Although potent antifungal agents are currently available, invasive fungal infections continue to cause highly prevalent disease and death, especially in our patients with defective immune systems. AIDS, organ transplantation, and more aggressive cancer treatments all contribute to ever-expanding patient groups who are at risk for these serious infections. In addition to finding new targets for antifungal drugs, we need to better understand the ways in which the host interacts with invading fungal cells. The next horizons in advancing antifungal therapy will likely include host immune modulation in addition to killing the infecting microorganism. In this proposal, we will study both of these aspects of te infectious process, using insights that we have gained through our experiments with a central signal transduction pathway in the human fungal pathogen Cryptococcus neoformans (Cn). We began studying the Cn Rim signaling pathway as a regulator of surface capsule expression and fungal cell fitness. A fungal-specific process, Rim signaling contains several elements that are novel targets for antifungal therapy. Indeed, the Rim101 transcription factor, the main effector protein of this pathway, is required for microbial growth under host-relevant conditions. Therefore, a rim101 mutant cannot survive within the infected host. Paradoxically, while these attenuated Rim pathway mutants are rapidly cleared by the host, they simultaneously induce a dramatic hyper-inflammatory response, leading to excessive host damage and premature host death. We hypothesize that this dysfunctional host-pathogen interaction results from several factors, including: (1) failed immune evasion by the fungus; (2) excessive innate immune activation; and (3) poor host immune recovery from infection. To pursue this set of hypotheses, we propose complementary genetic, bioinformatic, and immunologic experiments. Our detailed exploration of Cn Rim signaling will define basic principles of microbial adaptation and immune evasion within the host. Additionally, we will characterize ways in which innate immune priming determines the nature of subsequent host responses to this microorganism. In this way, we will develop foundations for rational microbe- and host-based therapies for life-threatening infectious diseases.
Cryptococcus neoformans is a common environmental fungus that infects most people at some point during their life. Typically, life-threatening disease due t this microorganism only occurs in patients with AIDS and other immunocompromising conditions. However, recent data from the CDC estimates more than one million cases of C. neoformans infection each year, most of these resulting in patient death. We have recently identified proteins and pathways that are involved in the pathogenesis of human fungal infections, such as those due to C. neoformans. To recognize the host and adapt to this hostile environment, this organism uses the Rim/Pac signaling pathway, a series of cascading protein interactions within the fungal cell. Targeted mutation of any of the Rim/Pac genes results in fungal strains that cannot survive well in the presence of host-derived growth conditions. Interestingly, rim pathway mutants also fail to appropriately evade host immune recognition. Therefore, as the infected host is rapidly clearing these attenuated strains, the mutant fungal cells elicit an overly dramatic immune response that can severely damage the host. We will use a combination of genetic, bioinformatics, and immunological experiments to probe this interface between the microbe and host. In this way, we will define novel mechanisms of host recognition of invading microorganisms, as well as the microbial response to specific host signals. Since this signaling process is only found in fungi, the Rim/Pac pathway represents a novel way to specifically target pathogenic fungal cells, sparing host toxicity.
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