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Of Bugs and Beetles: 
Deadly bacteria select for immune memory in beetles

We live in a world dominated by microbes, and most organisms have had to evolve strategies to deal with both, beneficial and pathogenic microbes. For humans as well as the animals we have domesticated, vaccination is by far the most popular and effective strategy against many pathogenic microbes. Vaccination relies on immune memory: on first exposure to a pathogen, our adaptive immune system generates specific antibodies, protecting against re-infection by the same pathogen.


Immune memory in insects, on the other hand, has been a topic of controversy. Numerous lines of evidence suggest that a prior weak infection can increase insect survival after a subsequent infection, as found in vertebrates. Yet the concept of immune memory in insects (known as “priming”) has been fiercely debated because, while insects have innate immunity (e.g. a melanisation pathway, antimicrobial peptides, and phagocytic cells), they lack the ability to produce antibodies. Thus, many people believe that the immune “memory” observed in insects is just longer-lasting protection via general activation of innate immunity. However, such long-lasting general responses cannot explain all of insect immune memory, such as highly specific responses that differentiate not only between different pathogens, but even strains of the same pathogen. This specificity seems paradoxical to the traditional ideas regarding the simplicity of insect immunity. Is immune priming a distinct phenomenon in animals without adaptive immunity? This remains to be proved. Meanwhile, many open questions remain: what is the evolutionary origin of immune memory? What are the costs and benefits of priming vs. innate resistance?


These questions have bothered Imroze Khan for a while. For his postdoctoral research, Khan, a former postdoctoral fellow in Deepa Agashe’s lab at the National Centre for Biological Sciences (NCBS), decided to test conditions under which immune priming could evolve in laboratory insect populations. He generated a large outbred population of flour beetles (Tribolium castaneum) collected from grain warehouses across India. This population had ample genetic diversity and reflected naturally occurring variation in immune function, making it ideal for experimental evolution in the laboratory. With Arun Prakash, a junior research fellow in the lab, Khan infected the beetles with a high dose of their natural bacterial pathogen, Bacillus thuringiensis (Bt), which killed over half the beetles. In each generation, Prakash and Khan infected thousands of adult beetles, allowing only resistant individuals to survive and reproduce. To provide an opportunity for the evolution of immune memory, they injected some beetle populations with dead Bt cells a few days before the live Bt infection. Populations were either exposed to the Bt antigen once (no priming opportunity; direct exposure to a single high-dose of infection), or twice (opportunity for priming before infection).


The results were intriguing. Beetles showed rapid evolution of either innate resistance or immune memory within 10 generations, whereas control populations that were injected only with buffer solution did not show any change in immune function. The two immune strategies were not only highly repeatable (i.e. evolved independently in many populations), but also mutually exclusive. In populations that encountered Bt twice per generation, beetles developed higher innate resistance effective against multiple Bt strains. In contrast, immune priming evolved only in beetle populations injected with a single high dose of infection each generation. Unlike resistance, this immune memory was specific to the Bt strain used in the evolution experiment; a feature that broadly resembles vertebrate adaptive immunity.


These results were reported in a recent paper published in the Proceedings of the Royal Society of London. This is the first demonstration of the rapid evolution of immune priming in an insect, offering a rare opportunity to understand the mechanisms underlying the evolution of immune memory vs. resistance. The authors speculate that the two immune strategies involve expressions of different immune response pathways, and are testing this possibility by analyzing the transcriptomes (i.e. total gene expression) of evolved beetles from different populations.


The mutually exclusive evolution of priming and resistance also raises new questions about the evolution of immune function. For instance, why did priming evolve only in some populations and not others? For one, improved innate resistance is beneficial because it dramatically improves survival after infection (up to 90%). Having said that, innate resistance is not specific and may incur large physiological costs if it is always “on”. The authors suggest that under repeated pathogen exposure, the benefits of improved innate resistance exceed the maintenance costs of immunity. However, when the pathogen is encountered relatively infrequently, immune memory may be more favourable, because it is specific and can be induced only when necessary. Khan – now an Assistant Professor at Ashoka University – plans to test these ideas in collaboration with the Agashe lab.


As the debate on insect immune memory intensifies, these new results provide a breakthrough for our understanding of insect immunity, raising exciting possibilities vis-a-vis the costs, mechanisms, and evolutionary impacts of immune function. While it is now clear that insect immune memory is an important evolutionary strategy, only future research can unravel the mystery of how alternative vertebrate-like memory can be achieved in insects. Regardless of the mechanisms underlying insect immune memory, the rapid evolution of diverse immune responses calls for a paradigm shift in our ideas about the simplicity of invertebrate immunology.


Experimental evolution of insect immune memory vs. pathogen resistance. Proceedings of the Royal Society of London B. Published online Dec 2017. DOI: 10.1098/rspb.2017.1583

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