This R01 renewal dissects the role and action of a fungal product that inactivates innate immunity. Even in healthy hosts, the systemic mycoses produce immune disturbances and progressive disease. This finding implies that the fungi disable immune responses, but little is known about the molecular bases. This knowledge gap limits development of new therapies. We've developed Blastomyces dermatitidis and murine infection into an excellent model to unravel such enigmas. We have reported that CCR2+ inflammatory monocytes promote fungal vaccine immunity, yet host mediators retard their influx into the lung upon vaccination at this site. We focus here on a yeast product that undercuts these cells and innate immunity, facilitating progressive infection. We propose that dipeptidyl peptitidase IVA (DPP4A) blunts innate lung immunity. DPP4A is an oligopepti- dase that cleaves protein after a 2-position proline at the N-terminus. Mammalian DPP4 (CD26) inactivates cytokine/chemokine, tempering immunity. While such activity is unreported in microbes, DPP4 is conserved in bacteria, parasites and fungi, and DPP4 inhibitors are being used to treat diabetes, heart disease & Alzheimer's. We have preliminary data that fungal DPP4A blunts innate immunity and that silencing or deleting DPP4A attenuates B. dermatitidis in a GM-CSF & CCR2 dependent manner. We hypothesize that DPP4A inactivates GM-CSF & CCL2 (recruits CCR2+ cells) and digests the lung extracellular matrix that displays chemokine, and that these events blunt influx/function of CCR2+ monocytes, macrophages and neutrophils.
We aim to: 1. Define DPP4A action on GM-CSF and its effect on macrophages and neutrophils. Fungal DPP4A will be studied for action on GM-CSF and inactivation of the cytokine. Mice infected with DPP4A-plus or -minus yeast will be used to study whether & how DPP4A-clipped GM-CSF disables leukocytes and assess drug inhibitor or cytokine therapy. 2. Delineate DPP4A action on CCL2 and the impact on CCR2+ inflammatory monocytes. Fungal DPP4A will be studied for inactivation of C-C chemokine, and the ensuing impact on CCR2+ monocyte recruitment and function to define the mechanics that underpin failed influx and function of the cells during innate resistance to fungal infection. 3. Analyze DPP4A action on cell matrix and the impact on CCR2+ cell migration. Fungal DPP4A will be studied for action on collagen I & the glycosaminoglycan heparin, ECM elements that display chemokine to leukocytes. CCR2+ GFP reporter mice/cells will be used to assay how DPP4A action on ECM alters cell migration in vitro and in vivo. Our work tackles a prevailing knowledge gap: the basis for disease progression during systemic mycosis. It breaks new ground by exposing yeast mimicry of a host tactic that tempers innate immunity by regulating 2 key mediators: GM-CSF & CCR2+ cells. The actions can be targeted with drug inhibitors or immune therapy.

Public Health Relevance

Systemic fungal infections represent a significant and growing public health problem. In the U.S. alone, invasive fungal infections are among the 10 leading causes of death (7th) ahead of mortality from tuberculosis. Our work tackles significant unmet needs of developing better ways to treat and prevent these infections by investigating a basic mechanism of pathogenicity in a human fungal pathogen. The new basic knowledge gleaned here can be harnessed for better fungal disease prevention and treatment.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Pathogenic Eukaryotes Study Section (PTHE)
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Love, Dona
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University of Wisconsin Madison
Schools of Medicine
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Kujoth, Gregory C; Sullivan, Thomas D; Merkhofer, Richard et al. (2018) CRISPR/Cas9-Mediated Gene Disruption Reveals the Importance of Zinc Metabolism for Fitness of the Dimorphic Fungal Pathogen Blastomyces dermatitidis. MBio 9:
McDermott, Andrew J; Tumey, Tyler A; Huang, Mingwei et al. (2018) Inhaled Cryptococcus neoformans elicits allergic airway inflammation independent of Nuclear Factor Kappa B signalling in lung epithelial cells. Immunology 153:513-522
McDermott, Andrew J; Klein, Bruce S (2018) Helper T-cell responses and pulmonary fungal infections. Immunology 155:155-163
Garfoot, Andrew L; Goughenour, Kristie D; Wüthrich, Marcel et al. (2018) O-Mannosylation of Proteins Enables Histoplasma Yeast Survival at Mammalian Body Temperatures. MBio 9:
Hernández-Santos, Nydiaris; Wiesner, Darin L; Fites, J Scott et al. (2018) Lung Epithelial Cells Coordinate Innate Lymphocytes and Immunity against Pulmonary Fungal Infection. Cell Host Microbe 23:511-522.e5
Fites, J Scott; Gui, Michael; Kernien, John F et al. (2018) An unappreciated role for neutrophil-DC hybrids in immunity to invasive fungal infections. PLoS Pathog 14:e1007073
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Nanjappa, Som G; Mudalagiriyappa, Srinivasu; Fites, J Scott et al. (2018) CBLB Constrains Inactivated Vaccine-Induced CD8+ T Cell Responses and Immunity against Lethal Fungal Pneumonia. J Immunol 201:1717-1726
Sharma, Akshat; Lawry, Stephanie M; Klein, Bruce S et al. (2018) LFA-1 Ligation by High-Density ICAM-1 Is Sufficient To Activate IFN-? Release by Innate T Lymphocytes. J Immunol 201:2452-2461
Hernández-Santos, Nydiaris; Klein, Bruce S (2017) Through the Scope Darkly: The Gut Mycobiome Comes into Focus. Cell Host Microbe 22:728-729

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