Exploring how the innate immune system shapes the adaptation of emergent and pre-emergent opportunistic pathogens

About This Grant

Infectious diseases caused by bacterial pathogens remain a major threat to human health. A wealth of studies have established the importance of host-pathogen interactions. However, the transition of environmental strains to become commensals or pathogens remains largely underexplored. In part, this is because the evolutionary forces that facilitate the transition of a strain from the environment to one that could establish an early stage infection are complex. Importantly, common features mark the transition: Strains must initially infect patients before causing disease. In a healthy individual, the innate immune system presents a sophisticated and multi-layered set of barriers to the establishment of infections such as bacteremias. Overcoming the multifaceted and robust barriers of the innate immune system requires a potential pathogen to adapt to these challenges. While there are many excellent studies on individual host-pathogen interactions, there is less consensus on how specific attributes of the innate immune response are integrated to eliminate specific strains and how a compromised innate immune system might shape the adaptive evolutionary landscape to allow for pathogen emergence. To investigate microbial emergence and adaptation, we are taking a high-throughput approach to the interactions of environmental bacteria with an in vitro model innate immune system that is comprised of the humoral and cellular components. Utilizing a unified experimental framework with a model innate immune system, we aim to identify how the humoral and cellular components of the innate immune response eliminate diverse environmental microbes (Aim 1) and how these microbes adapt in response (Aim 2). This combined approach, leveraging microfluidics, in vitro experimental evolution, and genomic/phenotypic characterization, will identify traits required for the environmental-to-pathogen/commensal transition and how a compromised innate immune system might shape their evolution. This knowledge can be harnessed for pre-emergent pathogen biosurveillance, improved early diagnostics, and potentially, the development of immunomodulatory therapies.