Flexible bacterial immunity as a strategy for widespread protection against protein threats

Abstract

How bacteria interact with their neighbors can have a large impact on community structure through cooperative measures like biofilm formation or antagonistic ones like pathogen invasion. These communications are often mediated by protein-protein interactions where a specific interaction can lead to cell survival. Effector immunity (EI) pairs are a main contributor of both competition and cooperation in dense bacterial communities, like the human microbiome. In EI pair systems, cell-modifying proteins (effectors) are injected into neighboring cells, and without the protective protein (immunity), the recipient cell’s behavior is disrupted. This action allows for specific attacks that, for some effectors, can be lethal for all except members of the same strains. As immunity proteins bind their cognate effector, protection is mediated by the reportedly strain-restricted interactions between the two proteins. However, flexibility in immunity protein binding could allow for broader protection during competition with foreign strains. We characterized an EI pair from the gut opportunistic pathogen Proteus mirabilis BB2000, IdrD-CTD and IdrE. In Chapter 2, my colleague Dr. Denise Sirias found that IdrD-CTD acts as a DNA nuclease and causes lethality when overexpressed in cells. My colleagues and I show that IdrE is its corresponding immunity protein and protects a vulnerable strain from competition. I found that IdrE binds to IdrD-CTD in vivo and in vitro. My colleagues and I used these proteins as sources to discover novel protein families that span across many bacterial phyla. Contrary to the predominant model, I then found that a member of this immunity protein family from the oral microbe Rothia dentocariosa C6B binds to and offers protection against the P. mirabilis IdrD-CTD. Combined with further biochemical analyses, our data indicate that immunity proteins can also offer protection against non-cognate effectors. In Chapter 3, I propose a white paper for flexible immunity as a broadly seen property of toxin antitoxin and effector immunity pairs. I describe other examples of flexible binding and protection between non-cognate partners in EI pairs and toxin antitoxin systems. Further probing the non-cognate interactions of other EI pairs, such as the bioinformatically-documented SUKH immunity protein family, could influence our understanding of bacterial interactions, protection, and community structure.