William F. Dietrich

Department of Genetics
Harvard Medical School
New Research Building, Room 358e
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: (617) 432-6785
Fax: (617) 432-3993
Email: dietrich@rascal.med.harvard.edu
3 postdoctoral fellows, 4 graduate students

Our approach is to take advantage of naturally occurring variation in mouse phenotypes to identify and isolate genes important for the susceptibility to disease. There are dozens of inbred mouse strains that exhibit substantial variation in disease phenotypes, and one can utilize the expanding arsenal of genetic tools for the mouse to map and clone the genes responsible for this phenotypic variation. It is our expectation that the isolation and study of disease genes will yield a wealth of important biological information, as well as providing important clues for the development of diagnostic and therapeutic regimens for human diseases.

We are currently interested in genetically determined differences in infectious disease susceptibility. For example, we have exploited the fact that macrophages from different inbred strains of mouse are differentially permissive for the intracellular replication of Legionella pneumophila, a human pathogen that causes severe pneumonia. We have recently identified a homolog of plant innate immunity genes that affects the Legionella permissiveness of mouse macrophages. We are now trying to understand the molecular mechanism whereby this innate immunity gene mediates host response to infection.

We are also working on a genetic model of differential susceptibility to anthrax. Bacillus anthracis, which causes anthrax, secretes a toxin that specifically kills mononuclear phagocytes. The mechnanism of action of this toxin, called Lethal Toxin (LeTx), is unknown. We have identified genetic variants of a kinesin (Kif1C) that alter the susceptibility of mouse mononuclear phagocytes to the killing effects of LeTx. We are now beginning to study a recently identified genetic suppressor of the role that Kif1C plays in the LeTx intoxication process.

We have begun to expand our genetic models to include studies on another intracellular pathogen called Chlamydia trachomatis. In collaboration with the Starnbach lab, we have identified mouse strains that are differentially susceptible to a systemic infection with Chlamydia, and we have mapped several quantitative trait loci (QTL) that affect this process. Positional cloning efforts for these QTL are underway.

References:

• Shaw,M.H., V.Boyartchuk, S. Wong, M. Karaghiosoff, J. Ragimbeau, S. Pellegrini, M. Muller, W. F. Dietrich, and G. S. Yap. 2003. "A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity." Proc. Natl. Acad. Sci. USA, 100: 11594-11599.
• Wright, E. K, S. A. Goodart, J. D. Growney, V. Hadinoto, M. G Endrizzi, E. M. Long, K. Sadigh, A. L. Abney, I. Bernstein-Hanley, and W. F. Dietrich. 2003. "Naip5 affects host susceptibility to the intracellular pathogen Legionella pneumophila." Curr. Biol., 13: 27-36.
• Watters, J. W., K. Dewar, J. Lehoczky, V. Boyartchuk, and W. F. Dietrich. 2001 "Kif1C, a Kinesin-Like Motor Protein, Mediates Mouse Macrophage Resistance to Anthrax Lethal Factor." Curr. Biol., 11: 1503-1511.