Fungal melanin modulation of calcium-mediated responses in lung epithelium

Active Project Grant Awarded Last action

Award ID
R01AI193212
Recipient
Awarding agency
Obligated
$1,692,214

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 25% complete
Place of performance
Worcester, MA 01655, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Invasive pulmonary fungal infections carry unacceptably high mortality rates and contribute to over $2.4 billion in direct healthcare costs in the US alone. The most prominent fungal pathogens causing lung disease include aspergillus fumigatus (AF). Although IT is well demonstrated that the immune system is critical to a proper response to invading fungi, the airway epithelium remains a vastly understudied component of antifungal immunity. We previously demonstrated that the recognition of aspergillus lacking the outer layer of 1,8-dihydroxy naphthalene (DHN) melanin by airway epithelial cells leads to higher transmigration of neutrophils. Our preliminary data demonstrate that purified AF melanin (termed melanin ghosts; MG) blocked the secretion of IL-8 and groα by the epithelium, muted calcium fluxing, reduced phosphorylation of key signaling molecules, induced distinct changes in the transcriptional signatures differentially in airway epithelial cell subtypes, altered actin filamentation, and dampened the production of reactive oxygen species (ROS). These data argue that fungal melanin actively triggers distinct immunomodulatory responses in primary human epithelial cells. Thus, our overall testable hypothesis is that AF melanin blocks calcium fluxing, which silences inflammatory circuits (i.e., exocytosis pathways, TLR and CLR signaling pathways, and ROS production) in airway epithelial cells to subvert the innate immune response. To address this hypothesis, we propose the following three specific aims: [1] dissect the mechanism of how AF fungal melanin inhibits chemokine secretion, [2] determine the TLR and CLR signaling pathways affected by AF melanin; and [3] reveal the mechanism by which melanin blocks ROS production in lung epithelial cells. This work will identify the mechanisms by which fungal melanin halts chemokine secretion by airway epithelial cells and define the pathway(S) altered by this suppression through the lens of calcium signaling. Completion of this proposal will provide novel therapeutic targets for invasive fungal infections caused by melanized fungi. Furthermore, lung diseases with the hallmark of a hyper- inflammatory state, such as asthma, could be treated with synthesized melanin to dampen exacerbated inflammation.

Transactions

Action Obligated Date
Amendment $838,677
Amendment $0
Original award $853,537

Subawards

Subrecipient Amount Awarded
The General Hospital Corporation Jayaraj Rajagopal, MDwill serve as a Co-Investigator will provide mice for the proposed experiments (studies to be collected at Columbia University) and will… $48,693
University Of Massachusetts Medical School The Levitz laboratory has over 35 years of expertise in fungal pathogenesis, including deep expertise in innate immunity and vaccine development. Dr. Levitz… $23,813
The General Hospital Corporation Jayaraj Rajagopal, MD will serve as a Co-Investigator will provide mice for the proposed experiments (studies to be collected at the University of Massachusetts… $48,696

Quick answers

Who received award R01AI193212?

R01AI193212 was awarded to University Of Massachusetts Medical School by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on August 8, 2025.

How much is award R01AI193212 worth?

$1,692,214 has been obligated on R01AI193212.

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