Fatal Frog Fungus Releases Toxicity That Disables Immune Response
October 18, 2013

Fatal Frog Fungus Releases Toxicity That Disables Immune Response

April Flowers for redOrbit.com - Your Universe Online

For the last 40 years, amphibian species around the world have been dying out. A type of chytrid fungus, Batrachochytrium dendrobatidis, was identified in 1998 as causing skin infections in frogs. Since then, it has become recognized as a leading contributor to worldwide amphibian decline.

A new study from Vanderbilt University, published in the journal Science, reports that the fungus is killing these animals by releasing a toxic factor that disables the immune response of the amphibians.

The study findings represent "a step forward in understanding a long-standing puzzle – why the amphibian immune system seems to be so inept at clearing the fungus," said Louise Rollins-Smith, PhD, associate professor of Pathology, Microbiology and Immunology.

The fungus inserts itself into the skin of the frogs, drying out a layer that the amphibians require to be hydrated, although the scientists say that the exact toxic factor, or factors, of the fungus remain a mystery. However, its ability to inhibit a wide range of cells -- including cancerous cells -- indicates that the fungus may offer new directions for the development of immunosuppressive or anti-cancer agents.

Rollins-Smith and her colleagues have been investigating the amphibian immune response to the fungus for more than a decade.

"Amphibians have excellent and complex immune systems – nearly as complex as humans – and they should be able to recognize and clear the fungus," she said.

In previous research, the team demonstrated that some frogs produce anti-microbial peptides in the skin as a first layer of defense against the fungus. Rollins-Smith said that as the fungus invades the skin, however, conventional lymphocyte (immune cell)-mediated immune response should be activated to clear it.

The current study found that recognition of the fungus by macrophage and neutrophil cells was not impaired.

"We think it's not a block at the initial recognition stage," Rollins-Smith said. "The macrophages and neutrophils can see it as a pathogen, they can eat it up, they can do their thing."

"It was a surprise that this fungus didn't appear to interfere with the first line of phagocytic defenses," she said.

The next stage of the immune response should activate the lymphocytes. Instead, the fungus exerts its toxic effects at this point. B. dendrobatidis cells and supernatants (the incubation liquid separated from the cells) impaired lymphocyte proliferation, the study showed, and induced cell death of lymphocytes from frogs, mice and humans. The researchers also found that the toxic fungal factor also inhibited the growth of cancerous mammalian cell lines.

"The immunosuppressive factors released by the amphibian chytrid fungus seem to target a conserved vulnerability shared by amphibian and mammalian lymphocytes," Rollins-Smith said. "This mechanism of cellular suppression may be unique to this fungus or shared by other fungi. That is a question that awaits further research."

Because the toxic factor was resistant to heat and proteases (enzymes that cut proteins into pieces), the scientists suggest that it is not a protein. Rather, they believe it is a component of the cell wall, because drugs that interfere with cell wall synthesis reduce its inhibitory activity and because the zoospore – an immature form of the fungus that lacks a cell wall – does not produce the factor.

The results of this study suggest the possibility that toxic factors might get into the circulation and have neurotoxic effects, as well as acting locally to inhibit the immune system.

"Fungal infection causes rapid behavioral changes – frogs become lethargic and start to crawl out of the water – suggesting that even though the fungus stays in the skin, the toxic material is having effects elsewhere."

New conservation measures for medically important species could also result from the study findings.

"[Frog skin] has long been favored in folklore for its medicinal properties," Rollins-Smith said. "Frogs are a rich source of potentially useful molecules that might work against human pathogens."