Our goal is to identify molecular interactions between mammal hosts and African trypanosomes that affect the development of protective immune responses as well as pathophysiologic processes. African trypanosomes are flagellated protozoa that cause sleeping sickness in people and Nagana in domestic animals. These diseases are fatal if left untreated. The diseases are endemic in the humid and semi-humid zones of Africa affecting a landmass of 10 million km 2 and 36 countries. Trypanosomiasis precludes cattle-based agriculture from much of this area and threatens up to 60 million people, of whom about a half million are presently infected. We are taking three approaches: (i) elucidating the protective responses that develop in Cape buffalo. These trypanosomiasis-resistant bovids co-evolved with African trypanosomes and efficiently suppress trypanosome parasitemia to a cryptic level upon infection. (ii) Elucidating the CD1d-restricted protective immune response that arises in mice that are vaccinated against the GPI anchor of the trypanosome variant surface glycoprotein, or infected with phospholipase C knock-out trypanosomes. (iii) Elucidating the contribution of TNF ” , ADAM 17 (TACE) and TIMP3 to regulation of trypanosome-induced pathology