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Research Article

In vivo Hypoxia and a Fungal Alcohol Dehydrogenase Influence the Pathogenesis of Invasive Pulmonary Aspergillosis

  • Nora Grahl,

    Affiliation: Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana, United States of America

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  • Srisombat Puttikamonkul,

    Affiliation: Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana, United States of America

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  • Jeffrey M. Macdonald,

    Affiliation: Joint Department of Biomedical Engineering, University of North Carolina, Chapel Hill, and North Carolina State University, Raleigh, North Carolina, United States of America

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  • Michael P. Gamcsik,

    Affiliation: Joint Department of Biomedical Engineering, University of North Carolina, Chapel Hill, and North Carolina State University, Raleigh, North Carolina, United States of America

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  • Lisa Y. Ngo,

    Affiliation: Infectious Disease Sciences, Vaccine and Infectious Disease Division, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America

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  • Tobias M. Hohl,

    Affiliation: Infectious Disease Sciences, Vaccine and Infectious Disease Division, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America

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  • Robert A. Cramer mail

    rcramer@montana.edu

    Affiliation: Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana, United States of America

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  • Published: July 21, 2011
  • DOI: 10.1371/journal.ppat.1002145

Reader Comments (2)

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Response to Kausik Comment in User Ratings

Posted by rcramer22 on 02 Aug 2011 at 18:03 GMT

Dear Kausik,

Thank you for reading and commenting (in user ratings) on our recent study. Yes, the difficulties in detecting the ethanol were frustrating for us as it prevented us from definitively attributing the in vivo phenotype of the alcC mutant to loss of ethanol production. The lack of cell wall alteration in the mutant argues strongly for a secreted factor being responsible, but without the robust ethanol data, we could not definitively state the mechanism to be due to ethanol. We are working on detecting EtOH in live animals, so it can be monitored over the time course of infection to further improve our understanding of the fungal-host interaction.

With regard to the immunosuppression, the effects of triamcinolone and cyclophosphamide on the immune system are complex and still not fully understood. One important point: while the doses of cyclophosphamide used in our model and other murine models of IPA do induce leukopenia, most often this has been measured in uninfected animals. For example, see the IPA murine model papers by Steinbach et al. 2004 Medical Mycology and Sheppard et al. 2004 AAC. Of course, in the context of a microbial infection, we and others, find that the mice are never truly 100% leukopenic, particularly at the site of infection. In addition, I encourage you to take a look at work by David Cole’s group on the effects of Cyclophosphamide on host microenvironments (Salem et al. 2010, Journal of Immunology). Depending on dose, Cyclophosphamide can actually increase the number of precursor/circulating dendritic cells, which of course has important ramifications for IPA. This is further emphasized by Borna Mehrad’s recent work demonstrating an increase in dendritic cell recruitment to the lungs of neutropenic mice, and Stu Levitz’s recent work on the important of plasmacytoid dendritic cells in controlling A. fumigatus infection. We also did take a look at the cellular infiltrates in our cyclophosphamide treated animals. While the number of neutrophils was depleted compared to the triamcinolone only treated animals, a significant number of neutrophils were still observed at the site of infection, likely contributing to the hypoxia. So in the end, I think much work remains to be done regarding the impact of different immunosuppression regimens on the host response to Aspergillus fumigatus and how they contribute to the host microenvironment (along with how they affect the fungus!). Thanks again for your comments!

Competing interests declared: I am the senior author on the commented manuscript.