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 microbial and host populations. Our long-term goal is to better understand how host-microbe associations evolve as well as the consequences of these interactions 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 that shape 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 secreted siderophores and cell surface receptors, in order to scavenge this nutrient from the host. Our research indicates that this ‘battle for iron’ has been a major hotspot of host-microbe 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 antibacterial immune defenses.

EVOLUTION OF IMMUNE PROTEIN FUNCTIONS

LF_strikingLong-term coevolution of microbes and 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 the processes by which new protein functions emerge as a consequence of host-microbe associations. Our recent work focused on the mammalian-specific immune protein lactoferrin, which acquired cationic antimicrobial peptide (AMP) domains since its divergence from the related transferrin gene over 100 million years ago. Evidence of natural selection acting on these AMP domains suggests that their activity and potency have been modulated over relatively short evolutionary timespans (Barber et al., 2016). We are continuing to investigate the molecular basis by which new host and microbial protein functions evolve as well strategies to engineer the functions of existing genes.

MECHANISMS OF BACTERIAL ADAPTATION

Evolutionary conflicts at host-microbe interfaces.

Many host-associated bacteria are restricted to life in a single host species, but the mechanisms underlying this specificity are largely mysterious. We are developing new experimental systems to investigate how bacteria adapt to challenges imposed by host immunity as well as other barriers to cross-species transmission. In addition to improving our understanding of the fundamental process of evolutionary adaptation, identifying the molecular determinants of host specificity in human pathogens could reveal new avenues for infectious disease treatment and prevention.