In a genetic leap that could help fast track vaccine and drug development to prevent or tame serious global diseases, DMS researchers have discovered how to destroy a key DNA pathway in a wily and widespread human parasite.
The feat surmounts a major hurdle for targeting genes in Toxoplasma gondii , an infection model whose close relatives are responsible for diseases that include malaria and severe diarrhea.
"This opens a wide window on a complex parasite family and can help accelerate the development of safe and effective genetically modified vaccines and drug therapies," says team leader David Bzik, PHD, professor of microbiology and immunology. The work is reported in the April issue of Eukaryotic Cell with Barbara Fox, senior research associate of microbiology and immunology who is the lead author and innovator of the study.
Parasites steal shamelessly from their hosts, co-opting resources to survive and infect. T gondii, however is a clever contrarian: it invites destruction and goes underground.
"Most parasites, along with bacteria and viruses, are shape shifters, so the immune system can't catch up with them; but T. gondii actually wants to be destroyed,'' says Bzik. "It has a unique strategy to elicit an immune response that stops the actively growing parasite and something in that response drives it to a latent stage which is necessary for its transmission."
The food borne parasite, often transmitted from cats, can be serious, even fatal for immune deficient people or newborns of mothers infected in pregnancy. While the T. gondii infection is harmless in most people, the parasite does takes up permanent residence inside its host. Its virulent cousins include Plasmodium, which causes lethal malaria and Cryptosporidium, a common source of waterborne diarrhea that can be severe or intractable in children or those with HIV.
"There is an amazing immune response hard-wired into this parasite to deliver life-long immunity to T. gondii ," Fox says. "So our work has been recently focused at creating safe, attenuated (weakened), and genetically defined T. gondii strains that also piggyback antigens to deliver sorely needed vaccines for malaria, cryptosporidiosis, tuberculosis, HIV/AIDS, or even cancer. This finding overcomes the bottleneck for quickly developing multiple manipulated and completely safe strains where each genetic manipulation is precisely defined and irreversible."
T. gondii is easy to grow in the lab and has other amenable attributes that have made it a leading model for understanding intracellular pathogens. It belongs to the Apicomplexan family of protozoa, along with its other medically important relatives. Family members share numerous genes, but many are unique to Apicomplexa, making it difficult to predict or determine gene functions.
Employing a cut and paste genetic engineering technique, scientists can knock out or replace a gene to determine or change its functions. Most model organisms rejoin the manipulated pieces at the location of their proper and predictable sequence.