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Frog-​killing fun­gus paral­y­ses amphib­ian immune response

pub­lished 21 Octo­ber 2013 | mod­i­fied 13 Sep­tem­ber 2014

A fun­gus that is killing frogs and other amphib­ians around the world releases a toxic fac­tor that dis­ables the amphib­ian immune response, Van­der­bilt Uni­ver­sity inves­ti­ga­tors report this week in the 18 Octo­ber issue of the jour­nal Sci­ence.

Dendrobates azureus tinctoriusThe 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, Ph.D., asso­ciate pro­fes­sor of Pathol­ogy, Micro­bi­ol­ogy and Immunol­ogy. Although the iden­tity of the toxic fun­gal fac­tor (or fac­tors) remains a mys­tery, its abil­ity to inhibit a wide range of cell types — includ­ing can­cer­ous cells — sug­gests that it may offer new direc­tions for the devel­op­ment of immuno­sup­pres­sive or anti-​cancer agents.

The pop­u­la­tions of amphib­ian species have been declin­ing world­wide for more than 40 years. In the late 1990s, researchers dis­cov­ered that an ancient fun­gus, Batra­chochytrium den­dro­ba­tidis, was caus­ing skin infec­tions, and the fun­gus is now recog­nised as a lead­ing con­trib­u­tor to global amphib­ian decline.

Amphib­ians have excel­lent and com­plex immune sys­tems — nearly as com­plex as humans — and they should be able to recog­nise and clear the fungus
Louise Rollins-​Smith, asso­ciate pro­fes­sor of Pathol­ogy, Micro­bi­ol­ogy and Immunol­ogy, Pedi­atrics and Bio­log­i­cal Sci­ences, Van­der­bilt University »

Rollins-​Smith and her col­leagues have been study­ing the immune response to the fun­gus for more than 10 years. In early stud­ies, the inves­ti­ga­tors demon­strated that some frogs pro­duce anti-​microbial pep­tides in the skin that offer a first layer of defense against the fun­gus. But when the fun­gus gets into the lay­ers of the skin, Rollins-​Smith said, the con­ven­tional lym­pho­cyte (immune cell)-mediated immune response should be acti­vated to clear it.

They found in the cur­rent stud­ies 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.”

But dur­ing the next stage of the immune response, when lym­pho­cytes should be acti­vated, the fun­gus exerts its toxic effects. The inves­ti­ga­tors demon­strated that B. den­dro­ba­tidis cells and super­natants (the incu­ba­tion liq­uid sep­a­rated from the cells) impaired lym­pho­cyte pro­lif­er­a­tion and induced cell death of lym­pho­cytes from frogs, mice and humans. The toxic fun­gal fac­tor also inhib­ited the growth of can­cer­ous mam­malian cell lines. The toxic fac­tor was resis­tant to heat and pro­teases (enzymes that cut pro­teins into pieces), sug­gest­ing that it is not a pro­tein. It appears to be 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 new find­ings sug­gest the pos­si­bil­ity that toxic fac­tors — in addi­tion to act­ing locally to inhibit the immune response — might also get into the cir­cu­la­tion and have neu­ro­toxic effects, Rollins-​Smith said. “Fun­gal infec­tion causes rapid behav­ioural 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.”

The stud­ies, led by J. Scott Fites, a grad­u­ate stu­dent in the Depart­ment of Bio­log­i­cal Sci­ences, and Jeremy Ram­sey, Ph.D., a for­mer grad­u­ate stu­dent in the Depart­ment of Pathol­ogy, Micro­bi­ol­ogy and Immunol­ogy, could also sug­gest new con­ser­va­tion mea­sures for species that may be med­ically important.

“Amphib­ian skin has long been favoured in folk­lore for its med­i­c­i­nal prop­er­ties,” Rollins-​Smith said. “Frogs are a rich source of poten­tially use­ful mol­e­cules that might work against human pathogens.”

The above news item is reprinted from mate­ri­als avail­able at Van­der­bilt Uni­ver­sity. Per­mis­sion granted.
(Source: Van­der­bilt Uni­ver­sity research news, 17.10.2013)

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