Featured Research

from universities, journals, and other organizations

Gene Targeting Discovery Opens Door For Vaccines And Drugs

Date:
April 14, 2009
Source:
Dartmouth Medical School
Summary:
In a genetic leap that could help fast track vaccine and drug development to prevent or tame serious global diseases, 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.

David Bzik (left) and Barbara Fox examine flasks for infection.
Credit: Image courtesy of Dartmouth Medical School

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.

The dominant pathway in T. gondii, however, is random insertion. The parasite uses a pathway of nonhomologous end joining (NHEJ), which is also used to repair DNA in broken chromosomes, and arbitrarily reinserts targeting DNA segments at incorrect locations. That makes isolating strains with defined and targeted gene knockouts a difficult, time consuming and painstaking adventure.

Using a strategy Fox devised, the DMS team disrupted and killed a parasite gene called KU80 that is involved in the NHEJ DNA repair pathway. Their success effectively turned the parasite into a dependable genetic workhorse for all the diverse organisms in the Apicomplexa phylum. It permits a direct approach to determine gene function by examining mutants lacking a specific gene.

"The KU80 knockout strain holds much genetic magic," says Bzik. "Remarkably, it exhibits 100 percent homologous recombination and gene targeting efficiency compared to the parent strain. This also provides the first biological proof of a functional NHEJ DNA repair pathway in a protozoan."

The work makes T. gondii an effective model for understanding a globally significant parasite family and holds promise for speeding up new therapies. "To create safe, genetically modified products or vaccines to put into people, we need to be able to efficiently and reliably target strains for genetic manipulation," Fox explains.

"Fundamentally, all possible growth and virulence factors as well as the potential for transmission must be first genetically deleted; then key protective antigens or genes from other sources must be introduced in a precisely defined way. We needed to be able to do this efficiently, reliably and, cleanly. Now we can."

Coauthors of the study (in Vol. 8, No. 4: 520-529) are Jessica Ristuccia, a former research assistant now at Tufts School of Dental Medicine, and Jason Gigley, a former student now at George Washington University. The work was funded by grants from the NIH National Institute of Allergy and Infectious Diseases.


Story Source:

The above story is based on materials provided by Dartmouth Medical School. Note: Materials may be edited for content and length.


Journal Reference:

  1. Barbara A. Fox, Jessica G. Ristuccia, Jason P. Gigley, and David J. Bzik. Efficient Gene Replacements in Toxoplasma gondii Strains Deficient for Nonhomologous End Joining. Eukaryotic Cell, 2009; 8 (4): 520 DOI: 10.1128/EC.00357-08

Cite This Page:

Dartmouth Medical School. "Gene Targeting Discovery Opens Door For Vaccines And Drugs." ScienceDaily. ScienceDaily, 14 April 2009. <www.sciencedaily.com/releases/2009/04/090413185728.htm>.
Dartmouth Medical School. (2009, April 14). Gene Targeting Discovery Opens Door For Vaccines And Drugs. ScienceDaily. Retrieved September 23, 2014 from www.sciencedaily.com/releases/2009/04/090413185728.htm
Dartmouth Medical School. "Gene Targeting Discovery Opens Door For Vaccines And Drugs." ScienceDaily. www.sciencedaily.com/releases/2009/04/090413185728.htm (accessed September 23, 2014).

Share This



More Health & Medicine News

Tuesday, September 23, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Ebola Costs Keep Mounting

Ebola Costs Keep Mounting

Reuters - Business Video Online (Sep. 23, 2014) The WHO has warned up to 20,000 people could be infected with Ebola over the next few weeks. As Sonia Legg reports, the implications for the West African countries suffering from the disease are huge. Video provided by Reuters
Powered by NewsLook.com
Ebola Cases Could Reach 1.4 Million Within 4 Months

Ebola Cases Could Reach 1.4 Million Within 4 Months

Newsy (Sep. 23, 2014) Health officials warn that without further intervention, the number of Ebola cases in Liberia and Sierra Leone could reach 1.4 million by January. Video provided by Newsy
Powered by NewsLook.com
WHO: Ebola Cases to Triple in Weeks Without Drastic Action

WHO: Ebola Cases to Triple in Weeks Without Drastic Action

AFP (Sep. 23, 2014) The number of Ebola infections will triple to 20,000 by November, soaring by thousands every week if efforts to stop the outbreak are not stepped up radically, the WHO warned in a study on Tuesday. Duration: 01:01 Video provided by AFP
Powered by NewsLook.com
5 Ways Men Can Prevent Most Heart Attacks

5 Ways Men Can Prevent Most Heart Attacks

Newsy (Sep. 23, 2014) No surprise here: A recent study says men can reduce their risk of heart attack by maintaining a healthy lifestyle, which includes daily exercise. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins