The dimorphic fungus, Histoplasma capsulatum (Hc), is endemic to the midwestern and southeastern US and is the most frequent cause of fungal respiratory infection. It thrives within the intracellular environment of macrophages. We propose to investigate how the transcription factor, Kr?ppel like factor (KLF) 2, modulates the ability of myeloid cells to regulate the host response to Hc in vivo. KLF2 is essential in embryogenesis, acts as a molecular switch in the generation of pro-inflammatory cytokines and chemokines, and exerts a profound effect on T cell migration. Virtually no information exists concerning its importance in the ontogeny of inflammation and host resistance to pathogens. We have created a mouse that lacks KLF2 in myeloid cells. Preliminary data indicate that Hc infection in these animals is associated with an increase in interleukin (IL)-4 and a higher fungal burden. KFL2-deficient macrophages manifest an alternatively activated phenotype that is associated with impaired killing of Hc. We seek herein to determine how the absence of KLF2 in myeloid cells skews the immune response.
In aim 1, we will determine if KLF2 excision alters the inflammatory response and course of infection and we will examine the chronology of IL-4 generation.
In aim 2, we will identify the origins of IL-4 and determine if IL-25, -33 or thymic stromal lymphopoietin, three inducers of IL-4, are upregulated in the KLF2 conditional knockouts and if so, which cell is the source. This exploratory proposal will endeavor to establish the necessity of KLF2 in the host-microbe battle. Our findings are likely to extend far beyond the scope of Hc and apply to other intracellular pathogens and to inflammatory diseases.

Public Health Relevance

This grant seeks to understand the role of a transcription factor immunity to histoplasmosis. The gene known as Kr?ppel like factor regulates production of molecules that are necessary for the immune system. Here, we seek to determine how this gene regulates the production of a cytokine that worsens histoplasmosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI096823-02
Application #
8263744
Study Section
Special Emphasis Panel (ZRG1-IDM-S (03))
Program Officer
Duncan, Rory A
Project Start
2011-05-13
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$202,218
Indirect Cost
$73,417
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, 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