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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunity and Host Defense Study Section (IHD)
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Duncan, Rory A
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University of Cincinnati
Internal Medicine/Medicine
Schools of Medicine
United States
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Verma, A H; Bueter, C L; Rothenberg, M E et al. (2017) Eosinophils subvert host resistance to an intracellular pathogen by instigating non-protective IL-4 in CCR2-/- mice. Mucosal Immunol 10:194-204
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
Xiong, Ye; Lingrel, Jerry B; Wüthrich, Marcel et al. (2016) Transcription Factor KLF2 in Dendritic Cells Downregulates Th2 Programming via the HIF-1?/Jagged2/Notch Axis. MBio 7:
Verma, A; Kroetz, D N; Tweedle, J L et al. (2015) Type II cytokines impair host defense against an intracellular fungal pathogen by amplifying macrophage generation of IL-33. Mucosal Immunol 8:380-9
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
Subramanian Vignesh, Kavitha; Landero Figueroa, Julio A; Porollo, Aleksey et al. (2013) Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival. Immunity 39:697-710
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
Wüthrich, Marcel; Deepe Jr, George S; Klein, Bruce (2012) Adaptive immunity to fungi. Annu Rev Immunol 30:115-48

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