ARRA: CRASP-2 proteins of Lyme disease Borrelia

The causative agent of Lyme disease, Borrelia burgdorferi, can persistently infect humans and other mammalian hosts for great lengths of time. Understanding the mechanisms by which Lyme disease spirochetes establish and maintain chronic infections will be crucial for developing improved treatments for long-term human infections. Lyme disease spirochetes are generally resistant to their hosts' alternati'Je pathway of complement activation. Studies with cultured bacteria found that either of two borrelial outer surface proteins facilitate resistance to host complement. These proteins, CRASP-1 and CRASP-2 (complement regulator-acquiring surface proteins 1 and 2), both bind the human complement regulatory proteins factor H and FElL-i (factor H-like protein 1), plus other, unidentified serum components. However, we found production of GRASP-I is repressed within the first few days of mammalian infection, while CRASP-2 production is greatly induced during mammalian infection. Thus, CRASP-2 is the only borrelial protein demonstrated to facilitate resistance to host complement that is produced during established mammalian infection. Our studies lead us to hypothesize that production of GRASP-2 during mammalian infection permits the bacterium to avoid killing by its host's alternative pathway of complement activation, and thereby enables the spirochete to persistently, infect humans. Experiments are outlined in this proposal to test our hypothesis by (1) evaluating the essential nature of CRASP-2 production during mammalian infection and the necessity for precise control of GRASP-2 synthesis, and (2) characterizing mechanisms by which GRASP-2 expression is regulated.