Genetics

Fungi are a large group of eukaryotic micro-organisms which are ideally suited to studying fundamental aspects of biology such as gene regulation and development. These organisms are also important from an industrial, agricultural and human health perspective where they can be either beneficial or harmful.

Fungal Pathogens

Fungal pathogens represent an increasing threat to human health and represent one of the fastest growing public health problems. Like bacteria, fungi pose a serious threat to infected individuals. This is especially true for individuals whose immune system is compromised due to (i) the direct action of other diseases such as AIDS, (ii) treatments for diseases like cancer or (iii) treatment to prevent rejection after organ transplantation. The problem is compounded by the lack of safe and effective treatment for fungal infections. Understanding the biology of these fungal pathogens is central to understanding how these fungi cause disease.

Penicillium marneffei

Penicillium marneffei is an emerging fungal pathogen endemic to South-east Asia. In response to an extrinsic stimulus (temperature), P. marneffei is capable of alternating between a hyphal and a yeast growth form, a process known as dimorphic switching.

Life cycle of P. marneffei

P. marneffei grows in the filamentous form at 25°C and in the yeast form at 37°C. At 25°C the free-living saprophyte grows vegetatively as multinucleate filamentous hyphae and can undergo asexual development (conidiation). Conidiation proceeds with the formation of an aerial stalk from a hyphal foot cell. The stalk which is produced by apical growth switches to a budding mode of division to produce uninucleate metula cells. These in turn bud at their distal tip to produce phialide cells which then bud repeatedly at their distal tip to produce asexual spores (conidia). Conidia are likely to be the infectious agent. At 37°C growth occurs as uninucleate yeast cells which divide by fission and which represent the pathogenic growth form. These yeast cells exist intracellularly in the mononuclear phagocyte system of the host. The transition from the hyphal to the yeast growth form occurs by a process known as arthroconidiation where nuclear and cellular division become tightly coupled, junctions between hyphal cells break down and uninucleate arthroconidia are liberated which grow and divide by fission. Little is known about the molecular events involved in the establishment and maintenance of the developmental states in P. marneffei and the control of the dimorphic switching process.

Research

We are studying a number of aspect of P. marneffei biology and pathogenicity and are particularly interested in understanding the molecular mechanisms which control the dimorphic switching and asexual development (conidiation) programs. We have shown that the dimorphic switching and asexual development programs share some components but not others. The current research projects aim to identify genes important in dimorphic switching using both genetic and molecular methods and to understand how this program is related to asexual development. Some of the fundamental questions we are interested in addressing are:

• What regulatory genes control this developmental switch?
• How is the differentiated state maintained?
• What genes do these regulatory genes control to alter cell shape and division?
• How conserved are these developmental pathways in other organisms?
• How do these developmental programs impinge on virulence and pathogenicity?

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