Hutch News

She's from the mold school

July 18, 2002
Dr. Kieren Marr reaches into a lab incubator.

Dr. Kieren Marr reaches into a lab incubator to remove a petri plate containing a growing sample of the Aspergillus mold.

Photo by Clay Eals

It's hard to believe that inhaling a warm spring breeze or digging in the garden can seriously endanger your health.

Yet much of the air and ground around us teems with invisible microbes that, while harmless to the healthy, may be mortal enemies of those with seriously damaged immune systems.

Just as most burglars never gain entry to a home with locked doors and windows, many disease-causing bugs never make it over the threshold of a healthy immune system. Standard security measures like a normal white-cell blood count and an intact gastrointestinal tract are enough to keep most opportunistic pathogens at bay.

But when basic defenses go down - as in the case of a bone-marrow or stem-cell transplant - many immune-system portals are left ajar, inviting typically harmless bugs to cause hard-to-treat, potentially life-threatening diseases.

Among the most dangerous is the class of fungi known as molds, which travel as airborne spores indoors and out. Their ubiquity is apparent to anyone who has seen them propagate in fuzzy patches on a loaf of bread past its prime.

Particularly worrisome, these usually benign creatures' incidence in transplant wards is on the rise, said Dr. Kieren Marr, an infectious-disease specialist in the Clinical Research Division.

Largest-ever study

Marr and colleagues recently published results of the largest-ever study of mold infections in patients who underwent transplants at Fred Hutchinson between 1985 and 1999.

Their findings, which parallel those of other transplant centers, reveal that mold infections, particularly those caused by an organism called Aspergillus fumigatus, have increased steadily over the last decade.

Marr's challenge is to identify characteristics that put patients at highest risk for developing mold infections and to understand the Jekyll-Hyde behavior of Aspergillus, which causes harm to the immunocompromised while sparing the healthy.

Fungal infections, Marr said, are among the worst potential complications of transplantation and can be more difficult to treat than diseases caused by bacteria or viruses. The one-year survival rate for patients with mold infections is about 20 percent.

"Fungi are like us," she said. "So the drugs used to treat them also damage our own tissue. Also, we don't have the ability to catch these kinds of infections early and often don't find them until pneumonia has set in, when outcomes are poor."

The changing landscape of infectious organisms in the transplant ward has less to do with the prevalence of microbes in the environment than with advances in how infections are treated, Marr said.

"Really, we are victims of our own success," she said. "It used to be that bacterial infections were problematic, but good antibiotics now prevent and treat them. That allowed viruses like cytomegalovirus (CMV) to become a more serious risk factor for transplantation.

"Thanks to studies by Dr. Michael Boeckh (an investigator in the Clinical Research Division) and others, we've made enormous progress using new antiviral drugs to treat CMV infection. The biggest problems now are fungal infections."

What's happening, Marr said, is that keeping one infectious organism at bay simply opens up the body to the next pathogen in line.

"All of these infections can occur, but what we see in the patients evolves based on whichever type of organism we treated yesterday," she said. "The hardest question to answer is, what will be the organism that comes forth next?"

Among the fungal pathogens that plague transplant patients, over the last decade there has been a shift from yeasts to molds.

Deaths caused by the yeast Candida albicans have declined in transplant patients thanks to prophylactic treatment with fluconazole, a potent antifungal medication. The drug is ineffective, however, against molds such as Aspergillus. Marr said elimination of invasive Candida infections likely has created an opportunity for Aspergillus and other molds to thrive.

Such mold infections typically occur with late onset, from 50 to more than 100 days post-transplant. The delayed timing of infection is probably due to the fact that ever more patients survive transplantation despite complications that were formerly fatal. These include graft-vs.-host disease (GVHD), a condition in which donor immune cells react against the patient's own tissue. Patients with GVHD must take immunosuppressive drugs that compromise the body's ability to fight infection.

"Thanks to advances in transplantation, we now have more and more people surviving their disease, but that brings with it more cases of patients surviving with severe GVHD, which is a risk factor for mold infections."

Prompted by the serious nature of such infections, Marr has turned her attention to identifying the genes and cellular pathways that enable Aspergillus to cause disease in immunocompro-mised patients.

Aspergillus is different from what Marr describes as "real pathogens" like the bacterium that causes cholera.

"Organisms like those that cause cholera would cause disease in healthy people," she said. "They have 'big-bang' toxins. It's obvious that these fungi don't have weapons like that, because you find Aspergillus spores in the airways of most healthy individuals."

Ability to escape host defenses

Instead, the real virulence of opportunistic pathogens like Aspergillus is related to their ability to escape host defenses, which function well in healthy individuals.

"If you chip away at these defenses, a person becomes vulnerable," she said.

A clue to what may be responsible for Aspergillus fumigatus' virulence may lie in a mutant version of the fungus that lacks its normal pigmentation. "The pigmentless mutant is the only form of the bug ever found to be incapable of causing disease," Marr said. "That is a strong hint that either the pigments themselves or something related to pigment production is associated with the ability to cause disease."

One possibility is that pigment production is associated with the organism's ability to shift between its two developmental stages: spores and a filamentous form called hyphae. Airborne spores settle in nasal passages and airways, and in immunocompromised patients they can shift to filamentous growth to cause invasive disease.

To identify the genes critical to this developmental pathway, Marr has worked with Dr. Jeff Delrow, manager of the DNA microarray facility, to construct gene chips that will let her compare the expression of Aspergillus developmental genes in normal strains and in the pigmentless mutants.

While molds may receive most attention for their effects on the immunocompromised, Marr noted that the bugs have been implicated in other conditions that affect large segments of the population, including allergic reactions like asthma and sinusitis.

And there may be many other as-yet undiscovered health complications caused by these ubiquitous microbes.

"There has been a lot of hype lately about the potential health impact of environmental exposure to molds, such as in the case of 'sick building' syndromes," she said.

"Discovering whether molds are associated with diseases of unknown causation will keep scientists busy for the next several decades."

 

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