# Innate control of the inflammatory process during fungal infections

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $531,000

## Abstract

PROJECT SUMMARY
 The dialogue between innate and adaptive branches of the immune system is a central paradigm of modern
immunology and is vital for protection against infections as well as for the pathogenesis of autoimmune, allergic
and inflammatory diseases. According to the current model, innate immune sentinels dispersed throughout
peripheral tissues sense, via their pattern recognition receptors (PRRs), the presence of microbial clues or
endogenous moieties released during an infection, are activated and migrate to the draining lymph node (dLN).
This process enables a transfer of “information” from peripheral tissue to the dLN, where the antigen-dependent
adaptive immune response against the pathogen is initiated. The dLN also hosts an initial antigen-independent,
innate immune response governed by migrating phagocytes that enables expansion of the LN and establishes
a pro-inflammatory milieu. These events are required for the development and polarization of the adaptive
immune response. Here, we focused our attention on the capacity of ligands derived from the cell wall of Candida
(C.) albicans to dictate the LN innate response. Our working hypothesis is that the size and solubility of
stimuli that activate the PRRs affect not only the LN innate response itself, but also the final outcome of
the immune response. Also, that the LN innate response initiated by soluble fungal ligands can be
harnessed to develop a potent and protective adaptive immune response to prevent life-threatening
systemic fungal infections. Our preliminary data demonstrate that the physical form of fungal ligands dictates
the location where the initial immune response takes place, and thereby determines the activation of adaptive
immunity. In particular, we have found that small soluble fungal ligands that are immunosilent in the periphery
and do not cause an inflammation in the tissue, become potent immunogens once they reach the dLN. Also, that
the LN innate response initiated by these ligands completely bypasses the need of phagocyte migration from the
periphery into the dLN and, instead, requires a unique gene signature that is characterized by the production of
interferons and that is driven by the activation of the noncanonical NFkB transcription factor RelB in subcapsular
sinus macrophages. Notably, Dectins are required for this process but CARD9, the key signaling adaptor
downstream of Dectins, is largely dispensable. Plus, the initial innate response to the dLN instructs a potent
type 1 adaptive immunity and allows the production of antibodies directed against the most external layer of the
fungal cell wall. Fungal diseases are a global health problem and Candida species are the most common cause
of invasive fungal infections. We propose to unravel how physical properties of the PAMPs can be harnessed as
a therapeutic intervention against systemic fungal infections that are a major medical problem in the US. We
anticipate that identifying new features of the im...

## Key facts

- **NIH application ID:** 10293993
- **Project number:** 2R01AI121066-06A1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Ivan Zanoni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $531,000
- **Award type:** 2
- **Project period:** 2016-03-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10293993

## Citation

> US National Institutes of Health, RePORTER application 10293993, Innate control of the inflammatory process during fungal infections (2R01AI121066-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10293993. Licensed CC0.

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