1. Fungal pathogenesis
---Cryptococcus neoformans
---Aspergillus fumigatus
2. Antifungal discovery
LAB MEMBERS
Xiaorong Lin (PI)
Srijana Upadhyay (research assoc.)
Nadia Chacko (postdoc)
Xiuyun Tian (postdoc)
Linqi Wang (postdoc)
Rachana Gyawali(grad student)
Bing Zhai (grad student)
Dylan Foyle (undergrad)
Angelyn Hilton (undergrad)
Gail Pereira (undergrad)
Guadalupe Torres (undergrad)
Research
1. Fungal pathogenesis
There are about 1.5 million or more fungal species on earth. Yet only few fungi can cause systemic infections in humans and animals. We are interested in the molecular mechanisms employed by these fungi that govern their virulence, and the impact of development and morphological differentiation on fungal pathogenicity. We focus on two pathogens: Aspergillus fumigatus and Cryptococcus neoformans. These two fungi belong to two different phyla in the Kingdom of Fungi and they diverged about 1 billion years ago (the earth is about 4.6 billion years old). Thus, virulence traits shared by these two divergent organisms are very likely to be conserved among other fungal pathogens.
Cryptococcus neoformans:
Cryptococcus neoformans is the causative agent for cryptococcal meningitis, which is considered an AIDS-defining condition. Cryptococcal meningitis is the most common fungal infection of the central nervous system (CNS) and the third most frequent neurological complication in AIDS patients (> 40 million people worldwide suffer from AIDS). Cryptococcal meningitis can cause up to 30% mortality in AIDS patients in Southeast and Sub-Sahara Africa.
Human infection is acquired by inhalation of airborne fungal cells from environment. Infection is typically asymptomatic, and it can be either cleared or enter a dormant, latent form. When host immunity is compromised, the dormant form can be reactivated and disseminate hematogenously to cause systemic infection with a propensity to the CNS.
Although morphologically similar to the model budding yeast Saccharomyces cerevisiae, Cryptococcus neoformans is a capsulated basidiomycetous yeast, which belongs to a totally different phylum in the fungal kingdom.
Research in our lab is focused on characterization of virulence genes than enable this fungus to cause human diseases. The image above shows a scanning electronic photograph of a mother and daughter Cryptococcus neoformans cells (left). The right panel shows a light microscopic photograph of the yeast capsule due to exclusion of Indian ink.
Aspergillus fumigatus is an ascomyceteous mold. It grows in the hyphal form and produces asexually by conidiation. The grayish green conidia are small (2-3 μm) and can lodge in the alveoli of the lungs once inhaled. Conidia can germinate to form hyphae and invade the lung tissue in host with impaired immunity. Hyphal form is the only form observed during invasive infection. The clinical manifestations of aspergillosis vary from an allergic response, aspergillomas, to severe invasive aspergillosis. Aspergillus fumigatus is a major treat to bone marrow and solid organ transplant patients worldwide. The abilities of A. fumigatus to grow rapidly on food sources with limiting nutrients, to withstand high temperatures, and to produce massive numbers of easily airborne and resilient melanized conidia, all contribute to its pathogenicity.
Research in our lab is focused on characterization of pathogenicity associated growth characteristics of this fungus. The image above shows a Aspergillus fumigatus colony on a petri-dish plate (left), its conidiophores bearing grayish green conidia (middle), and growing hyphal tips (right).
2. Antifungal discovery
The current antifungal therapies have high mortality rates (10-90%). This is partly due to the extremely limited number of classes of clinically available antifungals and the development of antifungal drug resistance (particularly to fungistatic azoles). Therefore, there is a critical need to develop alternative options for the treatment of mycoses. We investigate drugs that are potent against fungal pathogens and have novel antifungal mechanisms. We study their efficacy in treating fungal infections in animal models of mycoses. We further elucidate their mode of action through genetic and molecular techniques.