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 immunocompetent or immunosuppressed individuals. We have shown that the chemokine receptor, CCR2, is critically important in controlling pulmonary infection with Hc in mice. The absence of this receptor is associated with exacerbation of infection and the induction of interleukin (IL)-4 by unconventional sources-macrophages and dendritic cells. Neutralization of IL-4 restores immunity. We have obtained evidence that signaling by the chemokines CCL7 and 2, two CCR2 ligands, are important in optimal host defenses. In the following proposal, we will explore the mechanisms by which CCR2 signaling is important in constraining IL-4 generation and promoting an effective cellular immune response.
Specific aim 1 will examine the role of CCL2 and 7 in host defenses and inflammation. We will identify the cells producing these chemokines in situ and ex vivo. We will investigate if the absence of the receptor or the chemokines alters the in vivo residence of yeast cells. We will ascertain if CCR2 ligands manifest a direct or indirect activation of phagocytes.
In specific aim 2, we will utilize a mouse that has green fluorescent protein linked to the IL-4 gene to investigate the evolution and temporal appearance of IL-4- transcribing cells. Studies will be performed to determine if Hc modulates expression of CCR2. We also will investigate the pathways that macrophages and dendritic cells utilize to generate IL-4.
In specific aim 3, we will examine mechanisms by which the absence of CCR2 and/or IL-4 contributes to defective immunity. We will assess the possibility that the absence of CCR2 promotes the emergence of alternatively activated macrophages or myeloid suppressor cells. We will determine if either or both of these populations dampen antifungal immunity. We will test T cell function and expansion. We will assess the possibility that the failure of T cells to expand in the lungs is consequence of active inhibition as well as modulation of surface receptors. The goal of these studies is to better understand the pathogenesis of Hc, thereby enhancing knowledge of how Hc escapes host defenses. These findings contribute to the influence of the chemokine- cytokine network in microbial pathogenesis and evince a new role for CCL7.

Public Health Relevance

This grant seeks to understand the interaction between two types of soluble mediators known as chemokines and cytokines in host resistance 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 appropriate signaling through a surface receptor for a particular chemokine 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 #
5R01AI083313-03
Application #
8215901
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Duncan, Rory A
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$388,575
Indirect Cost
$141,075
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Kroetz, Danielle N; Deepe, George S (2012) The role of cytokines and chemokines in Histoplasma capsulatum infection. Cytokine 58:112-7
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
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