Research

Animals and bacteria encode a variety of molecules to sense, manipulate, and defend against each another. The outcome of these exchanges can mean the difference between peaceful coexistence and deadly infection, creating the potential for evolutionary conflict between microbes and hosts. Our long-term goal is to determine how host-microbe molecular interactions evolve and the implications for adaptation, immunity, and disease. Below are a few examples of current project areas in the lab.

HOST-MICROBE EVOLUTIONARY CONFLICTS

Infectious diseases are a potent force of natural selection. Repeated bouts of adaptation at host-pathogen protein interfaces can lead to molecular arms races, providing some of the most dramatic examples of rapid evolution observed in nature. One of our major goals is to understand the underlying mechanisms and consequences of such evolutionary conflicts.

Rapid evolution at the transferrin-TbpA binding interface.

Recently we have been studying interactions between bacteria and primates relating to the essential micronutrient iron. In addition to dedicated immune defenses, the sequestration of iron by host proteins provides a potent barrier to infection termed nutritional immunity. Microbes in turn deploy dedicated iron acquisition factors, including siderophores and cell surface receptors, in order to steal this nutrient from the host. Our research suggests that this ‘battle for iron’ has been a major hotspot of host-pathogen evolutionary conflict during millions of years of primate divergence, and even in modern human populations (Barber & Elde, 2014). We are further expanding this work to investigate evolutionary conflicts in relation to other host innate defenses against bacteria.

EVOLUTION OF NEW PROTEIN FUNCTIONS

LF_strikingLong-term evolution of pathogens and their hosts has produced an array of remarkable biological innovations including adaptive immunity in vertebrates as well as CRISPR-Cas defense systems in bacteria and archaea. We are exploring how new protein functions emerge as a consequence of host-microbe interactions. Our recent work focused on the mammalian-specific immune protein lactoferrin, which acquired cationic antimicrobial peptide (AMP) domains since its divergence from its paralog transferrin. Evidence of natural selection acting on these AMPs suggests that their activity and potency have been modulated over relatively short evolutionary timespans (Barber et al., 2016). In the future we will continue to investigate the molecular basis by which new host and microbial protein functions evolve as well strategies to modify the functions of existing genes.

MICROBIAL EVOLUTION

Evolutionary conflicts at host-microbe interfaces.

Many bacteria are restricted to life in a single host species, but the genetic and molecular mechanisms underlying this specificity are largely mysterious. We are developing systems to investigate how bacteria adapt to challenges imposed by host immunity and genetic diversity. Understanding the molecular basis of host specificity in human pathogens could reveal new avenues for infectious disease treatment and prevention.