Bacterial Pathogenesis and the Plant Immune Response
Infectious diseases caused by pathogenic bacteria, fungi, oomycetes, viruses, and nematodes pose major economic and environmental challenges to agriculture throughout the world. It is estimated that 15% of food, fiber, and fuel crops is lost annually to diseases worldwide. One way to address this problem is to develop plant varieties that are inherently more resistant to diseases as a result of classical plant breeding or genetic engineering.
Research in the Martin lab is focused on understanding the molecular details of the infection process as well as the host immune response, from the perspective of both the pathogen and the plant. On the pathogen side, the lab studies the causative agent of speck disease in tomato, Pseudomonas syringae pv. tomato. As part of its infection process, this bacterial pathogen delivers a large number of virulence proteins directly into the plant cell where they interfere with the host immune system. The lab is determining which features of these virulence proteins are responsible for undermining host immunity and investigating the mechanisms they use to compromise specific host proteins. This research lays the foundation for developing genetic resistance in plants that avoids or counteracts the activities of virulence proteins. Discoveries from this work could have implications in both agriculture and medicine as it has recently become apparent that many disease-causing organisms of plants and humans use fundamentally similar virulence mechanisms to infect their hosts.
On the plant side, the lab uses tomato because it is the natural host for Pseudomonas syringae and it is an economically important and experimentally tractable plant species. A major goal has been to determine the structural basis of the interactions between pathogen and host proteins. This knowledge is expected to enable the design of host proteins that evade interference by pathogen virulence strategies, resulting in plants with more durable, broad-spectrum disease resistance.
In the near term, the research will add to the understanding of pathogenesis and plant immunity not only in the tomato – Pseudomonas syringae system but also in other important vegetable crops. Moreover, because it is now apparent that all plants (both monocots and dicots) appear to use fundamentally similar resistance mechanisms, the research is relevant to many economically important plant species and to the control of diseases caused by diverse pathogens.
Three projects with potential application in the Ag and Pharma industry are described below.
1) Plant Disease Resistance: Engineering the plant BAK1 gene to enhance PAMP-triggered immunity. (Include link to slide deck).
To infect plants, Pseudomonas syringae pv. tomato delivers ∼30 type III effector proteins into host cells, many of which interfere with PAMP-triggered immunity (PTI). One effector, AvrPtoB, suppresses PTI using a central domain to bind to the host BAK1 protein, a kinase that functions with several pattern recognition receptors to activate defense signaling. The structure of the AvrPtoB-BAK1 interaction surface has been solved, and AvrPtoB mutations at the interface have been shown to disrupt bacterial virulence. These results suggest approaches for altering the plant BAK1 protein to increase plant resistance to this bacterial pathogen. Though this work is most immediately applicable to tomato, analogous approaches to disrupt host:pathogen protein interactions can be envisioned for other host:pathogen interactions.
2) Therapeutic Proteins: Effector proteins that can modulate programmed cell death (PCD) and immune responses in diverse eukaryotes.
Programmed cell death is an important physiological process and is in fact required for maintenance of a healthy organism. PCD is well-conserved across evolution, from bacteria and plants to humans. A number of neurological diseases, including Parkinson’s and Huntington’s disease, are linked to an abnormal increase in PCD in neurological tissues. PCD is also a major component of the plant immune response to bacterial infection. Pathogenic bacteria have developed mechanisms to counteract this plant immune response. The Martin lab has discovered a number of bacterial effectors involved in PCD. One such effector is AvrPtoB (US patent number 7,888,467), which has been shown to prevent PCD in plants and other eukaryotic organisms. Given the conservation of these types of proteins, this or related effector proteins could prove to be useful in the treatment and prevention of diseases related to an abnormally high rate of PCD or other diseases related to disorders of the immune system.
3) Vaccine and Protein Production: Enhancing accumulation of proteins in diverse eukaryotic expression systems.
The ability to express recombinant proteins in eukaryotic cells is the basis for the
production of many vaccines and industrial enzymes It is also an essential step in fundamental studies of protein structures important in medicine and agriculture. However, expressing large amounts of protein is often challenging. The effector protein AvrPtoB is a potent suppressor of programmed cell death (PCD) induced during the plant immune response. It also suppresses PCD induced by expression of foreign proteins in plants. Furthermore, AvrPtoB suppresses PCD in yeast induced by hydrogen peroxide or menadione (vitamin K), suggesting that targets of effector proteins may be highly conserved across evolutionary space. The Martin lab has shown that AvrPtoB suppresses PCD that is induced by the expression of certain vaccine proteins in N. benthamiana, resulting in enhanced accumulation of the vaccine protein in this transient plant expression system. Thus, AvrPtoB, and presumably many other effector proteins, have the potential to enhance the synthesis of “hard-to-express” proteins in diverse eukaryotic expression systems.
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