Grant: Operating Grant

Our first line of defense against bacteria and other invading organisms are white cells called neutrophils. To find these bacteria, the neutrophils must follow cues or road signs provided by our own immune system called chemokines. However, when in close enough proximity to bacteria, the neutrophils begin to sense the bacteria directly and must ignore our own chemokines. Understanding how this transpires is the main theme of this grant. We have set up a simple system of 3 wells where we put neutrophils in a center well and we place a chemokine in a left well and bacterial products in a right well. We will begin to study the molecules within the cells that signal the cells to decide to go right instead of left. We believe there are two separate signaling pathways involved inside the neutrophils that include p38 MAPK, PIXa and PLA2 for bacterial products and PI3K, PTEN and SHIP1 in response to chemokines. Finally, we developed a way to watch neutrophils make these decisions in vivo, using a technique termed intravital microscopy. We believe that in a live animal, the crawling of neutrophils will be a very complex situation. The final series of experiments will involve the use of bacteria to ascertain that results from our simplified systems do in fact apply to a relevant infection model. The mechanisms will be elucidated in mice that lack the aforementioned molecules.