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The Role of CCR5 in Protection Against Histoplasma capsulatum Infection

Kroetz, Danielle N.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1305030008

Abstract Details

2011, PhD, University of Cincinnati, Medicine: Molecular Genetics, Biochemistry, and Microbiology.
Histoplasma capsulatum is a dimorphic fungus that is found worldwide, but is endemic in the Midwest and Southeast regions of the United States. Infection with this fungal pathogen can range from a mild pulmonary infection in immunocompetent individuals to a disseminated, lethal infection in immunocompromised individuals. The ability to mount a Th1 immune response is required to control H. capsulatum infection. Several chemokine receptors, including CCR5 and its ligands CCL3, CCL4, and CCL5, are rapidly induced in the lungs upon exposure to H. capsulatum; however, the significance of these proteins in host protection is unresolved. Herein, we uncover multiple roles for CCR5 in innate and adaptive immunity using a murine model of histoplasmosis. Although signaling through CCR5 was required for optimal inflammatory cell infiltration to the lungs, mice lacking CCR5 or its ligand CCL4 controlled H. capsulatum infection more efficiently than controls. Accelerated fungal resolution in CCL4-neutralized and CCR5-/- mice correlated with a decreased proportion and number of regulatory T cells (Tregs). Fewer Tregs in CCR5-/- lungs, which was associated with diminished proliferation and accumulation in thymus and lymph nodes, resulted in an amplified proinflammatory Th17 response that was required for enhanced host protection (Chapter 2 and 3). Lastly, we characterized the role of TNF-α in the emergence, homing, and function of Tregs in wild-type and CCR5-/- mice. The effect of TNF-α antagonism was dramatically different between the two groups of mice. In wild-type animals, administration of anti-TNF-α was lethal and caused the mice to succumb to infection by day 14 post-infection. Remarkably, more than one-third of CCR5-/- mice resolved infection without TNF-α. The major difference between the two groups was the absolute number of Tregs in infected lungs which is demonstrated in Chapter 4. Overall, these findings elucidate the significance of CCR5 in H. capsulatum infection and unearth the potential benefits and disadvantages of therapeutically targeting CCR5, as well as Tregs, to control infection and other conditions such as cancer and autoimmunity.
George Deepe, MD (Committee Chair)
Jane Strasser, PhD (Committee Member)
Julio Aliberti, PhD (Committee Member)
William Miller, PhD (Committee Member)
James Stringer, PhD (Committee Member)
125 p.
Immunology
Histoplasma; CCR5; Treg; Th17; chemokine

Recommended Citations

Citations

  • Kroetz, D. N. (2011). The Role of CCR5 in Protection Against Histoplasma capsulatum Infection [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1305030008

    APA Style (7th edition)

  • Kroetz, Danielle. The Role of CCR5 in Protection Against Histoplasma capsulatum Infection. 2011. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1305030008.

    MLA Style (8th edition)

  • Kroetz, Danielle. "The Role of CCR5 in Protection Against Histoplasma capsulatum Infection." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1305030008

    Chicago Manual of Style (17th edition)

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© 2011, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.