Alpaca-derived antibodies may protect plants against disease | Science

Tragically, COVID-19 has 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 scientists from a British plant research institute have found a way to give plants an antibody-based defense against a specific threat, potentially speeding up the creation of crops resistant to all kinds of new viruses, bacteria or fungi.

“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 efficient.”

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 Sciencethis approach equipped a model plant species with immunity to an engineered version of a virus that infects potatoes and related crops.

Farmers lose many billions of dollars to plant diseases every year, and new pathogens pose new threats to food security in developing countries. Plants have evolved their own multi-stranded 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 can trigger its own death to save the rest of the plant. But plant pathogens often evolve and avoid these receptors.

A long-standing dream in plant biotechnology is to create designer genes for disease resistance that can be produced as quickly as pathogens emerge. One approach is to edit the gene for a plant immune receptor, changing the protein’s shape to recognize a particular pathogen 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 exploited an animal’s immune system to make the receptor modifications. During an infection with a new pathogen, animals produce billions of subtly different antibodies, eventually 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 make compact versions, called nanobodies, encoded by tiny genes. As a proof of principle for 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 nanomaterials to detect test viruses, in this case a potato virus, engineered to make the fluorescent proteins.

Jiorgos Kourelis, a postdoctoral fellow in Kamoun’s lab, first fused the gene for the GFP-targeting 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 that recognized the other glowing protein. It took several trials and tweaks to create plants that did not produce autoimmune reactions due to the modified receptors, which would have stunted growth and impaired fertility.

Then Clémence Marchal, also a postdoctoral fellow in Kamoun’s lab, examined how well plants with the nanobody-enhanced receptors detected the altered potato viruses. Marchal found that the plants mounted a strong immune response—the patches of self-destructive cells were visible to the naked eye—and experienced almost no virus replication, while leaves from control plants suffered from infection.

Plant breeders often “stack” resistance genes into plant varieties to provide protection against multiple diseases at once. In the team’s experiment, plants given genes for both types of nanobodies protected against both viruses. “The exciting part about this technology is that we have the potential to make resistance genes to order and keep pace with a pathogen,” says Kamoun.

The group has since developed a crop to produce nanobodies that detect actual pathogen molecules, although Kamoun refuses to identify the plant until the team has tested whether it can withstand attack by the pathogens. The Sainsbury Laboratory has filed patent applications worldwide for the strategy, including in Europe, where public opposition to genetic engineering means it is unlikely to be commercialized anytime 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 amount of biomedical knowledge for plant scientists. “We can now use all that research and translate it to save crops. We have a perfect merging point here.”

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