Tick-borne infections in the United States are now the most common form of vector-borne infection, despite their regular occurrence each year, predictable geographic locations, and ready availability of antibiotic treatments. Yet their incidence has increased markedly over the last two decades. Two of these infections, Lyme disease, caused by Borrelia burgdorferi, and human granulocytic anaplasmosis, caused by Anaplasma phagocytophilum, are both transmitted by black-legged or "deer" ticks and account for over 75% of all tick-borne infections in the US since 2011. Research to identify better ways to prevent or treat these infections has been slow to emerge despite significant advances using in vitro and animal studies. Here, we propose to use advance human model systems that closely replicate in vivo blood vessels, the conduits through which infection is initiated and by which infection spreads in the body. We will use advanced 3D microvessels engineered to replicate the conditions in the skin at the site of the tick bite to study how B. burgdorferi and A. phagocytophilum eventually gain access to the blood, what other components in tissue or from the tick affect the entry into the blood, and what components of B. burgdorferi or the blood vessels are important for that process to occur. Likewise, we will also study how B. burgdorferi gets to specific tissues and organs by escaping the blood stream, using a 3D model of brain blood vessels. The detailed analyses will help us to define the kinetics, influences of blood flow, and other mechanical forces at play that interact with cells and molecules, with the concept that their identification could help to find new targets for vaccination strategies or for new drugs to prevent these key steps for disease.