# Deciphering a novel lipid-based mechanism of innate immune modulation

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $201,875

## Abstract

Our understanding of antifungal immunity remains relatively limited, and examples of fungal mechanisms to
modulate these responses are even rarer. C. albicans is a ubiquitous fungal component of mammalian gut
microbiota as well as the most common cause of fungal infections in humans. We identified the lip2-/- virulence
mutant in a screen of ~1500 C. albicans mutants in a mouse model of systemic infection (Basso et al., Cell Host
and Microbe, in press). Whereas a lip2-/- strain exhibits normal virulence attributes during the first 6 hours of
infection, including dissemination through the bloodstream, solid organ invasion, and yeast-to-hypha
morphogenesis, its titers progressively decline at subsequent timepoints, and the host typically survives. Immune
profiling of infected kidneys (the primary target organ in this infection model) revealed significant increases in
levels of IL-17 mRNA and protein in organs infected with lip2-/- compared to wild-type C. albicans (WT).
Strikingly, the virulence of lip2-/- was fully restored when infections were performed in Il17af-/- animals that fail to
produce IL-17. These results suggested that 1) IL-17 is required for a potent antifungal response during systemic
candidiasis and 2) Lip2 somehow opposes this response. We identified renal 𝛄δ T cells as a major source of IL-
17 in lip2-/--infected kidneys and renal dendritic cells as a major source of IL-23 (a cytokine known to stimulate
IL-17 production by 𝛄δ T cells). Further, under in vitro conditions, we observed that lip2-/- (but not WT C. albicans)
activates IL-23 expression by co-cultured bone marrow-derived dendritic cells (BMDCs). Using BMDCs prepared
from Tlr2-/-, Tlr4-/-, Tlr2/Tlr4-/-, and Clec7a-/- animals, we further showed that TLR2 and/or TLR4 but not Dectin-1
are required for this response. Remarkably, immune activation was blocked when the coculture experiment is
performed in the presence of 0.1 𝛍M palmitic acid, a hydrolysis product of Lip2. The data support a model in
which WT C. albicans secretes Lip2 in solid organs, thereby raising local concentrations of palmitic acid, which
suppresses TLR2- and TLR4-dependent activation of tissue-resident DCs and, thereby, a downstream IL-17-
dependent antifungal immune response. Beyond unveiling a novel fungal virulence mechanism, this work unveils
a role for IL-17 during systemic fungal infection, in addition to its previously well-documented role in defense
against mucocutaneous candidiasis. To understanding this novel lipid-mediated modulation of the innate
response to C. albicans, we will use a forward genetic approach to identify factors required for modulation of the
innate responses to C. albicans by free fatty acids produced by its lipase activity. These exploratory, high-risk
studies will provide insights lipid-mediated immunosuppression, a novel mechanism of fungal pathogenesis and
immune modulation.

## Key facts

- **NIH application ID:** 10846789
- **Project number:** 5R21AI178231-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Roarke Alexander Kamber
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $201,875
- **Award type:** 5
- **Project period:** 2023-05-23 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846789

## Citation

> US National Institutes of Health, RePORTER application 10846789, Deciphering a novel lipid-based mechanism of innate immune modulation (5R21AI178231-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10846789. Licensed CC0.

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