Innate immune cells and barrier tissues are the first line of defense in the fight against invading pathogens. Our group focuses on understanding molecular mechanisms that innate and mucosal immune host defense use to protect the host from microbial insult, and how some responses wind up damaging the host. For example, second messengers such as reactive oxygen species (ROS) or nitric oxide that are produced during infection can have beneficial as well as detrimental effects. The overall outcome depends on precise spatial and temporal regulation of these second messengers by the affected cell populations. The intracellular signaling pathways that regulate the production of these molecules constitute an ideal target for intervention in disease.

Almost all of the processes connected to pathogen up-take, pathogen elimination, or sustained inflammation are governed by small GTPases of the Rho family. Research in our laboratory centers on Rac, Cdc42, and RhoA, which control various leukocyte functions ranging from ROS production to chemotaxis and phagocytosis. Superoxide generation is accomplished by the Rac-dependent NADPH oxidase Nox2 upon stimulation with chemotactic factors or phagocytic stimuli. GTPases of the Rho family are also involved in signaling cascades, which originate from Toll-like receptors (TLR) and lead to gene transcription. Our laboratory studies different aspects of TLR signaling in immune cells as well as in genetically altered mouse models to discern the impact of GTPases and their targets on innate immune cell functions.

A related area of research is the interaction and communication between innate immune cells and mucosal epithelia. Several ex vivo and in vivo models are used to study the influence of pathogens, bacterial-derived ligands and toxins on barrier function and how the host responds. Of particular interest are ROS-generating NADPH oxidases, which are a crucial part of the first line of host defense.  Nox/Duox proteins serve as compartmentalized signaling modules, thereby activating or inhibiting signaling cascades, as host defense mechanism, or as pro-inflammatory triggers. Elucidating physiological stimuli and control mechanisms for these Nox/Duox enzymes combined with structure-function studies will help defining the biological functions of oxidases in health and disease, and constitutes a prerequisite for drug development and therapeutic intervention in oxidant-induced stress and tissue injury.

Mandy Lehmann PhD- Effect of B. anthracis toxin on human lung epithelium 2008

Sylvia Luxen PhD - Regulation and function of Dual Oxidases 2008

Postdoctoral Fellows

Luis Alvarez, PhD
 
Patti Hayes, PhD 

Collaborators

Dr. Billy Burke, Dr. Nicolae Corcionivoschi

Dr. Jeremy Simpson