Abortion in sheep due to Salmonella enterica subspecies enterica serovar Abortusovis is an important animal health problem in areas of the Mediterranean, where the sheep industry has a significant economy impact. The pathogen is host restricted to ovines where it invades the intestinal epithelium and causes a systemic infection that often goes undetected, until it manifest as an abortion. In animals that are not pregnant, there are no overt signs of disease, suggesting that the organism can evade detection by the innate immune system during invasion, but the underlying mechanisms are currently unknown. The long-term goal of this study is to elucidate mechanisms involved in the pathogenesis of S. Abortusovis infection. Our central hypothesis is that S. Abortusovis prevents recognition through Toll-like receptors, which renders the host unable to control infection before pathogens reach the uterus and cause abortions. We will contrast S. Abortusovis to a closely related pathogen, S. enterica serovar Typhimurium , whose invasion of the intestinal epithelium is detected by the innate immune system, resulting in overt signs of disease associated with intestinal inflammation. Aim 1, we will determine whether S. Abortusovis evades recognition by TLR5 during invasion of the intestinal epithelium. Aim 2, we will determine whether S. Abortusovis evades recognition by TLR4 during its persistence in tissue macrophages. The proposed studies will take an innovative approach that links clinical observations to molecular virulence mechanisms. By establishing these connections, our studies are to demonstrate that innate immune evasion is a S. Abortusovis-specific virulence mechanism that can explain S. Abortusovis infection in sheep differs drastically from gastroenteritis caused by S. Typhimurium. This outcome is significant because it will establish a new paradigm in Salmonella pathogenesis, which is expected to have a measurable impact on the field of bacterial pathogenesis.