The temporal dynamics of translation efficiency during an innate immune response

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PROJECT SUMMARY/ABSTRACT The induction of an innate immune response to bacterial infection is a complex process that requires the rapid and efficient conversion of the microbial detection event into a set of functional defense responses. Thousands of genes can become differentially regulated at the transcriptional level in the early stages of this process, setting off the suite of physiological shifts that prepare the host to respond to the infection. However, there is currently a large gap in our knowledge concerning the dynamics of the progression of these messages into functional proteins during an innate immune response. Recent evidence suggests that regulatory components responsible for guiding and preparing transcripts to attach to ribosomes for translation can introduce selective bias into the translation process. Thus, translation initiation represents a potential source of substantial immunological variation from individual to individual. In particular, across a large swath of taxa from insects to mammals, previous exposure to microbes can impart a form of memory to future innate immune responses, resulting in heightened resistance and survival outcomes upon subsequent infection. Our recent data from primed Tribolium castaneum flour beetles suggests a role for shifts in translation initiation dynamics in the priming phenotype, resembling translation initiation shifts recently observed in mammalian macrophages trained against microbial elicitors. These parallel innate immune memory phenomena challenge our canonical understanding of the functional and evolutionary divide between innate and adaptive immune systems, and demand further investigation into the role of translation initiation biases in generating defense phenotypes. The first aim of this proposal is to investigate the fidelity of translation initiation to transcriptional shifts observed during the innate immune response induced by bacterial infection over time. We will determine the role of translation initiation in facilitating biases in translation efficiency using ribosomal profiling (Ribo-Seq) in the powerful model organism T. castaneum infected with Bacillus thuringiensis, taking advantage of the tight evolutionary conservation of translation initiation machinery from yeast to humans. The second aim of this project is to manipulate the expression of translation initiation factors using RNAi-mediated knockdown to investigate the role of translation efficiency in generating variation in innate defense and memory phenotypes. Our long-term goal is to understand the underlying mechanisms of variation in the dynamics of innate immune responses so that more effective approaches can be designed for the treatment of sepsis and immuno- pathological conditions. By investigating the dynamics of translation initiation during the early phase of bacterial infection and its contribution to variation in innate immune phenotypes, we will be developing a promising frontier for the treatment of bacterial infections and immunopathology that is both conceptually exciting and clinically relevant.