Decrypting Crypto

Gene sequence provides valuable new insights for combating a dangerous intestinal parasite.

By Mary Hoff

 It lurks on pitchforks and vegetables, in swimming pools and drinking water. When it sets up housekeeping in humans, it causes horrendous and occasionally deadly diarrhea. In dairy cattle, it can have a devastating effect on production.

It’s Cryptosporidium parvum, a microscopic pathogen that infects the digestive tracts of humans and other mammals. Even though it’s smaller than a red blood cell, this parasite is formidable. It builds a hard shell around itself to survive harsh environmental conditions, so conventional disinfectants such as chlorine don’t destroy it, making it hard to control. There’s no known cure: Folks who get sick from it pretty much have no choice but to let the illness run its course. For some, it can be fatal.

“Normal humans aren’t going to die from it, but for three or four days they’re going to wish they were dead,” says Mitchell Abrahamsen, professor in the College of Veterinary Medicine’s Department of Veterinary and Biomedical Sciences. “In immune-compromised individuals, such as persons with AIDS, Cryptosporidium infection is very devastating and can have a serious impact on patient health and mortality.”

More than 200 cases of cryptosporidiosis were reported in 2002 in Minnesota alone. In 1993, C. parvum contaminated Milwaukee’s water supply, making ill more than 400,000 residents and causing billions of dollars worth of damage.

But crypto, as it’s called, may finally have met its match. Last spring Abrahamsen and colleagues, with the help of the Biomedical Genomics Center and Advanced Genetic Analysis Center, announced they had sequenced the microbe’s genome, identifying all of the 9 million or so base pairs that make up its genetic material. That effort, funded by NIH, has yielded fascinating insights into how the parasite survives in the intestinal tract and why it is resistant to the therapies that have been tried. Eventually, Abrahamsen anticipates it will lead to the development of medicines to treat individuals with cryptosporidiosis.

“One of the things we learned from analyzing the genomic sequence is that Cryptosporidium parvum is missing most of the biochemical pathways that conventional antiparasitic drugs target,” Abrahamsen says. “On the opposite side of the coin, now that we have decoded the genome, we’ve identified a number of biochemical pathways previously unknown to be present in Cryptosporidium parvum. This has allowed us to identify some very good targets for designing new anti-crypto drugs.”

With information gleaned from cryptosporidium’s genome, Abrahamsen and colleagues have revealed that the parasite is unable to synthesize purines, one of the building blocks of DNA. That means Cryptosporidium is absolutely dependent on purines from the host cell. Detailed analysis of the genome has identified the biochemical pathway involved in salvaging purines from the host cell. Abrahamsen’s laboratory was recently awarded a grant from NIH to identify drugs that will inhibit this pathway, which is distinct from that used by other parasites and mammals. If researchers can find compounds that selectively prevent the uptake of purines from the host cell, this might open doors to the development of drugs that could disable the parasite without harming its host.

In addition to providing leads for patient care, the genome sequencing effort opens doors for a variety of other approaches for quashing crypto. It has yielded key information regarding how the parasite recognizes and invades the cells that line the intestine, which may have important implications for the development of vaccines to protect individuals from cryptosporidiosis.

Another important impact has been the identification of genetic markers that can be used to develop new approaches for tracking disease transmission and understanding the virulence associated with various strains of the parasite. Abrahamsen’s laboratory is now pursuing a better understanding of how cryptosporidium protects itself from environmental insults such as disinfectants, leading to new opportunities to find chinks in the parasite’s armor.