Project 3

Project Summary/AbstractMiddle East Respiratory Syndrome (MERS) was recognized as a significant illness onthe Saudi Arabian peninsula in mid-2012, and the causative agent was rapidly identifiedas a novel coronavirus (CoV), termed MERS-CoV. MERS has a high mortality (~35%),associated with severe lung disease. Similar to the SARS virus that caused an epidemicin 2003-4, there is ongoing global concern due to MERS high fatality rate. To date,cases of MERS have been reported in 26 countries. Dipeptidyl peptidase 4 (DPP4,CD26) is the receptor for MERS-CoV. Epidemiologic studies have established thatMERS is zoonotic in origin, with evidence for a closely related virus in dromedary camelson the Arabian peninsula and throughout Africa. Spread from camels to people isdocumented, as well as person-to-person spread among health care workers in hospitalsettings. A lack of autopsy studies from MERS fatalities has hindered understanding ofMERS-CoV pathogenesis. Thus, MERS is the most recent confirmation thatcoronaviruses can jump from their animal hosts, infect humans, and cause severedisease of global significance. There is a pressing need to better understand MERSdisease pathogenesis and to develop vaccines and therapies. There are 3 specific aims.Aim 1. To understand how an in vivo evolved MERS-CoV causes lethal lungdisease. We developed mice that have the human receptor for MERS-CoV. Using theseanimals we developed a mouse-adapted virus that causes significant lung disease.These studies will advance our knowledge of the causes of MERS-related lung disease.Aim 2. To investigate how adaptive mutations in MERS-CoV contribute toincreased virulence. We sequenced the mouse-adapted virus strains and assembledtheir genomes. We will use this genetic information to investigate relationships betweenthe virus gene products and the host responses that lead to severe lung disease.Aim 3. To investigate how DPP4 abundance and function influence MERS diseasepathogenesis. DPP4 has enzymatic activity that cleaves two amino acids off of targetprotein substrates, thereby changing protein functions. DPP4 abundance and enzymaticactivity may contribute to disease. These experiments will advance our knowledge ofhow DPP4 activities may underlie to disease outcomes.