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.
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.
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