Innate immune responses against infections provide a first line of host defense that occurs rapidly and is aimed at a wide range of pathogens. Activation of innate responses involves the coordinated actions of several cell types, including neutrophils, monocytes, and natural killers cells. Neutrophils are key to controlling infectious diseases, which can be deadly in cancer patients. Chemotherapy-induced myelosuppression can cause severe neutropenia. There is evidence to indicate that increasing the number of circulating neutrophils or enhancing neutrophil function may be useful for cancer patients with neutropenia. Research in my laboratory has focused on improving the functional status of neutrophils and analyzing human neutrophil activation and signaling pathways that control the neutrophil's biological functions.
By use of biological, biochemical, and gene manipulation methods, we have identified a key signaling pathway vital in normal cell function. This key signaling pathway involves mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) in neutrophils for inhibition of Candida albicans growth. Contact with C albicans triggered MAPK activation and fungicidal activity, while blocking MAPK activation, either by pharmacologic reagent PD098059 or by dominant-negative MAPK expression via vaccinia viral delivery, suppressed antimicrobial activity. Rac and Cdc42, but not Ras or Rho, were responsible for this MAPK activation, indicating that Rac/Cdc42-dependent activation of MAPK is a critical event in the immediate phagocytic response of neutrophils to microbial challenge.
Our lab is also investigating large granulocytic lymphocyte (LGL) leukemia, a syndrome of increased numbers of circulating LGLs associated with chronic neutropenia as well as other systemic symptoms. LGL leukemia is commonly associated with anemia, neutropenia, rheumatoid arthritis, and occasionally idiopathic primary pulmonary hypertension. We have generated data suggesting that perforin proteins and granzymes released from natural killer cells isolated from LGL leukemia patients significantly contribute to elevated autoimmunity and induce vascular endothelial cell death, which is capable of causing local tissue damage and chronic vascular cell injury. The lab is examining the signaling mechanism that activates perforin and granzyme release upon cell-target contact, and is attempting to provide the critical biological, biochemical, and molecular information necessary to support future design of small molecule inhibitors to reduce autoimmune reaction-mediated self-tissue damage.