Evolutionary Design Principles of Innate Immunity

Innate immunity is the mammalian host’s first (and essential!) line of immune defense against infection. It faces the daunting task of recognizing and defending against the wide world of pathogens, including viruses, with a limited set of defense proteins.

One of the most difficult challenges that the innate immune system faces is an evolutionary problem. Unlike adaptive immunity, innate immune defenses are invariant within an individual and are therefore limited to two alleles of a small handful of defense proteins, yet they are responsible for detecting the same immense array of viruses. Even worse, their viral targets have massive evolutionary potential and can rapidly evolve to escape innate immune defense. In response, innate immune proteins evolve rapidly (for a mammalian host, at least) to select counter-mutations that regain defense, which viruses evolve to escape again, in an endlessly repeating evolutionary arms race. These arms races are visible in the evolutionary record, where the interface between innate immune proteins and their viral targets shows massive variation and rapid evolution.

Viruses evolve escape mutations from innate immune defenses, driving counter-adaptation of innate immune proteins, in recurring cycles of evolutionary arms races
Viruses evolve escape mutations from innate immune defenses, driving counter-adaptation of innate immune proteins, in recurring cycles of evolutionary arms races

How can innate immune proteins possibly compete in these arms races, given that viruses evolve so much faster than their mammalian hosts? What strategies might allow for temporary or even long-term victory? To answer these fundamental questions, we dissect the evolutionary landscapes (the fitness of accessible sequence space around an extant protein) of innate immune proteins and their viral targets to map the possible evolutionary outcomes. We probe the biophysical features that make such landscapes possible, and we use the incredibly rich data to gain mechanistic insight.

An evolutionary landscape describes the fitness consequences of sequence space around an extant protein: which mutations, and how many of them, confer gains or loss in antiviral or viral protein function
An evolutionary landscape describes the fitness consequences of sequence space around an extant protein: which mutations, and how many of them, confer gains or loss in antiviral or viral protein function.

 

Biochemical mechanisms of pathogen recognition

We also aim to understand how innate immune proteins directly engage their viral targets, a problem that has often been difficult to solve through traditional crystallographic methods and remains a major gap in the field.

We use a variety of tools to resolve these interfaces, including evolutionary signatures and experimentally determined fitness landscapes. Our bioinformatic and experimental datasets allow us to identify sites of interaction, as well as site-specific biochemical rules for engagement. We analyze both the host and viral side of the interface, allowing us to identify highly potent variants of antiviral proteins as well as highly susceptible viral variants, as promising candidates for structural and mechanistic studies.

Our ultimate goal is to understand how innate immune defenses function to successfully defend the host from viral infection, and the viral Achille’s heels that these systems are keyed on.