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Leveraging iPSC-derived Neutrophils to Identify Novel Approaches to Combat Invasive Mold Infections

Award Number: F32AI200170
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/15/2026
PERIOD OF PERFORMANCE END DATE: 12/14/2027

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Leveraging iPSC-derived Neutrophils to Identify Novel Approaches to Combat Invasive Mold Infections - Abstract Invasive mold infections (IMIs), primarily afflicting immunocompromised individuals, pose a growing threat to global human health, associated with more than two million deaths annually. Invasive aspergillosis, typically caused by Aspergillus fumigatus, is the most common of these infections, but IMIs can be caused by many diverse filamentous fungal species. These severe infections are extremely difficult to treat resulting in striking mortality rates well above fifty percent. This is largely due to rising rates of resistance to an already limited arsenal of antifungal drugs. After Aspergillus spp., Mucor and Fusarium spp. lead the way in annual morbidity, and both consistently demonstrate concerning resistance to all but one approved class of antifungal drugs. Considering the limitations of current approaches to the treatment of invasive fungal diseases, there is an urgent need for novel therapeutic strategies to control these infections. Granulocyte transfusion therapy is one approach that has been put forth based on scientific evidence showing that neutrophils are the primary immune cell involved in the defense against IMIs, but its success has been hindered by the short half-life of primary neutrophils coupled with a limited supply of willing human donors. However, recent work by several groups has demonstrated that induced pluripotent stem cells (iPSCs) can be differentiated in vitro to produce a population of neutrophil-like cells referred to as iNeutrophils. Dr. Anna Huttenlocher is a pioneering expert in this area, and recent work by her lab found that deletion of the GATA1 transcription factor, which directs basophil and eosinophil development, from iPSCs allows the generation of a homogenous population of iNeutrophils displaying neutrophil extracellular surface markers. Furthermore, her group showed that GATA1-/- iNeutrophils exhibit significantly more inhibition of A. fumigatus strain CEA10 growth in vitro than wild-type iNeutrophils. This antifungal activity was similar to that of primary neutrophils suggesting that GATA1-/- iNeutrophils may offer a potential alternative in granulocyte transfusion therapy circumventing the need for human donors. This proposal aims to build on these findings, to further investigate the utility of GATA1-/- iNeutrophils as a novel therapeutic approach in the treatment of diverse IMIs including those by caused by drug resistant fungi. Aim 1 of the research training plan herein proposes to leverage the antifungal activity of GATA1-/- iNeutrophils against A. fumigatus to assess their broad-spectrum activity against other human-pathogenic molds as well as their synergy with approved antifungal drugs. Aim 2 seeks to build on preliminary data suggesting a negative modulatory effect of myeloid derived growth factor (MYDGF) on iNeutrophil antifungal activity by generating GATA1-/- MYDGF-/- iNeutrophils to test the hypothesis that MYDGF acts as a paracrine signal to dampen neutrophil antifungal responses. This work will be carried out by at the University of Wisconsin-Madison under the mentorship of Dr. Anna Huttenlocher, a renowned neutrophil immunologist whose lab offers the unique expertise in immunology and iPSC biology necessary to successfully achieving the goals of the research training plan.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $78,243 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Allergy and Infectious Diseases Research	000	1	6/15/2026	NEW	$78,243
														Subtotal = $78,243

Grand Total All Awards = $78,243

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Leveraging iPSC-derived Neutrophils to Identify Novel Approaches to Combat Invasive Mold Infections

Award Number: F32AI200170

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/15/2026

PERIOD OF PERFORMANCE END DATE: 12/14/2027

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