Susceptibility determinants to Legionella pneumophila infection in smokers Abstract Legionella accounts for majority of drinking water-associated pneumonia outbreaks with high percentage of death. Legionella infection presents with a higher risk and worse outcome in the elderly, immune-compromised and smokers. Several epidemiological studies have demonstrated a strong association between tobacco smoking and an elevated risk of Legionella infection. However, the underlying mechanism is still unclear. To determine the mechanism by which smoking predisposes to Legionella infection, we will perform the following aims: Aim 1. Determine the methylomic and RNAseq profile of human alveolar macrophages from current smokers (>10 pack years) and non-smokers. Aim 2. Determine the function of genes with altered methylation and expression and identify those responsible for the increased susceptibility of macrophages to Legionella infection.