Research Projects:

The Lencer laboratory focuses primarily on mechanisms of microbial pathogenesis and host defense in the human intestine, and on mechanisms and regulation of ion transport responsible for secretory and inflammatory diarrheas.

In The Cholera Toxin project, we study how cholera toxin produced by V. cholerae breeches the intestinal epithelial barrier and enters host epithelial cells to cause disease. Studies over the last 15 years have shown that the toxin exploits endogenous mechanisms of lipid and membrane traffic to move retrograde from cell surface through theGolgi apparatus into the ER of the host epithelial cell. Once in the ER, the chaperonesPDI and ERO1 unfold the enzymatically active A-chain. Somehow, the free A-chain retro-translocates to the cytosol to induce toxicity, presumably by moving through the translocon, sec61. The toxin co-opts mechanisms of protein and lipid trafficking and of protein quality control that are fundamental to the biology of the mammalian cell itself.

In The Fc-receptor FcRn project, we examine the cell and molecular biology of FcRn-dependent IgG transport across mucosal barriers. Our work on this project has defined a new paradigm for mucosal immunology. Here, we find that epithelial cells of the adult human intestine and lung express the MHC class I related protein FcRn, FcRn binds IgG and acts as a trafficking receptor, moving IgG intact across mucosal surfaces in both directions. Such trafficking of IgG by FcRn establishes a steady state distribution of IgG across mucosal barriers and this explains a mechanism by which IgG may act in immune surveillance to retrieve luminal antigens for processing in the lamina propria or systemically.

In a third project, we aim to understand the regulation of Cl- secretion and water transport in the intestine. These studies address the biology of Paneth Cell cryptdins (alpha-defensins that act as innate mediators of host defense) and small compound inhibitors of K+ channels. Recent studies have examined mechanism by which the HIV protease inhibitors elicit secretory diarrhea. Aspartyl-protease inhibitors (API) effectively extend the length and quality of life in HIV-infected patients, but dose-limiting side effects such as lipodystrophy, insulin-resistance, and diarrhea have limited their clinical utility. Our studies show that the API nelfinavir induces a secretory form of diarrhea in HIV-infected patients. Nelfinavir potentiates muscarinic stimulation of intestinal CI- secretion by amplification and prolongation of an apical membrane Ca2+- dependent CI- conductance. This stimulated ion secretion is associated with increased magnitude and duriation of muscarinic-induced intracellular Ca2+ transients via activation of a long-lived, store-operated Ca2+ entry pathway. The enhanced intracellular Ca2+ signal is associated with uncoupling of the CI- conductance from down-regulatory intracellular mediators generated normally by muscarinic activation.