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 identify mechanisms underlying the evolution of host-microbe interactions as well as the consequences for infectious and inflammatory disease. Below are some examples of current project areas in the lab.

HOST-MICROBE EVOLUTIONARY CONFLICTS

Infectious diseases are a potent force of natural selection. Repeated episodes 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 mechanisms that shape such evolutionary conflicts.

Rapid evolution at the transferrin-TbpA binding interface.

Evidence of evolutionary conflict between primate transferrin and bacterial TbpA

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 hotspot of evolutionary conflict during millions of years of primate divergence, and even in modern human populations (Barber & Elde, 2014; Choby et al., 2018). We are continuing to investigate evolutionary conflicts between bacteria and primate hosts in relation to other antibacterial immune defenses.

IMMUNE PROTEIN EVOLUTION

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Human lactoferrin (gray) bound to bacterial inhibitor (orange)

Long-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 has focused on the mammalian-specific immune factor lactoferrin, which acquired antimicrobial function since its divergence from the related transferrin gene roughly 165 million years ago. Evidence of natural selection acting on cationic antimicrobial domains suggests that their activity and potency have been modulated over relatively short evolutionary timespans (Barber et al., 2016). We are currently investigating the origins of such immune protein functions as well as exploring strategies to engineer the activity of existing proteins.

MECHANISMS OF MICROBIAL ADAPTATION

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E. coli (photo courtesy NIAID)

Many bacteria are restricted to life in a single host species, but the mechanisms underlying this specificity are largely mysterious. In addition, numerous bacteria capable of causing disease in humans colonize a large proportion of the populations asymptomatically. One of our emerging goals is to determine the genetic and molecular basis by which bacteria adapt to the host environment and the factors that impact host-associated bacterial behavior. In addition to advancing our understanding of the fundamental process of adaptation, identifying the determinants of host specificity in human pathogens could reveal new avenues for infectious disease treatment and prevention.

 


Current research sponsors:

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Past research sponsors:

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