The Levin lab studies the evolution of infectious diseases, seeking to understand how evolutionary “arms races” between hosts and pathogens dynamically shape the biology of immunity and pathogenesis. We approach these questions using a combination of high-throughput genetics, microbiology, and evolutionary genomics, focusing on the opportunistic pathogen Legionella pneumophila and its natural hosts, environmental amoebae.
Through this work, we are excited to discover general principles for how bacteria and hosts drive each others’ evolution.
Our questions include:
How do new pathogens emerge from nature?
What sorts of host-microbe or microbe-microbe interactions in the environment select for these new pathogens?
How do new mechanisms of immunity and pathogenesis evolve?
What were the origins of modern genes that mediate host-microbe interactions?
What are the molecular mechanisms of their interactions?
And how do these mechanisms change over time?
The emergence and evolution of new human pathogens
We use Legionella pneumophila as a model for how new bacterial pathogens can emerge from the wild. Legionella normally live in water and soil, where they encounter predators, such as environmental amoebae. When Legionella gets eaten by amoeba cells, they can avoid being digested by injecting effector proteins into the host cell. These effectors hijack many aspects of host cell biology, allowing the bacteria to massively replicate in the cell, explode out of the host, and continue its lifecycle.
When Legionella get inhaled by humans, they use these same effectors to infect and hijack human macrophages, causing a pneumonia-like illness called Legionnaires’ disease. Our lab seeks to understand how adaptation to amoebae has shaped Legionella’s molecular weaponry, thereby facilitating the emergence of a new pathogen.
Our lab utilizes a variety of genetic, cellular, and molecular approaches including experimental evolution and Tn-seq genetic screening to uncover how Legionella effectors hijack host cells and understand how those effectors evolve.
Dictyostelium cells infected with Legionella pneumophila release bacteria after cell lysis
Dictyostelium amoebae and the ancestry of innate immunity
In addition to their ecological roles as phagocytic predators of bacteria, amoebae are eukaryotes that possess their own “immune” pathways for microbial detection and killing. While some innate immune genes are shared between amoebae and animals, others are highly diverged, making these species ideal systems to study the origins and evolution of innate immunity.
We use Dicty amoebae as genetically tractable hosts to study the co-evolution between environmental pathogens like Legionella and free-living amoeba predators. Our studies leverage computational biology, microbiology, genetics, and molecular biology techniques to uncover and characterize novel innate immune mechanisms in amoebae and other diverse eukaryotes.
Past studies
Central line of L. pneumophila inhibits the growth of nearby L. micdadei
Battles between bacteria for environmental persistence
When Legionella are outside the amoeba cell, they need to survive and compete in a world filled with other species of bacteria. We discovered that L. pneumophila uses the molecule HGA to inhibit the growth of other Legionella species.
Surprisingly, L. pneumophila can itself be inhibited by HGA when at low-density, although they are resistant at high density. We are now investigating how this paradoxical, density-dependent resistance happens.