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Neutrophils, Nutritional Immunity and NETs: Host-Pathogen Interactions in Aspergillus fumigatus Infection

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2017, Doctor of Philosophy, Case Western Reserve University, Pathology.
The filamentous fungal pathogen Aspergillus fumigatus is a leading cause of corneal infection (keratitis). Neutrophils are the most abundant cell type in corneal ulcers of fungal keratitis patients and are critical to controlling fungal growth, through reactive oxygen species (ROS) production and release of antimicrobial proteins (AMPs). We investigated the role of the neutrophil AMP calprotectin (CP) and neutrophil extracellular trap (NET) release in A. fumigatus infection, as well as the role of zinc (Zn) acquisition as a virulence determinant of A. fumigatus. Furthermore, we studied the effect of atovaquone as a novel anti-fungal agent targeting fungal Zn homeostasis. We demonstrated that neutrophil CP is required for control of A. fumigatus corneal infection and hyphal growth through Zn and manganese chelation. Furthermore, we found that the A. fumigatus transcription factor ZafA is required for zinc uptake and virulence in vivo or in the presence of neutrophils and CP. Due to the importance of Zn acquisition in fungal virulence, we investigated the effect of atovaquone, a ubiquinone analog, that was shown to disrupt Zn homeostasis in yeast, on filamentous fungi. We found that atovaquone significantly inhibited growth of Aspergillus clinical keratitis isolates in vitro through disruption of mitochondrial activity and intracellular zinc homeostasis. Finally, NETs have been shown to contribute to CP release and immunity microbial infection. We found that the fungal polysaccharide ß 1,3 glucan induced NET release which was mediated in part by complement receptor 3 (CR3), ROS production and peptidyl arginine deiminase 4 (PAD4) activation. However, we found that CR3, but not PAD4, was required for neutrophil CP release and killing of hyphae in vitro. Finally, we identified NET formation in vivo in corneas of mice infected with A. fumigatus by citrullinated histone H3 (H3cit) antibody staining, which is a specific marker of NETs. In conclusion, we found an essential role for neutrophil CP and CR3 signaling in controlling A. fumigatus infection. We also found that A. fumigatus Zn acquisition is required for virulence and that targeting Zn homeostasis of fungi with atovaquone may represent a new anti-fungal strategy.
Eric Pearlman, PhD (Advisor)
George Dubyak, PhD (Committee Chair)
Clive Hamlin, PhD (Committee Member)
Amy Hise, MD (Committee Member)
Theresa Pizarro, PhD (Committee Member)
214 p.

Recommended Citations

Citations

  • Clark, H. L. (2017). Neutrophils, Nutritional Immunity and NETs: Host-Pathogen Interactions in Aspergillus fumigatus Infection [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1480451373752014

    APA Style (7th edition)

  • Clark, Heather. Neutrophils, Nutritional Immunity and NETs: Host-Pathogen Interactions in Aspergillus fumigatus Infection. 2017. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1480451373752014.

    MLA Style (8th edition)

  • Clark, Heather. "Neutrophils, Nutritional Immunity and NETs: Host-Pathogen Interactions in Aspergillus fumigatus Infection." Doctoral dissertation, Case Western Reserve University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1480451373752014

    Chicago Manual of Style (17th edition)