# DAP12 and the host response to cryptococcosis

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2022 · $571,755

## Abstract

Project Summary
Cryptococcus neoformans is an opportunistic fungal pathogen that is inhaled into the lungs and can
disseminate to the brain, causing a highly fatal meningoencephalitis in immunocompromised patients,
particularly those with HIV/AIDS, solid organ transplantation, and cancer. Even with contemporary combination
antifungal therapy, the mortality rate for cryptococcosis approximates 25%, and the at-risk population is
expanding with the development of new immunosuppressive regimens for autoimmunity and cancer. Our ability
to develop new treatments for cryptococcosis remains limited because we do not yet fully understand how the
fungus evades host immunity. We recently discovered that C. neoformans is able to suppress the response of
inflammatory monocytes, innate immune cells that give rise to macrophages and dendritic cells and typically
aid in fungal recognition and clearance by the host. C. neoformans directs inflammatory monocytes to
differentiate into alternatively activated (M2) macrophages that are permissive for fungal proliferation and
dissemination, leading to increased mortality from the infection. We have identified a signaling adapter DNAX-
activating protein of 12 kDa (DAP12) that may play a crucial role in suppressing the inflammatory monocyte
response to C. neoformans. The deletion of DAP12 improves fungal clearance and survival in a murine model
of cryptococcosis, and DAP12-deficient monocyte-derived macrophages have better uptake and killing of the
fungus. Additionally, the lungs of Dap12-/- mice have increased numbers of CD8+ T cells, cytotoxic adaptive
immune cells that can be recruited and activated by macrophages and are important for the clearance of C.
neoformans. Thus, DAP12 may be an important target for reversing the suppressive effects of C. neoformans
on the fungicidal activity of inflammatory monocytes and their ability to prime CD8+ T cells. Our preliminary
data indicate that this repressive DAP12 activity may be regulated by the binding of C. neoformans to the cell
surface receptor triggering receptor expressed on myeloid cells 2 (TREM2) on monocyte-derived
macrophages. The goal of this proposal is to further define this novel DAP12 signaling pathway. We
hypothesize that C. neoformans induces formation of a TREM2-DAP12 signaling complex that coordinates
effector molecules to inhibit the anti-cryptococcal defenses of inflammatory monocytes and CD8+ T cells,
thereby subverting the host response to infection. The specific aims are to 1) determine the mechanism by
which DAP12 signaling is initiated by C. neoformans, 2) define the signaling cascade that mediates the
suppressive effects of DAP12 during infection, and 3) ascertain the role of inflammatory monocyte-intrinsic
DAP12 in the regulation of CD8+ T cell responses to C. neoformans. Defining these mechanisms will deepen
our understanding of host immunity to opportunistic fungi and inform new opportunities for immunomodulatory
interventions against C. neofo...

## Key facts

- **NIH application ID:** 10449347
- **Project number:** 5R01AI162765-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Lena J Heung
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $571,755
- **Award type:** 5
- **Project period:** 2021-07-12 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449347

## Citation

> US National Institutes of Health, RePORTER application 10449347, DAP12 and the host response to cryptococcosis (5R01AI162765-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10449347. Licensed CC0.

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