Induction of Fungal Dormancy as a Potential Disease Therapy

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Valley Fever disease is initiated when an arthroconidium, the asexual soil-borne spore of Coccidioides spp. is inhaled into the host lung. In both resistant and susceptible hosts the disease cycle produces endospore-containing spherules, but only in a susceptible host are endospores released to repeat the cycle. In a resistant host an important aspect of the resolution of illness is that the fungus ceases to proliferate, enters a state of quiescence, and the host recovers from the infection. In spite of patient recovery, the pathogen remains present in the host indefinitely with the potential for re-activation if the host's immune system becomes compromised. This project will explore the genetic basis of quiescence in Coccidioides spp. The genes that regulate this process are novel targets for development of new therapeutics to treat coccidioidomycosis. To identify these genes, objective one will develop an in vitro profile of gene expression during all stages of growth of Coccidioides spp. using the powerful method of serial analysis of gene expression (SAGE). Gene expression during the saprobic stages of mycelial growth, and arthroconidium development will be compared to expression during several stages of the disease cycle from early active growth, to production of mature spherules that mimic the quiescent in vivo stage. Objective two will use SAGE to profile fungal gene expression in vivo, in both susceptible and resistant mice for comparison to in vitro patterns. Genes differentially expressed in resistant mice may be involved in fungal entry into, or maintenance of, the quiescent state. Objective three will test the functional importance of quiescence genes, by creation of gene replacement mutants in Coccidioides. Mutants will be assayed for infectious phase growth, both in vitro and in vivo, in resistant, susceptible and vaccinated mice. Mutants may show reduced virulence by being more susceptible to host defenses if quiescence is important for fungal survival, or may show increased virulence if the quiescent state is an important component of host control of infection.