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Zinc: An Immunomodulator of Innate Defense against Pathogenic Infection

Subramanian Vignesh, Kavitha
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1383909171

Abstract Details

2013, PhD, University of Cincinnati, Medicine: Molecular Genetics, Biochemistry, and Microbiology.
Zinc (Zn), an essential element, critically regulates immune function. Aberrant Zn regulation is associated with inadequate innate and adaptive responses. Macrophages phagocytose fungi and play a critical role in regulating infection. These phagocytes can favor or restrict fungal survival depending on the cytokine mileu. Under resting conditions, macrophages harbor yeasts permissively, while exposure to proinflammtory cytokines results in macrophage activation and inhibition of fungal survival. The goal of this work is to uncover the significance of Zn homeostasis driven by cytokines in shaping macrophage resistance against a fungal pathogen. The pro-inflammatory cytokine GM-CSF confers defensive properties on macrophages to inhibit growth of Histoplasma capsulatum both in vitro and in vivo. We investigated the mechanism by which GM-CSF arms macrophages to counter fungal attack. The cytokine triggered deprivation of labile Zn by enhancing binding to metallothioneins (MTs) and inducing Zn localization in the Golgi apparatus, associated with elevated expression of Zn transporters ZNT4 and ZNT7 known to localize on the Golgi membrane. Zn deprivation enhanced hydrogen gated voltage channel HV1 function, augmenting the production of reactive oxygen species (ROS) by NADPH oxidase. This coordinated program of Zn modulation in activated macrophages specifically led to Zn limitation and increased oxidative stress abrogating survival of the intracellular fungus. GM-CSF triggered Zn sequestration in vivo as well as in human macrophages. The cytokine interleukin 4 (IL-4) is permissive, reverses the growth inhibitory property of GM-CSF activated macrophages and alleviates host immunity against fungal infection. The concept that functional attributes of alternatively activated macrophages may be influenced by Zn homeostasis has not been investigated. We found that IL-4 treated macrophages, in sharp contrast to GM-CSF activated macrophages, enhanced the content of labile Zn and increased Zn acquisition by intracellular yeasts. IL-4, in a STAT6 dependent manner increased expression of the brain specific form of MT, Mt3, which was the key player in elevating labile Zn in macrophages. Proteomic analysis identified cathepsins in IL-4 treated macrophages. Broadly targeting cathepsins using inhibitors had an attenuating effect on labile Zn increase. Both, RNA interference of MT3 and inhibition of cathepsins reduced Zn acquisition by intracellular yeasts, suggesting their role in increasing Zn bio-availability. These observations illuminate a role for IL-4 in Zn modulation and release, and its' impact on directing the outcome of host defense against infection. In summary, using a multidisciplinary approach involving immunology, mass spectrometry and bio-informatics analysis, the investigation in this work provides novel insights into metal regulatory mechanisms in innate defense against pathogen attack.
George Deepe, M.D. (Committee Chair)
Edmund Choi, Ph.D. (Committee Member)
David Hildeman, Ph.D. (Committee Member)
William Miller, Ph.D. (Committee Member)
John Monaco, Ph.D. (Committee Member)
209 p.
Immunology
Zinc; Macrophage; GM-CSF; Metals; IL-4; Fluorescent probes

Recommended Citations

Citations

  • Subramanian Vignesh, K. (2013). Zinc: An Immunomodulator of Innate Defense against Pathogenic Infection [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1383909171

    APA Style (7th edition)

  • Subramanian Vignesh, Kavitha. Zinc: An Immunomodulator of Innate Defense against Pathogenic Infection. 2013. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1383909171.

    MLA Style (8th edition)

  • Subramanian Vignesh, Kavitha. "Zinc: An Immunomodulator of Innate Defense against Pathogenic Infection." Doctoral dissertation, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1383909171

    Chicago Manual of Style (17th edition)

ucin1383909171
502
© 2013, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.