Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS) are coronavirus-mediated human respiratory diseases with high case-fatality rates. Disease is especially severe in aged populations. In the previous funding period, we showed that age-dependent increases in prostaglandin D2 (PGD2) and an upstream phospholipase A2, PLA2G2D contributed to poor immune responses and decreased survival. The lung is in a state of chronic inflammation, resulting from continued exposure to environmental antigens. We postulated that PLA2G2D, which has anti-inflammatory properties, is upregulated to counter this low grade inflammation, resulting in delayed responses to innocuous antigens but also to rapidly replicating viruses like MERS-CoV and SARS-CoV. Transient blockade of PGD2 signaling or genetic absence of PLA2G2D greatly increased survival. In marked contrast, ?knock-out? of DP1, the PGD2 receptor on myeloid cells, converted a sublethal SARS-CoV infection to a lethal one, indicating that PGD2/DP1 signaling has additonal roles in the infected lung. Our central hypothesis is that PGD2 and PLA2G2D along with other members of the small lipid mediator pathways have central roles in modulating the inflammatory state of the lung. In specific, they regulate multiple steps in the innate and subsequent T cell responses in mice infected with SARS-CoV, MERS-CoV and likely other viral respiratory pathogens. This hypothesis will be approached in the following specific aims: 1. To determine the mechanism of PLA2G2D upregulation and the role of PLA2G2D in vaccine responses in 12m old mice. CoV replication includes extensive cellular membrane rearrangements. The role between these rearrangements, the induction of oxidative stress and the upregulation of PLA2G2D will be investigated. 2. To determine the role of PGD2-DP1 signaling in the immune response to SARS-CoV in 12 m mice. The absence of PGD2-DP1 signaling results in diminished rDC activation and type I IFN (IFN-I) expression and increased inflammasome activation. Our goal is to determine whether changes in inflammasome activation are the major pathogenic effect of absent PGD2-DP1 signaling or if other factors are also involved. 3. To determine whether PGD2 and PLA2G2D contribute to poorer outcomes in mice infected with MERS-CoV, another infection in which severity is age-dependent. Using our newly developed hDPP4-KI mice and mouse-adapted MERS-CoV, we will determine whether MERS-CoV in mice also causes an age-dependent disease and whether changes in eicosanoid expression contribute to more severe disease.

Public Health Relevance

Severe Acute Respiratory Syndrome-coronavirus (SARS-CoV) and Middle East Respiratory Syndrome- coronavirus (MERS-CoV) cause severe respiratory disease, especially in aged populations. This project is based on new information showing key roles for prostaglandin D2 and a single phospholipase A2, required for PGD2 synthesis, in age-dependent disease severity. Enhanced understanding of the role of these molecules in CoV pathogenesis may identify novel therapeutic targets.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Stemmy, Erik J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Schools of Medicine
Iowa City
United States
Zip Code
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
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
Wang, Yanqun; Sun, Jing; Channappanavar, Rudragouda et al. (2017) Simultaneous Intranasal/Intravascular Antibody Labeling of CD4+ T Cells in Mouse Lungs. Bio Protoc 7:
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
Channappanavar, Rudragouda; Fett, Craig; Mack, Matthias et al. (2017) Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection. J Immunol 198:4046-4053

Showing the most recent 10 out of 14 publications