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Summary The cell wall as a target for antifungal drug design
- Instelling
- Universiteit Utrecht (UU)
Uitwerking college VCB
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Voortgezette Celbiologie Evelien FloorThe cell wall as a target for
antifungal drug design
Mycoses
Mycosis is a fungal infection of animals, including humans. Mycoses are common and a variety of
environmental and physiological conditions can contribute to the development of fungal diseases.
When someone has a weakened immune system, it is possible for fungi you carry all day to invade
your body. Fungi need proteins to survive because amino acids consist of C-O-H-N-S. Fungi that are
located on the skin are not harmful, the skin renews, and the organisms will eventually fade away.
When the fungus gets into the body it can be very dangerous. But for many fungi the body
temperature is too high to grow in.
Tinea capitis is also called scalp ringworm by shining filtered ultraviolet light on the lesion, the fungi
fluorescence green in a darkened room. The classical appearance of ringworm is the round scaly
lesion where the rim is more inflamed and scaly than the center. Oral candidiasis is a common
infection of immunocompromised patients.
Opportunistic fungi
Three fungi that are common in the hospital:
1. Aspergillus fumigatus
2. Candida albicans
3. Cryptococcus neoformans
There are two types of fungi:
1. Pathogenic
Cause disease both in immunocompetent hosts (persons with normal immune
responses) and in immunocompromised hosts (persons whose immunity is altered
because of the presence of a debilitating disease or because of the use of
immunosuppressive drugs).
2. Opportunistic
Cause disease if the general of local immune resistance of the host is compromised.
They are only rarely pathogenic in immunocompetent hosts but can cause life-
threatening disease in immunocompromised hosts, including persons being treated
with immunosuppressive drugs (such as cancer and organ transplant patients) and
those with serious diseases such as AIDS.
Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans are all types of opportunistic
fungi.
Aspergillus fumigatus
Aspergillus fumigatus is typically found in soil and decaying organic matter, such
as compost heaps, where it plays an essential role in carbon and nitrogen
recycling. Colonies of the fungus produce from conidiophores who form spherical
conidia. Its spores are ubiquitous in the atmosphere, and everybody inhales an
estimated several hundred spores each day; typically, these are quickly eliminated
by the immune system in healthy individuals.
In immunocompromised individuals, such as organ transplant recipients and
people with AIDS or leukemia, the fungus is more likely to become pathogenic,
over-running the host's weakened defenses and causing a range of diseases
generally termed aspergillosis.
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, Voortgezette Celbiologie Evelien Floor
Candida albicans
Candida albicans is an opportunistic pathogenic yeast that does not proliferate outside the human
body. It lives on the skin and on mucosa of the gastrointestinal tract. Via the gastrointestinal tract it
can enter the bloodstream and end up in the kidney to destroy it. It can grow in blood because it
contains a lot of proteins, lipids and glucose. The infection caused by Candida species is called
candidiasis.
Candida albicans has two main morphologies: a hyphal form or yeast form. Several changes in
conditions can trigger the switch from the yeast form to the hyphal form, such as addition of serum.
The yeast-to-hypha switch is essential for virulence and fully reversible. This helps it to be infectious
because it can use the yeast form to migrate and the hyphal form to move through barriers. The
hypha are formed by germ tubes that grow out. An antifungal drug that can stop this switching will
stop infection with Candida, but there is no drug yet.
People who use antibiotics can get a fungi infection because there is an opportunity for the fungi to
grow. People with immune diseases are also sensitive for infection with Candida. Penetration of the
skin, invasive surgery, catheters and diabetes mellitus patients are also risk factors. Invasive systemic
infection in immunocompromised patients is life-threating and affects organs like the liver, kidney, or
brain.
A macrophage can phagocytose a Candida cell which then forms a phagosome. The macrophage will
try to destroy the Candida cell with a lot of enzymes, but Candida uses those proteins to grow. In the
end the Candida cell can break through the plasma membrane of the macrophage. Eventually,
eosinophils and neutrophils are needed to fight the Candida cells.
Cryptococcus neoformans
Cryptococcus neoformans is an encapsulated yeast and an obligate aerobe that can live in both plants
and animals. It is often found in the droppings of pigeons, when the droppings dry the fungus can get
into the air. C. neoformans replicates by budding.
It is difficult to produce
antifungal drugs against
C. neoformans because
of the similarity with
animal cells. They have a
lot of genes and
organelles in common,
so targeting genes can
also affect animal cells.
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