Singular Vulnerability

Why some pathogens have little to fear from vaccines.

A biological mechanism crucial to the creation of life could also play a role in hastening death, researchers working at MU and the Imperial College in London have found.

Gary Clark, an associate professor of obstetrics, gynecology and women's health at MU, along with Imperial College's Anne Dell, a biological sciences professor specializing in mass spectrometric analysis, have spent the past decade working to unravel the role carbohydrates play in human health and disease. Their recent investigations have sought to shed light on why the world's best scientists have, despite thousands of lab hours logged and billions of dollars spent, failed to come up with vaccines for controlling diseases such as HIV/AIDS, certain forms of cancer, bacterial infections that cause stomach ulcers, and schistosomiasis.

This failure, Clark and Dell have determined, is likely related to a singular vulnerability built into the human immune system. In order to reproduce successfully, our bodies must avoid attacking the "foreign" cells and tissues that make reproduction possible; that is, the sperm, egg and fetus. Certain diseases and parasites, over time, have evolved to mimic the carbohydrate sequences that confer this reproductive free pass.

"It's our major Achilles heel," says Clark. "We are hard-wired to protect our sperm and eggs, as well as our unborn babies, from any type of immune response. Unfortunately, our results suggest that many pathogens and tumor cells also have integrated themselves into this protective system, thus enabling them to resist the human immune response."

When sperm are made, they specifically label their glycoproteins with "Lewis carbohydrate sequences," a specific chain of carbohydrates. When these "foreign" sperm enter the female body, the female's immune system does not recognize them as foreign, probably because of these Lewis sequences. Similarly, the unborn baby also could be seen as foreign by the mother's immune system, but she produces other types of glycoproteins that likely block immune response in the womb.

In their study, published late last year in the Journal of Biological Chemistry, Clark and Dell determined that the schistosome parasite, certain aggressive tumors, HIV-infected immune cells and H. pylori -- a bacteria that causes stomach ulcers -- all carry the Lewis sequence. Because the Lewis sequence shuts down immune responses that vaccines require to do their work, efforts to develop drugs conferring immunity against Lewis-sequence-carrying pathogens have failed.

"This work is creating an entirely new way of thinking about how we must combat viruses like HIV and aggressive tumor cells," says Clark. "We have literally spent billions of dollars developing vaccines for AIDS and cancer. However, the latest high profile HIV and tumor vaccine trials have been spectacularly unsuccessful, perhaps for some very good reasons. We must become more clever if we are ever going to solve the problems of cancer and AIDS."

Published by the Office of Research.

©2009 Curators of the University of Missouri. Click here to contact the editor.