Developmental genetics and gene regulation.
Assoc. Prof. Alex Andrianopoulos
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 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 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
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.
P. marneffei hyphal cells stained with
P. marneffei hyphal cells with GFP-labelled
P. marneffei yeast cells with propidium
iodide labelled nuclei
P. marneffei conidia stained with calcofluor
infected with P. marneffei cells expressing GFP
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
- How conserved are these
developmental pathways in other organisms?
- How do these developmental programs impinge on virulence and