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. One of the major risk factors for acquisition of disseminated Hc is the use of the TNF- antagonist. In the past 3+ years, we have examined the role of the chemokine receptor, CCR5, in hastening the clearance of Hc. Our data demonstrate that this receptor is pivotal in dictating the balance between regulatory T cells and Th17 cells. In the CCR5 knockout mice or in mice that lack one of this receptor's major ligand, CCL4, the number of regulatory T cells in lungs is diminished whereas the number of Th17 cells is elevated. Neutralization of IL-17 reverses the salutary effect of a lack of CCR5 signaling. As an extension of these studies, we examined if the inimical effects of anti-TNF- on host defenses to Hc were mitigated in the CCR5 knockout mice. We pursued this consideration since regulatory T cells arise after anti- TNF- treatment and are responsible, in part, for the demise of animals. The absence of CCR5 mitigated the deleterious consequence of anti-TNF- treatment. This finding has rekindled an interest in understanding the cells that drive the expansion of regulatory T cells in Hc-infected mice given anti-TNF- and in examining how the lack of this cytokine or regulatory T cells blunt the innate immune response. Our preliminary data demonstrate that anti-TNF- has a profound effect on recruitment of inflammatory monocytes and dendritic cells to the infected lung. Moreover, the cells that do reach the lungs are grossly impaired in their ability to inhibit the growth of Hc. In this proposal we will pursue aims to enhance knowledge regarding how anti-TNF- promotes Treg expansion and how the lack of this cytokine and/or regulatory T cells alter recruitment and function of mononuclear phagocytes.
Specific aim 1 will endeavor to identify a population or populations of dendritic cells or monocyte/macrophages that promote expansion of regulatory T cells in the absence of TNF- and to investigate the phenotype of regulatory T cells that arises in TNF--neutralized mice.
Aim 2 will examine why recruitment of inflammatory monocytes and dendritic cells is defective. We will attempt to separate the contribution of the lack of this cytokine from that of regulatory T cells.
Aim 3 will pursue how antibody to TNF- or regulatory T cells cause dysfunction of monocyte/macrophages and dendritic cells. These studies will generate a better understanding of the mechanisms by which anti-TNF- enhances susceptibility to infection.
Many veterans reside in areas of the country that are endemic for Histoplasma capsulatum, and they are constantly at risk for exposure. Moreover, those that resided or trained in endemic regions and relocated may harbor the fungus since it establishes a dormant state. Should a veteran require a TNF-? inhibitor or other immunosuppressive therapy, their chance of developing histoplasmosis is amplified greatly. For physicians unfamiliar with the clinical manifestations, diagnosis may pose problems and treatment may be toxic and/or expensive. The VA provides care for a medically underserved population that may not seek early medical attention. Consequently, this population may burden medical resources since they present with more advanced disease. This is true for histoplasmosis as well. Hence, it remains an important infectious disease problem for the veteran population.
|Bueter, Chelsea L; Deepe Jr, George S (2018) Aeroallergens Exacerbate Histoplasma capsulatum Infection. J Immunol 201:3352-3361|
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|Tweedle, Jamie L; Deepe Jr, George S (2018) Tumor Necrosis Factor Alpha Antagonism Reveals a Gut/Lung Axis That Amplifies Regulatory T Cells in a Pulmonary Fungal Infection. Infect Immun 86:|
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|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|
|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|
|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|
|Horwath, Michael C; Fecher, Roger A; Deepe Jr, George S (2015) Histoplasma capsulatum, lung infection and immunity. Future Microbiol 10:967-75|
|Verma, Akash; Wüthrich, Marcel; Deepe, George et al. (2014) Adaptive immunity to fungi. Cold Spring Harb Perspect Med 5:a019612|
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