Learning Cut-and-Paste Rules to Fight a Deadly Fungus

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Learning Cut-and-Paste Rules to Fight a Deadly Fungus

UCSF Today - San Francisco,CA

By Tompa

http://pub.ucsf.edu/today/cache/feature/200705113.html

Like many other normally harmless microbes, the yeast Candida

albicans is always with us — on the skin and in the gut, for

instance.

But when conditions favor it, Candida may grow conspicuous. For

normally healthy people, the result may be vaginal infection, some

form of diaper rash or oral thrush. These infections are

uncomfortable, but rarely present serious risks.

For those with weak immune systems, however, Candida infection is a

different story. For example, patients undergoing treatment for

organ transplants or cancer cannot easily fight Candida growth, and

Candida infection leading to meningitis among newborn premature

infants is a growing concern.

When the single-celled fungus gains the upper hand, it changes its

itinerary. A multitude of cells invade the bloodstream. They travel

throughout the body and can infect many organs. This scenario is

known as systemic, or invasive, candidiasis. It can be fatal if not

treated early.

UCSF Quinn Mitrovich, PhD, a UCSF postdoctoral scientist, is

investigating the molecular nuts and bolts of this pathogenic

adaptation. He wants to know what allows Candida to enter the

bloodstream and bodily environs where it normally does not roam.

Through his work in the labs of developmental biologist

Guthrie, PhD, and microbiologist , PhD, Mitrovich

hopes to find ways to block these molecular events and halt raging

Candida infections.

The vagina, the bloodstream and the brain are quite different

environments. It is unusual for a single pathogenic microbe to adapt

so quickly to such different surroundings, Mitrovich explains. Yet

Candida is able to invade virtually every part of the body once

systemic candidiasis sets in — leaving researchers mystified.

Rapid Splicing When Time is of the Essence

Some scientists have begun looking at changes in Candida gene

expression during different stages of infection. An expressed gene

is one that is switched on. During gene expression, the genetic code

is transcribed into an RNA messenger molecule. The RNA encodes a

complementary message that is translated into protein within

factories inside each living cell.

A trademark of any pathogen is the ability to change its gene

expression in response to the host environment in order to elude the

host immune response. But the fact that Candida is able to invade

every human organ " means that it is very adaptive, " says

Mitrovich. " We speculate that this involves multiple changes in gene

expression. "

There's a good chance the quick-change artistry of Candida is due to

a biological phenomenon known as RNA splicing, Mitrovich says.

Similar to the way an audio or video engineer cuts and pastes

interview footage to obtain the desired presentation, Candida

manipulates its own genetic blueprint. It cuts and pastes RNA to

quickly change the proteins it makes.

The impetus for Mitrovich's work came from observations made in

another yeast species, Saccharomyces cerevisiae — brewer's yeast. It

does not cause disease. But of interest to those who study its

sometimes fearsome fungal brethren, scientists working in Guthrie's

lab found that RNA splicing in S. cerevisiae is highly controlled,

and that it occurs very quickly in response to different

environmental conditions.

" The production of new RNA can be slow, whereas the splicing

responses we see in S. cerevisiae happen very rapidly — within a few

minutes of exposure to a new environment, " Mitrovich says.

Guthrie, and Mitrovich wondered whether something similar

happens when the pathogenic yeast Candida is exposed to different

environments in the human body. " Splicing is a way for an organism

to be poised to adapt — to move into a new environment quickly, "

Mitrovich says.

Secrets of Shape Shifting

While scientists do not yet understand the tricks Candida uses to

invade its host, they do know that this yeast takes on many

different physical forms.

For example, it can exist in a " yeast " form, in which each cell is

round and separate from other cells. It can also exist in a " hyphal "

form, in which cells are elongated and attached to each other. There

also are different physical forms associated with stages of mating.

The ability of Candida to sample all these different forms is

thought to be important in its success as an infectious pathogen.

Mitrovich is surveying the entire complement of Candida genes — its

genome — to find out how RNA splicing is involved as Candida changes

from one form to another. He has already seen intriguing changes in

the splicing of a few specific genes when Candida switches from one

mating form to another.

Mitrovich hopes eventually to identify master regulators of splicing

responses in Candida. If Candida is indeed using splicing regulation

as a means to survive in the human body, then targeting the key

proteins involved could be a new avenue for better drug therapies to

fight infection.