Intracellular organisms manipulate their host cells to suit their intracellular life styles. These pathogens alter cellular processes by introducing bacterial factors into the host cell. Anaplasma phagocytophilum, which? causes Human Granulocytic Ehrlichiosis, is a unique intracellular organism because it is the only human? pathogen that specifically survives and multiplies in neutrophils. Neutrophils play an essential role in the? immune system and kill bacteria very efficiently. A. phagocytophilum is the exception as it escapes killing? by neutrophils. It is poorly understood how A. phagocytophilum manipulates the cellular processes in the? neutrophil for its survival. ? ? The global hypothesis is that A. phagocytophilum manipulates cellular processes by translocating bacterial factors into the neutrophil ensuring its survival. We have identified a candidate bacterial factor, AnkA, which may mediate these effects. Consequently, A. phagocytophilum infection of neutrophils provides an ideal? model to study the pathways involved in neutrophil biology and bacterial killing.? ? Aim 1 examines the tyrosine phosphorylation of AnkA, which allows it to interact with specific host cells? proteins through SH2 domains.? Aim 2 seeks to identify these host cell proteins and the signaling pathways manipulated by AnkA.? Aim 3 examines the effect of AnkA on the respiratory burst, the major killing pathway of the neutrophil.? ? The long-term goals are: 1) the identification of the mechanism leading to survival of A. phagocytophilum in? neutrophils, 2) the development new avenues to manipulate neutrophils, leading to potential new? treatments of inflammation or infections, and 3) enhancement of our understanding of neutrophil biology as? it relates to the immune system.? ? In the Unites States, Human Granulocytic Ehrlichiosis is an emerging tick-associated disease and in? endemic areas the incidence is second only to Lyme disease.
