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Avoiding neutrophil traps: How an invasive fungus defeats the mammalian immune response

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IMAGE: Scanning electron microscopy illustrates the difference in the abundance of cell wall-associated galactosaminogalactan (arrows) between the opportunistic fungal pathogen Aspergillus fumigatus and the minimally pathogenic species Aspergillus nidulans.... view more

Credit: Lee et al. (2015)

Invasive aspergillosis (IA) is a serious disease of immune-compromised individuals and the most common invasive mold infection in humans. Although more than 250 different Aspergillus species are found in nature, and most contribute spores to the air we breathe, over 80% of human disease is caused by one particular culprit called Aspergillus fumigatus. A study published on October 22nd in PLOS Pathogens explores what distinguishes this fungus from its relatives and likely makes it so dangerous.

Donald Sheppard, from the Research Institute of the McGill University Health Centre in Montreal, Canada, and colleagues set out to explore features that could facilitate infection by A. fumigatus as compared with less pathogenic Aspergillus species. Because they and others had previously identified a particular sugar in the cell wall of A. fumigatus called GAG, short for "galactosaminogalactan", as critical to the fungus' ability to outwit the host immune system, the researchers started by testing whether differences in GAG production contribute to differences in the virulence (i.e. the ability to cause disease) observed among Aspergillus species.

Comparing A. fumigatus with the less pathogenic species A. nidulans, they found that the amount of cell wall-associated GAG correlated with the reported virulence of these species. Further experiments suggested that the production of high levels of cell wall-associated GAG makes A. fumigatus more resistant than A. nidulans to neutrophil killing by neutrophil extracellular traps, or NETs (NETs are are networks of extracellular fibers, composed of DNA and proteins secreted by immune cells called neutrophils, that bind and trap various pathogens).

Increasing cell wall-associated GAG in A. nidulans enhanced resistance to NETs and increased the virulence of this species to the same level as A. fumigatus in immune-compromised mice with intact NET formation. Collectively, these data suggest that A. nidulans is more sensitive than A. fumigatus to NETs due to lower overall levels of cell wall-associated GAG.

Their study, the researchers say "establishes a role for cell wall-associated GAG in mediating resistance to killing of Aspergillus by NETs and provides the first example of a virulence factor of A. fumigatus that is able to mediate enhanced virulence when expressed in a less pathogenic Aspergillus species". As their results highlight the importance of GAG as a key virulence factor of A. fumigatus, they suggest that targeting GAG may be an effective antifungal approach in some human patients.

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Contact:
Donald Sheppard
e-mail: don.sheppard@mcgill.ca
phone: +1.514.398.1759

Please use this URL to provide readers access to the paper (Link goes live upon article publication): http://dx.plos.org/10.1371/journal.ppat.1005187

Authors and Affiliations: Mark J. Lee, McGill University, Canada
Hong Liu, University of California, Los Angeles, USA
Bridget M. Barker, Montana State University, USA
Brendan D. Snarr, McGill University, Canada
Fabrice N. Gravelat, McGill University, Canada
Qusai Al Abdallah, McGill University, Canada
Christina Gavino, McGill University Health Centre, Canada
Shane R. Baistrocchi, McGill University, Canada
Hanna Ostapska, McGill University, Canada
Tianli Xiao, McGill University, Canada
Benjamin Ralph, McGill University, Canada
Norma V. Solis, LA Biomedical Research Institute at Harbor--UCLA, USA
Mélanie Lehoux, McGill University, Canada
Stefanie D. Baptista, McGill University, Canada
Arsa Thammahong, Dartmouth College, USA
Robert P. Cerone, McGill University, Canada
Susan G. W. Kaminskyj, University of Saskatchewan, Canada
Marie-Christine Guiot, Montreal Neurological Hospital, Canada
Jean-Paul Latgé, Institut Pasteur Paris, France
Thierry Fontaine, Institut Pasteur Paris, France
Donald C. Vinh, McGill University Health Centre, Canada
Scott G. Filler, LA Biomedical Research Institute at Harbor--UCLA, USA; University of California, Los Angeles, USA
Donald C. Sheppard, McGill University, Canada

Please contact plospathogens@plos.org if you would like more information.

Funding: This work was supported in part by Operating funds from the Canadian Cystic Fibrosis Foundation, the Canadian Institutes of Health Research, and grant R01AI073829 from the National Institutes of Health, USA. DCS was supported by a Chercheur-Boursier award from the Fonds de recherche du Québec - Santé. MJL was supported by a studentship from the Research Institute of the McGill University Health Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

Citation: Lee MJ, Liu H, Barker BM, Snarr BD, Gravelat FN, Al Abdallah Q, et al. (2015) The Fungal Exopolysaccharide Galactosaminogalactan Mediates Virulence by Enhancing Resistance to Neutrophil Extracellular Traps. PLoS Pathog 11(10): e1005187. doi:10.1371/journal.ppat.1005187

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