Infection with eukaryotic pathogens places an enormous burden on the health of many species including humans. Intracellular eukaryotic pathogens such as the dimorphic fungus, Histoplasma capsulatum (Hc), require a T helper (Th) 1 response to promote elimination. Th2 that produce interleukin (IL)-4 and IL-13 override the influence of Th1 and exaggerate the severity of infection to this fungus. While a Th2 response is detrimental to Hc and other intracellular pathogens, it is vital for clearance of helminths. Activation of Th1 or Th2 requires communication with dendritic cells (DCs). Knowledge regarding transcriptional regulators that license the latter to promote a Th1 or Th2 response is incomplete. We have discovered that the transcription factor, Krppel-like factor (KLF) 2, in DCs calibrates the vigor of the Th2 response. A loss of KLF2 in DCs enhances release of IL-4 and IL-13 by Th2 and promotes accrual of these cells in lungs of Hc-infected mice. The net result is impaired clearance of the fungus. The enhanced release of type 2 cytokines is dependent on an expansion of DCs that express the Notch ligand, Jagged2. These preliminary data stimulated the central hypothesis that KLF2 is a key element in DCs that limits the magnitude of Th2 responses and thus, differentially regulates the severity of infection with Hc or with helminths. To test this hypothesis, we propose three Specific Aims.
Aim 1 will elucidate how KLF2-deficient DCs promote Th2 immunity. Studies will examine: 1) the influence of KLF2 on conventional DCs in lungs and draining lymph nodes, 2) the impact on Th2 recruitment, survival, and/or proliferation and 3) the role of DC KLF2 in controlling infection with a helminth.
Specific Aim 2 will shift the focus to T cells and examine the role of Notch receptors and Notch ligands on T cell function in Hc and helminth infection.
Specific Aim 3 will explore the genomic landscape regulated by KLF2 with a focus on the transcription factor hypoxia inducing factor-1?. In addition, we will open the aperture and perform RNA-seq and chromatin immunoprecipitation (ChIP)-Seq to identify the KLF2-dependent gene networks in DCs that regulate Notch signaling and Th2 accrual. A better understanding of the regulation of DCs by KLF2 during infection with intracellular and extracellular pathogens protective could lead to the development of new therapies that govern immunity to Hc and to helminths.

Public Health Relevance

Eukaryotic pathogens require different T cell families to limit infection. The transcription factor Krppel-like factor 2 in dendritic cells is dictates the strength of the T helper type 2 response. We will explore the means by which the transcription factor regulates non-protective T cells for fungi but protective for worms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI126818-03
Application #
9487847
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Love, Dona
Project Start
2016-06-10
Project End
2021-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
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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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:
Xiong, Ye; Lingrel, Jerry B; W├╝thrich, Marcel et al. (2016) Transcription Factor KLF2 in Dendritic Cells Downregulates Th2 Programming via the HIF-1?/Jagged2/Notch Axis. MBio 7: