The spirochete Borrelia burgdorferi is transmitted to humans and other warm blooded animals through the bites of infected Ixodes species ticks. Our studies indicate that these spirochetes utilize a quorum sensing mechanism to control protein expression patterns that involves the chemical signal autoinducer-2 (AI-2). Through this mechanism, a population of Lyme disease spirochetes may synchronize production of proteins needed for infection processes. AI-2 is produced by the B. burgdorferi LuxS protein, which we have demonstrated to be a functional enzyme. It has also been previously reported that luxS message is upregulated in feeding nymphal ixodid ticks. Among the B. burgdorferi proteins regulated through AI-2 are the complement inhibitory factor H binding Erp lipoproteins. We now report Erp protein expression is also increased during transmission of B. burgdorferi from nymphal ticks to mammalian hosts. Essentially no B. burgdorferi within unfed nymphal ticks expressed Erps, while almost all transmitted bacteria were Erp positive. These studies suggest that B. burgdorferi within feeding nymphal ticks produce AI-2 to coordinate expression of mammalian infection associated proteins, such as the factor H binding Erp lipoproteins. Binding of mammalian host factor H by Erps may then help promote bacterial dissemination through host tissues.