The dimorphic fungus, Histoplasma capsulatum (Hc) is endemic to the Midwestern and southeastern United States. Most infections are mild or asymptomatic. The organism establishes a latent state and can cause a life-threatening infection in immuno- suppressed individuals. We have shown that pulmonary infection with Hc in mice induces apoptosis of CD45+ lung leukocytes;apoptosis is controlled largely by tumor necrosis factor (TNF)-1 and Fas-Fas ligand interaction. Inhibition of apoptosis induced by neutralization of TNF-1 or Fas-Fas ligand interruption worsens the severity of infection. Inhibiting the activation of caspases, which are proteases involved in the apoptotic cascade, exacerbates infection. The aggressive nature of Hc in mice given an icaspase inhibitor is associated with elevations in interleukins 4 and 10. Each cytokine independently regulates the protective immune response in mice given the inhibitor. The effect of the caspase inhibitor is principally mediated by its effect on apoptosis and not an apoptosis-independent effect. We hypothesize that limited apoptosis is salutary for host defenses to Hc. In the following proposal, we will explore the mechanisms by which apoptosis contributes to protective immunity to Hc.
Specific aim 1 will examine the cellular sources of interleukins 4 and 10, and the kinetics of production by cell populations in mice given a caspase inhibitor. We will examine if phagocytes or T cells or both produce one or more of these cytokines. We will determine if the pathways for apoptosis are similar among these populations.
The second aim seeks to determine the functional consequences of apoptosis inhibition on human and mouse phagocyte function. We will examine the impact of caspase inhibition on nitric oxide release and on interleukins 4 and 10 release, and fungal handling by human and mouse phagocytes. We will examine if inoculum size modulates apoptosis of phagocytes.
In aim 3, we will determine the impact of inhibition of apoptosis on T cell function. We will examine if inhibition of apoptosis alters antigen recognition by T cells, skews the T cell receptor repertoire, prevents CD8+ cell activation, or leads to the emergence of T cells that can suppress immunity. The goal of these experiments is to better understand the immunopathogenesis of Hc, thereby enhancing knowledge of how Hc escapes host defenses. Project narrative This grant seeks to understand how the death of lymphocytes and macrophages modulates the expression of immunity to a fungus that causes human disease, Histoplasma capsulatum. This fungus which is found world-wide is a serious cause of lung infection in both normal humans and those who have impaired immunity. Our work will demonstrate how important it is for lymphocytes and macrophages to die in order that the host can survive.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI073337-05
Application #
8265587
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2008-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$382,239
Indirect Cost
$137,214
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Kroetz, Danielle N; Deepe Jr, George S (2012) CCR5 deficiency mitigates the deleterious effects of tumor necrosis factor ýý antagonism in murine histoplasmosis. J Infect Dis 205:955-63
Kroetz, Danielle N; Deepe, George S (2012) The role of cytokines and chemokines in Histoplasma capsulatum infection. Cytokine 58:112-7
Deepe Jr, George S (2012) NADPH oxidase regulates efficacy of vaccination in aspergillosis. J Clin Invest 122:1608-11
Deepe Jr, George S; Buesing, William R (2012) Deciphering the pathways of death of Histoplasma capsulatum-infected macrophages: implications for the immunopathogenesis of early infection. J Immunol 188:334-44
Kroetz, Danielle N; Deepe Jr, George S (2011) An aberrant thymus in CCR5-/- mice is coupled with an enhanced adaptive immune response in fungal infection. J Immunol 186:5949-55
Kroetz, Danielle N; Deepe Jr, George S (2010) CCR5 dictates the equilibrium of proinflammatory IL-17+ and regulatory Foxp3+ T cells in fungal infection. J Immunol 184:5224-31
Winters, Michael S; Chan, Qilin; Caruso, Joseph A et al. (2010) Metallomic analysis of macrophages infected with Histoplasma capsulatum reveals a fundamental role for zinc in host defenses. J Infect Dis 202:1136-45
Szymczak, Wendy A; Deepe Jr, George S (2010) Antigen-presenting dendritic cells rescue CD4-depleted CCR2-/- mice from lethal Histoplasma capsulatum infection. Infect Immun 78:2125-37
Deepe Jr, George S; Gibbons, Reta S (2009) Interleukins 17 and 23 influence the host response to Histoplasma capsulatum. J Infect Dis 200:142-51
Szymczak, Wendy A; Deepe Jr, George S (2009) The CCL7-CCL2-CCR2 axis regulates IL-4 production in lungs and fungal immunity. J Immunol 183:1964-74

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