Saturday, May 4, 2024
5/4/2024
PROJECT SUMMARY / ABSTRACT Understanding how intracellular pathogens survive in their host cells has led to better management/pre- vention of their diseases, as well as discovery of fundamental biology. In this application, we aim to start elucidating the strategies and mechanisms used by one of the commonest fungal pathogens, Cryptococcus neoformans, to survive inside macrophages. The treatment of cryptococcal disease is subpar, resulting in mor- talities that range from 20% to almost 90%, depending on the geographical region. The ability of this fungus to survive inside host cells is one of the main drivers of disease progression, and clinical studies show that intra- cellular survival in macrophages correlates with patient’s mortality. However, the molecular mechanisms that govern internalization and the ability to survive intracellularly are not known, hampering the development of more effective therapeutics. Our long-term goal is to understand the cellular and molecular mechanisms behind intra- cellular survival, a significant gap in knowledge in the field. Moving towards that goal, the objectives of this application are to define and characterize the cryptococcal-containing phagosome (CCP) in macrophages, and understand the role of host and fungal factors in the generation of this intracellular niche. We hypothesize that Cryptococcus actively targets Rab GTPases and phosphoinositides to delay the normal maturation of its phag- osome. This allows fungal factors, such as capsular hyaluronic acid and glucuronic acid, to modulate acidification of the CCP, resulting in a fungal permissive niche. Pro-inflammatory signals, mediated in part by Rab20 effects on phagosomal maturation, counter this fungal manipulation and prevent niche establishment. We plan to test this hypothesis by (1) defining and characterizing the intracellular niche of C. neoformans in naïve and activated macrophages; and (2) identify and explore the role of fungal factors in niche establishment. If completed, we will have identified the genetic (fungal genes), phenotypic (CCP properties) and immunological (host’s immune sta- tus) characteristics that enable Cryptococcus to live intracellularly, allowing us to pinpoint potential areas of intervention to block intracellular replication. Completion of these aims will have a positive impact in the field by generating a detailed molecular description of the strategies Cryptococcus uses to survive in macrophages and how host cells respond. Moreover, given the scarcity of well characterized intracellular survival strategies in fungi, the knowledge created here will impact the understanding and studies of other pathogenic fungi as well.
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