When it comes to immunity, plants and animals are much alike

The last common ancestor of plants and animals may have lived 1 billion years ago. Plants and animals have occasionally exchanged genes, but for the most part, have countered selective pressures independently. Microbes (bacteria, eukaryotes, and viruses) were omnipresent threats, influencing the direction of multi-cellular evolution. Receptors that detect molecular signatures of infectious organisms mediate awareness of non-self, and are integral to host defense in plants and animals alike. The discoveries leading to identification of these receptors and their ligands followed a similar logical and methodological pathway in both plant and animal research.

Bruce Beutler and I review the history of these discoveries in today's Science Magazine. Two of our favorite organisms (rice and mice) are highlighted in this review.

Mention of plant diseases was made as early as 750 BCE in the Hebrew Bible, and again in the writings of Democritus, around 470 BCE. Theophrastus made plants and plant disease a subject of systematic studies in 300 BCE. He and his contemporaries believed that plant diseases were a manifestation of the wrath of God. Very little useful knowledge about plant diseases was gained for another 2000 years. The devastating late blight of potatoes, an epidemic that began in 1845 and destroyed the principal food source for millions of people in Ireland, launched the first serious investigations into the basis of plant disease. Although some scientists believed that the causal agent was a fungal pathogen, this hypothesis flew in the face of the prevailing scientific view that fungi commonly found in diseased plant tissues were the products rather than the cause of disease. Today we know that Phytopthora infestans, an oomycete, caused this disease. De Bary (1853) showed that rusts and smut fungi caused diseases of cereal crops. Little known is the fact that his conclusions were published nearly a quarter of a century before the causal role of microorganisms in animal diseases was demonstrated conclusively by Koch, who studied anthrax in cattle, using the mouse as a model host, and who published his findings in 1876. Koch's postulates, developed in the course of these studies, applied equally to work with plant and animal pathogens thereafter.

In the era following the discovery of microbes, infection in animals and plants were seen as part of a continuum. Pasteur, for example, knew that the spoilage of beer and wine resulted from contamination by bacteria introduced during the necessarily non-sterile process of fermentation, and with Claude Bernard, introduced a gentle heating process to prevent it from occurring. He spoke of microbes as the cause of "diseases" of beer and wine, notwithstanding that beer and wine are not living organisms by formal definition, and imputed that diseases of humans and animals might also result from microbial infestation--as was known to be the case for plants. His insight was voiced in the context of a growing recognition, then confined to the elite of the scientific establishment, that all living things might share a common ancestry. Yet plants and animals seemed so different--in so many ways--that it was hard to see the similarities in their response to disease.

As the great afflictions of humans were shown to be caused by microbes from the 1870s onward, the strong host inflammatory responses to infection became an early focus of attention. Histopathologists, notably Cohnheim, pointed to the influx of leukocytes at sites of infection during these years, and Metchnikoff found experimental evidence of morphologically similar "phagocytes" in the control of infection in model organisms. Migratory phagocytes did not exist in plants, and a gulf began to open between students of plant and animal microbial pathogenesis. This gulf was to widen as multiple mechanisms of immunity were discovered in animals. On the one hand, "natural immunity," now called "innate immunity," permitted animals to recognize and respond to infections of most kinds, and was the only type of immunity most animal species (i.e., invertebrates) possess. On the other hand, in vertebrates, a second form of immunity had evolved, permitting the generation of receptors with immense diversity and exquisite specificity for foreign macromolecules of almost any kind, including toxins but also intrinsic molecular components of viruses, fungi, bacteria, and protozoa: whatever might invade the host. Moreover, the phylogenetically older innate immunity and the more recently evolved "adaptive immunity" often operated in concert with one another. This was obvious to Freund and his contemporaries, the developers of adjuvants, who knew that an inflammatory reaction helped to drive the production of antibodies directed against a specific antigen.

Lacking phagocytes, lymphocytes, antibodies, and many other parts of the animal armamentarium, plants ceased to stimulate much interest in the animal microbiology community. Yet there were common themes to the defensive measures employed by both plant and animal kingdoms. Their identification, discussed in detail in the review, followed a common approach focused on identifying the molecules recognized by the host as signatures of infection, and the receptors that mediate such recognition.

Discoveries over the past fifteen years demonstrate that the mechanisms that allow plants and animals to resist infection show impressive structural and strategic similarity (Fig. 1). Remarkably, the elucidation of these mechanisms followed a common approach involving a concerted attack on the same basic questions: What molecules are recognized by the host as signatures of infection? What receptors mediate recognition? These questions were ultimately answered by classical genetic studies.

Outlook
The lineages of humans and mice diverged 60-120 mya, monocots and dicots about 170-235 mya ago, insects and mammals >640 mya, and plants and animals perhaps one billion years ago. If evolution is depicted as a tree, and extant species as terminal leaves on that tree, it is clear that we have examined only a few of those leaves, gaining only a fragmentary impression of what is and what once was. As sequencing methodology advances, we will almost surely see that some species emphasize specific mechanisms of resistance to the relative exclusion of others. Witness Drosophila with its single immunologically active Toll receptor, Arabidopsis with its dozens of host sensors, and rice with its hundreds. Only recently we were surprised to discover the independent evolution of a system of recombinatorial receptors mediating adaptive immunity in the jawless fishes and the presence of a predicted microbial sensor in wheat with a structure that does not appear in rice (last common ancestor: a mere 50-70 mya). Many similar surprises likely await the examination of other "leaves."

In the future, researchers will increasingly focus on harnessing basic knowledge about host sensors to advance plant and animal health. A diverse array of conserved signatures from pathogenic microbes will likely be discovered. Many of these will almost certainly act as binding partners for the large class of predicted orphan host sensors present in agronomically important crops. Some will likely serve as new drug targets to control deadly groups of bacteria for which there are currently no effective treatments. Characterization of new host sensors will pave the way to interspecific and intergeneric transfer between plants of engineered receptors that confer resistance to a variety of pathogens. The effectiveness of this approach has already been demonstrated by the transfer of Xa21 and engineered derivatives to cultivated rice varieties, of a stripe rust resistance gene to cultivated wheat varieties, and of Arabidopsis EFR to tobacco and tomato. In vertebrates as well, there may be room to engineer resistance. Adult chickens are remarkably indifferent to LPS. Would they be more sensitive to it and better able to resist Gram-negative infection if they expressed the mammalian version of TLR4? Are some microbes pathogenic to humans because they have managed to evade detection by human TLRs? Other manipulations may be imagined now that some of the essential building blocks of immunity have been elucidated.

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This paper is dedicated to Julius Rothstein (1830-1899) and his wife, Fanny Rothstein née Frank (1834-1911), the great, great grandparents and last common ancestors of the authors.