M. Kathryn Liszewski

DEPARTMENT OF Internal Medicine
Keywords: immunology, complement, inflammation, xenotransplantation, genetics, cell biology

The complement system lies at the interface between innate and adaptive immunity. In its simplest description, it provides both an independent immune system capable of attacking microbes as well as other foreign material and an adjunct to the antibody system. Once activated, the complement system fires in a cascade-like fashion in which one component activates the next. Both swift and powerful, millions of complement components can deposit on an invading microbe within only a few minutes.

Our laboratory focuses on understanding how host cells avoid injury from complement and how pathogens as diverse as smallpox, monkeypox, measles virus, Streptococcus pyogenes, and pathogenic Neisseria (gonorrhea and meningitis) subvert complement attack.

One of my projects involves delineating structure/function of the human host regulator membrane cofactor protein (MCP; CD46). Attesting to its necessity, nearly every cell examined expresses MCP on its cell membrane. Its function is to control inadvertent complement activation on self cells. We and others have shown that MCP mutations are linked to development of atypical hemolytic uremic syndrome.

New therapeutic strategies employing MCP and other similar host proteins also are emerging. MCP has been engineered into animals, principally the pig, whose organs are being used in xenotransplantation. Soluble versions of MCP are being developed as inhibitors of complement activation. Currently, there is no effective complement inhibitor in the medicinal arsenal.

New public health concerns have emerged regarding use of smallpox as a bioterrorist weapon. Poxviruses such as smallpox express human-like complement regulatory proteins in order to evade complement attack. Another of my goals is to characterize structure/function of these regulators. Results in this area may serve as a guide to produce a less toxic smallpox vaccine and to identify potential treatment strategies.