# Deciphering the Role of Lysosomal Biogenesis in Anti-Aspergillus Immune Responses

> **NIH NIH F31** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $46,752

## Abstract

PROJECT SUMMARY/ABSTRACT
 This proposal describes a mentored three-year training plan that will provide the applicant with broad
training in fungal pathogenesis, cellular immunology, and cell biology. The sponsor’s clinical and laboratory
expertise in modeling and analyzing immune responses to microbial pathogens, the dedicated training plan, and
institutional strengths in immunology, microbial pathogenesis, and cell biology all contribute to an outstanding
training environment and a high likelihood of success.
 Aspergillus fumigatus is an opportunistic fungal pathogen and is the most common etiological agent of
invasive aspergillosis (IA). Despite being constantly exposed to A. fumigatus conidia, immunocompetent
individuals rarely get IA, because cells of the innate immune system are rapidly recruited to the lung where they
phagocytose and clear conidia asymptomatically. However, IA is major complication for immunosuppressed
individuals, such as those receiving solid organ or hematopoietic stem cell transplant and patients with
hematological malignancies. Because these patient groups are expanding and there is currently a lack of
effective anti-fungal drugs (fungus attributable mortality in these risk groups is upwards of 20%) there is a
significant unmet need to understand the host immune response to IA.
 Preliminary data from a murine model of IA suggests that in the lung, neutrophils upregulate lysosome
associated genes in response to fungal engagement. Regulation of lysosome biogenesis is controlled by the
master transcription factors TFEB and TFE3 (TFEB/3). Additionally, TFEB/3 are activated in macrophages (MΦ)
in response to stimulation with swollen heat-killed conidia. My training and research objective are to integrate
the role of TFEB/3 and lysosome biogenesis in the context of the pulmonary anti-fungal immune responses and
to acquire training in the technical disciplines needed for these studies. I hypothesize that A. fumigatus activates
TFEB/3 in leukocytes through C-type lectin receptor signaling, and that TFEB/3 contribute to sterilizing immunity
in the lung, by promoting intracellular killing of A. fumigatus conidia.
 Specific Aim 1 of the proposed research will determine the molecular basis for TFEB/3 activation in
response to A. fumigatus. Using a ΜΦ cell line as a model leukocyte and both genetic and pharmacological
strategies to inhibit key signaling molecules, I will uncover the relative contributions of various signaling pathways
to the activation of TFEB/3 in ΜΦs. Specific Aim 2 of the proposed research I will define the contribution of
TFEB/3 to anti-Aspergillus immunity. I will use a genetically engineered mouse model to deplete TFEB/3 from
myeloid cells combined with our model of IA to uncover the contribution of TFEB/3 to murine survival, to the
maintenance of lung tissue integrity, and to the ability of leukocytes to effectively clear conidia from the lung.
These studies will reveal novel mechanisms of phagolysosomal ki...

## Key facts

- **NIH application ID:** 10488583
- **Project number:** 5F31AI161996-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Mariano Alejandro Aufiero
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-08-31 → 2024-08-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488583

## Citation

> US National Institutes of Health, RePORTER application 10488583, Deciphering the Role of Lysosomal Biogenesis in Anti-Aspergillus Immune Responses (5F31AI161996-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10488583. Licensed CC0.

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