Microsporidia are the earliest diverging fungi and obligate intracellular pathogens that can specifically infect a diverse range of different hosts, including a number of species that cause death and disease in humans and agriculturally important animal species.
Microsporidia also have the smallest eukaryotic genomes, with some species having only 2000 protein coding genes. Microsporidia have rapidly evolved, containing only ~800 proteins that are conserved outside of microsporidia. Despite this limited coding potential, microsporidia have an unparalleled ability as a phylum to infect a large number of different hosts. These features make them a powerful model in which to study pathogen evolution.
Despite the ubiquitous nature of these pathogens, very little is known about them. To understand how microsporidia are able to successfully infect and proliferate inside of their hosts, the Reinke lab is taking advantage of several naturally occurring microsporidia species that infect experimentally tractable nematodes. Using this system, we will be able to make discoveries that so far have not been possible.
Function of microsporidia host-exposed proteins
We previously employed a location-based proteomics technique (Reinke et al, Science Advances, 2017) to identify potential pathogen effector proteins that are localized within host intestinal cells, providing the first large-scale experimental localization of pathogen proteins inside cells of a living animal host (Reinke et al, Nature Communications, 2017).
The experimentally identified host-exposed microsporidia repertoire is enriched for proteins containing targeting signals, rapidly evolving proteins, and greatly expanded gene families. We predict that each Nematocida species contains ~700 proteins that come in contact with host molecules. We will take biochemical approaches to study the function of these proteins with the goal of understanding how they are being used by the pathogen to be able to efficiently infect host cells.
Mechanisms of RESISTANCE against microsporidia
Understanding the genetic basis of pathogen resistance is important for determining both the factors that the host uses to defend against the pathogen and the host factors that the pathogen is exploiting for its own benefit.
Nematocida microsporidia and Caenorhabditis nematodes provides a powerful system in which to address these questions. This system has three critical advantages for studying pathogen evolution. 1) It is a natural system of evolutionary related coevolved pathogens that infect hosts that are genetically and biochemically tractable. 2) All infection stages can be studied entirely in vivo allowing physiologically relevant evolutionary studies not possible in other animal systems. 3) The related parasites exhibit different phenotypes including different host ranges and tissue tropisms.
My lab will approach this problem by performing screens to identify mutations that alter host resistance. We are also working on identifying naturally occurring mutations that are responsible for pathogen resistance. In addition to genetic mechanisms of resistance, we are also studying an epigenetic, transgenerational form of immunity.
Together this work will reveal how hosts evolve resistance against multiple related pathogen species and the extent to which pathogens influence host genome evolution.