Friday, May 9, 2025
5/9/2025
Fungal Pathogenicity Determinants through the Lens of Immune-Targeted Cancer Therapies - Project Summary. The advent of molecular therapies for cancer and autoimmunity have led to a rise in the number of serious infections caused by environmental microbes, exemplified by invasive aspergillosis (IA). While Aspergillus fumigatus is normally a benign environmental saprophyte, this ubiquitous mold can cause life-threatening invasive disease in the setting of leukopenia and/or high dose corticosteroid treatment. Fungal pathogenicity in leukopenic or corticosteroid-treated populations is historically thought to be a global property of all environmental A. fumigatus strains, based on their common property of reaching terminal airways and growing at human body temperatures. Recent bedside to bench research from our laboratories is challenging this long-standing paradigm of A. fumigatus strain-agnostic pathogenicity. Patients undergoing pharmacologic inhibition of Bruton’s tyrosine kinase (BTK) for lymphoid malignancies have an unexpected risk for IA. However, murine model studies to define the mechanism of A. fumigatus susceptibility during BTK inhibitor therapies revealed a striking fungal strain-specific pathogenicity. Standard pathogenic reference strains that are highly virulent in murine models of leukopenia or corticosteroid treatment failed to cause disease in BTK- deficient or -inhibited models. However, clinical isolates from BTK therapy patients initiated invasive disease and caused host mortality. Immunologic studies revealed that BTK inhibitors (BTKi) such as Ibrutinib surprisingly blunted myeloid antifungal activity, specifically the function of neutrophil NADPH oxidase and primary granule exocytosis. Our working hypothesis is that A. fumigatus strain-specific pathogenicity in the setting of BTKi is mediated by alterations in the fungal genetic network responsible for susceptibility to NADPH oxidase- and degranulation-mediated killing. In this proposal, we propose two aims to define the A. fumigatus strain-specific pathogenicity determinants responsible for IA in the setting of BTKi therapy. In aim 1, we utilize novel whole genome protein kinase, phosphatase, and transcription factor null mutant collections to define the genetic network responsible for fungal cell viability during interactions with host neutrophils. Preliminary data identified 3 protein kinases and 1 protein phosphatase whose function mediated susceptibility to neutrophil killing. These key regulatory proteins will be utilized to define the genetic network mediating neutrophil fungal killing susceptibility. In Aim 2, we leverage our novel collection of A. fumigatus isolates from patients on BTKi therapies. Preliminary whole genome sequencing data of these isolates identified a loss of function allele in the same protein phosphatase identified in our genetic screen in Aim 1. Further studies will detail the pathogenesis of these clinical isolates in our BTKi murine models and conduct mechanistic genetic analyses to pinpoint the key A. fumigatus pathogenicity determinants driving IA in this specific host setting. Our proposed studies are expected to reveal unexpected novel fungal pathogenicity determinants in the host setting of precision medicine therapy that is rapidly being employed in the clinic for the treatment of cancer.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).