The Barber lab seeks to understand how evolutionary processes shape host defenses against infectious microbes. We focus primarily on molecular interactions between vertebrates and pathogenic bacteria, integrating approaches from genetics, biochemistry, microbiology, and cell biology. Below are some examples of current project areas in our lab.
HOST-MICROBE EVOLUTIONARY CONFLICTS
Infectious diseases are a potent force of natural selection. Repeated episodes of adaptation at host-microbe interfaces can lead to molecular ‘arms races,’ providing some of the most dramatic examples of rapid evolution observed in nature. Our lab is working to identify biological interfaces that give rise to host-pathogen conflicts and the molecular mechanisms that govern their outcome.
Previously we have studied evolutionary conflicts between bacteria and primates relating to the essential micronutrient iron. In addition to dedicated immune defenses, the sequestration of iron by host proteins provides an important 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, driving rapid diversification of proteins contributing to nutritional immunity (Barber et al., 2014, Barber et al., 2015, Choby et al. 2018). Our ongoing work indicates that bacterial-host evolutionary conflicts have been pervasive during animal evolution, involving host factors involved in microbial colonization, mucosal barrier defense, and pattern recognition receptors. We are applying a combination of computational, genetic, and molecular approaches to determine the consequences of these conflicts for defense against human bacterial pathogens.
IMMUNE PROTEIN EVOLUTION
Long-term co-evolution 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. How has the amazing complexity of the immune system evolved, and what unique activities remain to be discovered? Work by our group and collaborators recently demonstrated how interferon-stimulated GTPases have diversified in primates, leading to enhanced recognition of intracellular bacterial pathogens (Kohler et al., 2020). These findings illustrate how leveraging diversity in host immunity genes can reveal otherwise cryptic functions that are hidden through studies of humans alone. We are further investigating how host immune protein divergence shapes microbial recognition to identify new pathways to target human pathogens.
MECHANISMS OF BACTERIAL ADAPTATION
Many bacteria are restricted to life in a single host species, but the mechanisms underlying this specificity are often unclear. In addition, bacteria capable of causing disease in humans often colonize a large proportion of the populations asymptomatically as harmless commensals. These observations can be explained in part by the presence of genetic variation in bacterial and host populations. One of our emerging goals is to determine how bacteria adapt to the host environment and identify new factors that impact bacterial pathogenicity. In addition to advancing our fundamental understanding of the evolutionary process, identifying determinants of host specificity in human pathogens could reveal new avenues for infectious disease treatment and prevention.