexing; Wang, Xiwen et al. (2017) DNA vaccine encoding Middle East respiratory syndrome coronavirus S1 protein induces protective immune responses in mice. Vaccine 35:2069-2075

Showing the most recent 10 out of 111 publications