# Dissecting the role of Bruton's tyrosine kinase and ibrutinib in fungal immune surveillance

> **NIH NIH R21** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $269,400

## Abstract

PROJECT SUMMARY
Aspergillus fumigatus is the most common etiologic agent of invasive aspergillosis, a devastating infection in
patients with hematologic malignancies and in hematopoietic cell transplant recipients. Classically, patients
with prolonged quantitative or qualitative defects in neutrophil and/or monocyte function are at risk for invasive
aspergillosis. However, recent advances in targeted lymphoma therapies have resulted in new at-risk patient
groups, particularly if a novel agent targets a signal transduction pathway implicated in cancer cell proliferation
as well as immune surveillance. In a clinical study, we identified ibrutinib (IBT) as a risk factor for invasive
fungal infections, and invasive aspergillosis in particular. Although IBT targets Bruton’s tyrosine kinase (BTK)
to interrupt tonic B cell receptor signaling in malignant cells, IBT therapy leads to a defect in fungal immune
surveillance, though the underlying molecular and cellular mechanisms remain undefined. BTK knockout mice
are susceptible to A. fumigatus challenge and preliminary studies in mice and in human neutrophils suggest
that IBT disrupts myeloid cell antifungal activity, in part by interfering with fungal cell phagocytosis. A critical
knowledge gap relates to BTK function in myeloid cells and its role in mediating sterilizing antifungal immunity.
The central hypothesis that underlies this proposal is that BTK signaling in myeloid cells is essential to couple
A. fumigatus recognition to innate immune activation and fungal eradication. This model predicts that IBT
impairs this immune surveillance function independent of its effects on B cells. To examine this model, we
harness a unique fluorescent fungal reporter strain that monitors fungal uptake and viability during cellular
encounters with murine leukocytes in the lung and human leukocytes in vitro and utilize gene knockout mice
and a conditional gene targeting strategy to target myeloid cells that respond to, engulf, and kill conidia. We
explore this model in the following aims: (1) define the fungal immune surveillance function and essential
cellular source of BTK signaling in the lung, and (2) define the fungal immune surveillance defect caused by
IBT administration in the lung and in human leukocytes. The proposed studies are significant and innovative
because they translate an unexpected clinical observation into a systematic approach to decipher how a novel
precision pharmaceutical compound interferes with a central pathway of fungal immune surveillance. Insight
into the IBT-dependent fungal immune surveillance defect is likely to inform screening and prophylactic
strategies for at-risk patients.

## Key facts

- **NIH application ID:** 9968011
- **Project number:** 5R21AI142639-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** TOBIAS M HOHL
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $269,400
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968011

## Citation

> US National Institutes of Health, RePORTER application 9968011, Dissecting the role of Bruton's tyrosine kinase and ibrutinib in fungal immune surveillance (5R21AI142639-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9968011. Licensed CC0.

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