Leveraging ipsc-derived neutrophils to identify novel approaches to combat invasive mold infections

Active Project Grant Awarded Last action

Award ID
F32AI200170
Recipient
Awarding agency
Obligated
$78,243

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 0% complete
Place of performance
Madison, WI 53715, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Quick answers

Who received award F32AI200170?

F32AI200170 was awarded to University Of Wisconsin System by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on December 15, 2026.

How much is award F32AI200170 worth?

$78,243 has been obligated on F32AI200170.

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