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Evolutionary Insights into Innate Immunity to Bacterial Pathogens

  • Author(s): Margolis, Shally Rebecca
  • Advisor(s): Vance, Russell E
  • et al.
Abstract

All living organisms have some form of innate immunity, which serves as the first line of defense against pathogen infection. Immune systems are under substantial selective pressure given that pathogens that can evade these defenses will be more evolutionarily successful; therefore studying the evolution of immune systems can inform our knowledge of both host-pathogen interactions and evolutionary forces. Examining immune systems in a variety of extant species can shed light on fundamental properties of innate immunity and also important ways in which mechanisms of immunity diverge under different selective pressures. In this thesis I will explore two innate immune pathways and discuss the evolutionary histories that may have led to their current state.

In chapter 1, I review the literature on the origin and functions of the cGAS-STING pathway. In mammals, this pathway is crucial for sensing viral infection and initiating an anti-viral interferon response. cGAS and STING are highly conserved genes that originated in bacteria and are present in most animals. By contrast, interferons only emerged in vertebrates; thus, the function of STING in invertebrates was unclear. In chapter 2, I introduce the model cnidarian, Nematostella vectensis, and describe my attempts to examine the ancestral functions of the cGAS-STING pathway. Here, I use the STING ligand 2′3′-cGAMP and RNA-sequencing to probe the consequences of pathway activation, and find a conserved role in immunity via the induction of both anti-viral and anti-bacterial genes. I then perform a series of knockdown experiments and discover a role for the conserved transcription factor NF-κB in specifically inducing anti-bacterial genes downstream of 2′3′-cGAMP. I go on to characterize the protein product of one of the putative anti-bacterial genes and demonstrate its conserved anti-bacterial activity. This work describes an unexpected role of a 2′3′-cGAMP sensing pathway in anti-bacterial immunity, and further implications of this work are discussed in chapter 3.

In chapter 4, I pivot to a different model system to understand the more recent evolution of the NAIP-NLRC4 inflammasome in mammals. Here I describe redundant outputs downstream of Legionella pneumophila detection by NAIP–NLRC4, either of which is sufficient for pathogen clearance. I speculate that redundancy is an important safeguard against pathogen immune evasion. Overall, this thesis expands our knowledge of how innate immune systems evolve.

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