Using tobacco to thwart West Nile virus

March 27, 2014

An international research group, led by Arizona State University professor Qiang "Shawn" Chen, has developed a new generation of potentially safer and more cost-effective therapeutics against West Nile virus and other pathogens.

The therapeutics, known as monoclonal antibodies (MAbs), and their derivatives were shown to neutralize and protect mice against a lethal dose challenge of West Nile virus – even as late as four days after the initial infection. A researcher holds a tobacco leaf that makes a vaccine against West Nile virus Download Full Image

"The overarching goal of our research is to create an innovative, yet sustainable and accessible low-cost solution to combat the global threat of West Nile virus," said Chen, a researcher at Arizona State University's Biodesign Institute.

West Nile virus is spread by infected mosquitoes, and targets the central nervous system. It can be a serious, life-altering and even fatal disease, and currently, there is no cure or drug treatment against West Nile virus, which has been widely spread across the U.S., Canada, Latin America and the Caribbean.

"The goal of this latest research was twofold," said Chen. "First, we wanted to show proof-of-concept, demonstrating that tobacco plants can be used to manufacture large and complex MAb-based therapeutics. Second, we've wanted to improve the delivery of the therapeutic into the brain to combat West Nile virus at the place where it does the greatest harm."

The study appears in the March 27 online edition of PLOS ONE. Along with Chen, the research team included Junyun He, Huafang "Lily" Lai, Michael Engle, Sergey Gorlatov, Clemens Gruber, Herta Steinkellner and long-time Washington University collaborator Michael S. Diamond.

Chen's group has been a pioneer in producing MAbs as therapeutic candidates in plants, including tobacco and lettuce plants. A couple of years ago, his team demonstrated that their first candidate, pHu-E16, could neutralize West Nile infection and protect mice from exposure. MAbs target proteins found on the surface of West Nile virus.

However, this antibody was not able to accumulate at high levels in the brain.

One approach to tackle this challenge is to program into the therapeutic antibodies the capability of binding to receptors that can help the MAbs to cross into the brain. Chen wanted to use this strategy to produce a more effective way to combat West Nile virus.

In the new study, they improved upon their pHu-E16 design, making half a dozen new variants that could, for the first time, lead to the development of MAbs that effectively target the brain and neutralize West Nile virus.

Mice were infected with a lethal dose of West Nile virus, and increasing amounts of a MAb therapeutic were delivered as a single dose the same day of infection. In another experiment, Chen's team tested whether the therapeutic, called Tetra pHu-E16, could be effective after infection. In this case, the therapeutic was administered four days after West Nile virus infection, when the virus has already spread to the brain. In each case, they protected up to 90 percent of the mice from lethal infection.

This is the first instance of such an effect, and makes possible neutralizing West Nile virus, even after infection by a tetravalent MAb. The tetravalent MAbs design will offer the researchers greater flexibility toward selection of disease, tissue and antigen targets.

For Chen, this also gives promise to his team developing a plant-based system to dramatically reduce the costs of commercial manufacturing of MAbs.

"This study is a major step forward for plant-based MAbs, and also demonstrates for the first time the capacity of plants to express and assemble large, complex and functional tetravalent MAb complexes," said Chen.

MAbs are a hot and highly competitive research field, having been shown to effectively target cancer, autoimmune and inflammatory diseases. Now a $60 billion market for the biotechnology and pharmaceutical sectors, growth of the market has been hampered by high development costs of producing these in animal cell systems, which – when factoring in a long period for manufacturing, research and development, and clinical trials – may reach around $1 billion per each therapeutic candidate.

Therapeutic MAbs are typically made in animal host cells, and assembled into Y-shaped complexes. Until now, tetravalent MAbs had never been made in a plant system before. To make the potential therapeutics, the group is able to use young tobacco plants and a protein expression system to make and harvest the proteins in the leaves.

For the study, MAbs were rapidly produced in tobacco plants in as little as 10 days, giving promise to change the image of scourged product that causes lung cancer into a manufacturing system for societal benefits against infectious diseases.

"It is our hope that these results may usher in a new age of cost-effective MAbs therapeutics against West Nile virus and other neurological diseases," said Chen. "Our next step is to move this forward with the development of bifunctional MAbs that can target the brain, with the ultimate goal of entering human clinical trials."

Joe Caspermeyer

Manager (natural sciences), Media Relations & Strategic Communications


Scholar to discuss 'moving beyond the asterisk' for American Indian students

March 28, 2014

American Indian students who come into a university environment may struggle with culture shock and feeling homesick, especially if they move from a small reservation community to an unfamiliar major metropolitan area.

Leading American Indian scholar Heather Shotton will explain how universities can help American Indian students succeed during “Moving Beyond the Asterisk: The University’s Role in Enabling Native Student Success,” at 6 p.m., April 10, in the Memorial Union Pima Auditorium on ASU's Tempe campus. portrait of Heather Shotton Download Full Image

“Heather is one of the emerging voices that examine and explore the experiences of American Indian students in institutions of higher education. She does so with an eye toward addressing the everyday challenges these students – and their institutions – face in helping them successfully navigate college and life,” said Bryan Brayboy, professor in the ASU School of Social Transformation and director of the Center for Indian Education. “She is, in many ways, setting the table for the next generation of scholars in this area of inquiry.”

In her talk, Shotton will discuss how campuses can move beyond an “asterisk mentality” and successfully support Native students. The “asterisk mentality” phenomenon describes the concept of American Indian students being excluded from scholarship and data, and represented by an asterisk, noting that the population is not statistically significant.

Shotton is an editor of the book, “Beyond the Asterisk: Understanding Native Students in Higher Education,” and a Native American Studies assistant professor at the University of Oklahoma. The book addresses strategies for supporting American Indian college students, and explains the “asterisk mentality” concept that is based on a lack of knowledge and understanding of Native college students, coupled with issues of invisibility that has generated a movement among American Indian higher education practitioners and scholars to challenge the mentality and share strategies for serving these students.

“Heather’s visit represents one of the many ways ASU is addressing the needs of American Indian students,” said Diane Humetewa, special adviser to the president on American Indian affairs. ASU has one of the highest American Indian student populations in the nation and offers indigenous students opportunities to connect with American Indian Student Support Services that provides academic and personal support while promoting traditional culture. Other initiatives, such as the Tribal Nations Tour, bring the university to young Native people throughout the state’s American Indian communities. Students who take American Indian Studies classes learn from faculty members who are all members of tribal nations, and five new Native American faculty members joined the university last year.

During a three-day visit to ASU, Shotton will discuss challenges and opportunities for the university to "move beyond the asterisk" through meetings with student focus groups, faculty roundtables, the Provost/President's Native American Advisory Committee and members of the administration. She is scheduled to appear with professor Brayboy on KAET-TV’s (Channel 8) Horizon program on April 16.

Shotton, a member of the Wichita and Affiliated Tribes, and also of Kiowa and Cheyenne descent, was recently awarded the National Center for American Indian Enterprise Development “Native American 40 Under 40” Award. She serves American Indian students and communities locally and nationally, and is past president of the National Indian Education Association.

This event is made possible by the Academic Excellence through Diversity Grant sponsored by the Office of the University Provost, and is the result of a collaboration of faculty and staff from the School of Letters and Sciences, School of Social Transformation, University Academic Success Programs American Indian Student Support Services, Center for Indian Education and the Special Council on American Indian Affairs, American Indian Initiatives.

The School of Social Transformation and the Center for Indian Education are research units in ASU's College of Liberal Arts and Sciences