Tecle Laboratory Research Areas
Innate Epithelial Immune Responses
The broad goal of the Tecle lab’s research program is to investigate the mechanisms that regulate innate epithelial immune responses. Specifically, we use infection of the C. elegans intestine by its natural microsporidian pathogen as a model system. Microsporidia are fungal-related, obligate intracellular spore-forming pathogens that can cause lethal infections in humans and agriculturally relevant animals; however, little is known about the mechanisms by which microsporidia infect and trigger immune responses in their hosts.
Microsporidia infection causes a lethal intestinal infection in C. elegans, a genetically tractable and transparent host that relies solely on epithelial defense due to a lack of professional immune cells. Recent work has demonstrated that microsporidia infection results in the up-regulation of a novel and distinct gene set in the C. elegans intestine. Interestingly, this gene set is also activated by a C. elegans natural viral pathogen and has thus been termed the Intracellular Pathogen Response (IPR). Aberrant activation of the IPR, due to genetic or chemical interventions, results in resistance to intracellular pathogens, but how the IPR is initiated and regulated remains to be determined. Therefore, we seek to determine how IPR is regulated at both the intracellular and extracellular levels.
First, we are investigating an exciting connection between purine metabolism and the IPR. We have demonstrated that perturbations of purine nucleotide recycling result in IPR activation and resistance to microsporidia infection. Specifically, pnp-1 and adah-1 are repressors of the IPR. pnp-1 and adah-1 are the only C. elegans homologs of the vertebrate purine recycling enzymes purine nucleoside phosphorylase and adenosine deaminase, respectively, which have been implicated in human immunological disorders. Using genetic and biochemical approaches, we will investigate the signaling pathways these enzymes use to regulate the IPR and how cellular pools of purine nucleotides and their metabolites are sensed to initiate IPR activation.
Second, we seek to determine how extracellular glycans regulate the invasion of intestinal epithelial cells by microsporidia. Microsporidia rely solely on the non-reversible process of polar tube firing to infect host cells. The polar tube is a specialized invasion apparatus that delivers a sporoplasm into the host cell cytoplasm. The sporoplasm replicates and differentiates into the infectious spore form. The host molecules exploited to initiate this firing process are unknown; however, we have preliminary evidence that glycosaminoglycan heparan sulfate (HS) may be involved. We are pursuing this by investigating the role of specific modifications of HS in this infection process and whether HS-regulated intracellular signaling pathways are involved in IPR regulation. We plan to extend this line of inquiry to other cell surface glycans in the future.