Project summary: Here we seek to identify the role of diabetes in Middle East Respiratory Syndrome Coronavirus (MERS-CoV) pathogenesis. MERS-CoV emerged in 2012 in Saudi Arabia leading to over 2200 infections with a ~35% case fatality rate. The majority of lethal MERS-CoV infections are associated with a comorbidity, with diabetes as the top comorbidity. We have found that MERS-CoV pathogenesis is exacerbated in a mouse with pre-existing diabetes. We will determine the mechanism for this enhanced disease by determining the role of the changes in lung architecture, and immune response. In Aim1 we will determine whether accessibility of the Type 2 alveolar cells, the target cells for MERS-CoV in the alveoli, is increased in diabetic mice compared to normal mice. Our data suggests that at the earliest points of infection, the alveoli are highly susceptible to MERS- CoV but normal mouse Type 2 alveolar cells are not. We will evaluate the mucus and architecture of the lungs to determine if there is a difference that could explain the differential infection. In Aim 2, we will determine if the immune response in diabetic mice is different than normal mice. A difference in the immune response, especially innate immune response, could explain the susceptibility differences in diabetic and normal mice. In Aim 3 we will determine whether therapeutics that are effective in normal mice are deficient in diabetic mice with the goal of altering those therapeutics in the future for more effective therapies for comorbid patients. Together this proposal will determine why diabetic mice and potentially humans are highly susceptible to MERS-CoV.