Crop production faces threats from plant pathogens. Traditional disease-resistance breeding relies heavily on natural plant resistance genes that encode immune receptors adapted to particular pathogens. However, rapidly evolving pathogens frequently overcome these natural defenses, and the limited diversity of naturally occurring immune receptors makes it difficult to develop crops with durable resistance.
Now, a team led by Prof. GAO Caixia from the Institute of Genetics and Developmental Biology (IGDB) of the Chinese Academy of Sciences has developed a programmable platform for on-demand design of synthetic plant immune receptors (SPIRs) that recognize proteins from diverse plant pathogens.
The study was published online in Science on July 23.
The immune receptors at the focus of this study—intracellular nucleotide-binding leucine-rich repeat receptors (NLRs)—mainly detect pathogens through large, highly repetitive leucine-rich repeat domains that are difficult to engineer. To counter this problem, the researchers exploited a distinct class of NLRs that recognize pathogens through compact, modular integrated decoy (ID) domains, which can be readily replaced with newly designed pathogen-recognition modules.
Using AI-assisted protein tools such as AlphaFold 3 and BindCraft, the researchers designed de novo proteins that specifically bind pathogen proteins. They then integrated these designed proteins into the rice immune receptor Pikm-1 by replacing its native ID domain, generating SPIRs with customized recognition specificities.
The researchers used this pipeline to design 391 SPIRs, which targeted proteins from a broad range of plant pathogens, including viruses, bacteria, fungi, and oomycetes. Of these, 71 (18.2%) recognized their intended targets and activated immune response, demonstrating that AI-assisted de novo protein design can generate functional plant immune receptors.
Many of the remaining designs, however, were either autoactive or inactive, indicating that AI-based design alone was not sufficient. To further improve receptor performance, the researchers turned to geminivirus replicon–assisted in planta directed evolution ( GRAPE ), a high-throughput platform they had established previously, and used it to optimize the newly designed SPIRs. This optimization significantly enhanced immune activity and reduced unwanted autoactivation. Transgenic Nicotiana benthamiana plants expressing optimized SPIRs showed effective resistance to Tomato brown rugose fruit virus (ToBRFV) infection, highlighting the potential of the technology for crop improvement.
Unlike resistance breeding that depends on naturally occurring resistance genes, the SPIR platform enables the customized design of immune receptors that can recognize entirely new pathogen targets. In principle, SPIRs targeting proteins from emerging pathogens can now be generated within weeks, providing a rapid and versatile strategy for protecting crops against evolving disease threats.
This work establishes a framework for programmable plant synthetic immunity, in which receptors can be designed, optimized, and deployed on demand. Programmable plant synthetic immunity may become a general strategy for developing next-generation disease-resistant crops and strengthening global food security.
