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Alpaca-derived antibodies could protect plants from disease

Alpaca-derived antibodies could protect plants from disease

COVID-19 has tragically given many people a crash course in the importance of antibodies, pathogen-targeting proteins produced by the sophisticated immune systems of humans and other animals. Now, researchers from a U.K. plant research institute have found a way to endow plants with an antibody-based defense for a specific threat, potentially speeding the creation of crops resistant to any kind of emerging virus, bacterium, or fungus.

“It’s a really creative and bold approach,” says Jeff Dangl, a plant immunologist at the University of North Carolina, Chapel Hill. Roger Innes, a plant geneticist at Indiana University, Bloomington, adds: “This would be much, much faster than standard plant breeding and hopefully much more effective.”

The strategy is to inoculate an alpaca or other camel relative with a protein from the plant pathogen to be targeted, purify the unusually small antibodies they produce, and engineer the corresponding gene segment for them into a plant’s own immune gene. In a proof of concept described today in Science, this approach equipped a model plant species with immunity against an engineered version of a virus that infects potatoes and related crops.

Farmers lose many billions of dollars to plant diseases each year, and emerging pathogens pose new threats to food security in the developing world. Plants have evolved their own multipronged immune system, kick-started by cell receptors that recognize general pathogen features, such as a bacterial cell wall, as well as intracellular receptors for molecules secreted by specific pathogens. If a plant cell detects these molecules, it may trigger its own death to save the rest of the plant. But plant pathogens often evolve and evade those receptors.

A long-standing dream in plant biotechnology is to create designer disease resistance genes that could be produced as fast as pathogens emerge. One approach is to edit the gene for a plant immune receptor, altering the protein’s shape to recognize a particular pathogenic molecule. This requires specific knowledge of both the receptor and its target on the pathogen.

Instead, Sophien Kamoun, a molecular biologist at the Sainsbury Laboratory, and his colleagues harnessed an animal immune system to help make the receptor modifications. During an infection with a new pathogen, animals produce billions of subtly different antibodies, ultimately selecting and mass-producing those that best target the invader.

Camelids, which include alpacas, camels, and llamas, are workhorses for antibody design because their immune systems create compact versions, called nanobodies, encoded by small genes. As a proof of principle of the new plant defense strategy, Kamoun’s group turned to two standard camelid nanobodies that recognize not pathogen proteins, but two different fluorescent molecules, including one called green fluorescent protein (GFP). The team chose these nanobodies to detect test viruses, in this case a potato virus, engineered to make the fluorescent proteins.

Jiorgos Kourelis, a postdoc in Kamoun’s lab, first melded the gene for the GFPtargeting nanobody to the gene for an intracellular immune receptor in the tobacco relative Nicotiana benthamiana. In a follow-up demonstration, he repeated the feat with the gene for the nanobody recognizing the other glowing protein. It took several tries and tweaks to create plants that did not mount autoimmune responses because of the modified receptors, which would have stunted growth and impaired fertility.

Next, Clémence Marchal, also a postdoc in Kamoun’s lab, investigated how well plants with the nanobody-enhanced receptors detected the altered potato viruses. Marchal found that the plants mounted a vigorous immune response—the patches of self-destructing cells were visible to the naked eye—and experienced almost no viral replication, whereas leaves from control plants suffered from infection.

Plant breeders often “stack” resistance genes into plant varieties to add protection against several diseases at once. In the team’s experiment, plants given genes for both kinds of nanobodies were protected against either viruses. “The exciting part about this technology is we have the potential of made-to-order resistance genes and keeping up with a pathogen,” Kamoun says.

The group has since engineered a crop to produce nanobodies that detect actual pathogen molecules, although Kamoun declines to identify the plant before the team has tested whether it withstands assault by the pathogens. The Sainsbury Laboratory has filed patent applications worldwide on the strategy, including in Europe, where public opposition to genetic engineering means it is unlikely to be commercialized any time soon. But Kamoun says there is commercial interest from elsewhere.

Dangl and others are optimistic that the nanobody approach should work in crops. “This technology is a potential game changer,” he says. Ksenia Krasileva, a geneticist at the University of California, Berkeley, says the fusion of nanobodies with plant immune receptors opens up a vast body of biomedical knowledge for plant scientists. “We can now tap into all of that research and translate it to save crops. We have a perfect merging point here.”

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