Maintaining protein homeostasis (proteostasis) after exposure to chemical, physical or microbial stressors is critical for organismal survival. It relies on complex cellular regulatory networks that include two major interconnected proteolytic degradation pathways: the ubiquitin-proteasome system (UPS) and the autophagy lysosome (autophagy) system. Genetic predispositions, aging, infectious agents and abiotic environmental factors, can all lead to dysregulation of these two pathways which underpins the pathobiology of numerous infectious (e.g. HIV), neurodegenerative (e.g. Alzheimer's disease), chronic inflammatory (e.g. inflammatory bowel diseases [IBD]), metabolic syndrome associated diseases (e.g. type II diabetes) and cancers. Microsporidia, are a group of highly diverse obligate intracellular pathogens, infecting most animal lineages including economically and ecologically important species. Several species can infect humans and represent a well-established threat to immunocompromised patients (e.g. HIV-AIDS, organ transplant recipients). Moreover, recent studies have also shown that asymptomatic Microsporidia infections are more common in healthy immune-competent individuals than previously thought. Microsporidia infections are also associated with chronic conditions including Crohn’s disease (a form of inflammatory bowel disease – IBD) and cancer, suggesting a broader relevance to human health that requires further investigation. In the C. elegans model, both autophagy and the UPS pathways play a role in controlling Microsporidia infections through the selective autophagy pathway called Xenophagy. In the mammalian model, my analyses of the unpublished results data from Robert P. Hirt’s lab have shown the upregulation of several autophagy and UPS related genes in mammalian cells infected by the Microsporidia suggesting that proteostasis could be perturbed Microsporidia infection in mammalian organisms too.
Given the lack of effective treatments, the common occurrence of Microsporidia infection and the potential impact on host proteostasis, obtaining a better understanding of the molecular interactions between Microsporidia and their mammalian hosts is of increasing importance. Therefore, the objectives of the project were to investigate mammalian cells proteostasis pathways interplay with microsporidia infection and compare it with knowledge from the C. elegans model.
Our results show that, as in the C. elegans model, proteostasis in involved in in the response to Microsporidia infection. We detected a mild increase in autophagy flux at various time point post infection as well as a targeting of the parasite with ubiquitin, suggesting that it could be part of the host cell innate immune response. However, in mammalian cells Microsporidia seems to have developed a way to escape that mechanism and even use it to divert nutrients from the host metabolism to promote their own proliferation and eventual differentiation into the infectious spore stage.
