The dimorphic fungus, Histoplasma capsulatum (Hc) is found world-wide, and endemic to the Midwestern and southeastern United States. The organism can cause a life- threatening infection in immunocompetent or immunosuppressed individuals. We have shown that the absence of chemokine receptor, CCR5, enhances the ability of mice to clear infection with Hc. Accelerated resolution is associated with a perturbation in the balance between regulatory T cells and interleukin (IL)-17+ cells. Mice lacking the CCR5 receptor manifest a decrement in the number of regulatory T cells in lungs and higher levels of IL-17. The paucity of regulatory T cells is multi-factorial. These cells do not emigrate from the thymus, and they proliferate poorly in the lungs. Moreover, we have demonstrated that the absence of CCR5 attenuates the deleterious effects of tumor necrosis factor (TNF)-a antagonism. Herein, we will explore the mechanisms by which the lack of CCR5 signaling is important in disturbing the balance between regulatory T cells and IL-17.
Specific aim 1 will investigate the specific mechanisms that lead to the imbalance between regulatory T cells and IL-17. We will produce CCR5-/- mice that express Foxp3-green fluorescent protein (GFP) and IL-17-GFP to track the migration of specific cells populations. We will investigate why regulatory T cells do not proliferate and why they fail to migrate from the thymus. We also will analyze the functional attributes of these cell populations in vivo.
In specific aim 2, we will analyze the cellular and molecular effectors that enhance fungal clearance. We will investigate the role of CCR5 ligands in dictating clearance, the direct and indirect influence of IL-17 and the roles of transforming growth factor-b and IL-23.
In specific aim 3, we will define the mechanisms by which the absence of CCR5 is salutary to mice lacking TNF-a. We will 1) determine the trafficking of regulatory T cells and IL-17+ cells in mice lacking TNF-a, 2) elucidate the role of specific molecular effectors, and 3) test if CCR5 inhibitors mimic the effect of the absence of CCR5. The goal of these studies is to better understand the host defense mechanisms that are activated to combat Hc. The studies investigating the salutary effect of the absence of CCR5 in mice lacking TNF-a are particularly germane to reports of progressive histoplasmosis in patients receiving TNF antagonists. Our findings will contribute to a greater understanding of how the host can successfully defend against histoplasmosis.

Public Health Relevance

This grant seeks to understand how the inability of soluble mediators known as chemokines to communicate with their receptor enhances the ability of the host to clear infection with a fungus, Histoplasma capsulatum, that causes human disease. This fungus, which is found world-wide, is a serious cause of lung infection in both normal humans and those who have impaired immunity. These studies are relevant to the veteran's population, especially those who reside in the endemic area or in those who may have been exposed to the fungus during training or in overseas duty. If they develop an immunosuppressive condition, these studies will enlighten how the fungus attacks and how it can be combated. New therapeutic advances for life-threatening histoplasmosis will possibly emerge from these studies.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX000717-01
Application #
7922945
Study Section
Infectious Diseases B (INFB)
Project Start
2010-04-01
Project End
2014-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
1
Fiscal Year
2011
Total Cost
Indirect Cost
Name
Cincinnati VA Medical Center Research
Department
Type
DUNS #
827658092
City
Cincinnati
State
OH
Country
United States
Zip Code
45220
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George, Mariam Mathew; Subramanian Vignesh, Kavitha; Landero Figueroa, Julio A et al. (2016) Zinc Induces Dendritic Cell Tolerogenic Phenotype and Skews Regulatory T Cell-Th17 Balance. J Immunol 197:1864-76
Subramanian Vignesh, Kavitha; Deepe Jr, George S (2016) Immunological orchestration of zinc homeostasis: The battle between host mechanisms and pathogen defenses. Arch Biochem Biophys 611:66-78
Subramanian Vignesh, Kavitha; Landero Figueroa, Julio A; Porollo, Aleksey et al. (2016) IL-4 Induces Metallothionein 3- and SLC30A4-Dependent Increase in Intracellular Zn(2+) that Promotes Pathogen Persistence in Macrophages. Cell Rep 16:3232-3246
Fecher, Roger A; Horwath, Michael C; Friedrich, Dirk et al. (2016) Inverse Correlation between IL-10 and HIF-1? in Macrophages Infected with Histoplasma capsulatum. J Immunol 197:565-79
Verma, Akash; W├╝thrich, Marcel; Deepe, George et al. (2014) Adaptive immunity to fungi. Cold Spring Harb Perspect Med 5:a019612