# Trained immunity and the regulation of anti-fungal defense

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2022 · $635,850

## Abstract

Abstract:
Although often overlooked as a significant health problem, pulmonary infections with fungal pathogens present
a clinical problem of growing concern. Aspergillus fumigatus (Af) and Cryptococcus neoformans (Cn) are two
clinically important fungal pathogens that affect immunosuppressed patients worldwide. Both infections are
difficult to treat and are associated with high mortality rates. A better understanding of immune mechanisms of
host defense against fungi hold the promise of providing the basis for the future development of novel, immune
based interventions to improve patient outcomes. Pulmonary macrophages are critical, front-line mediators of
host protection against fungi and other pulmonary pathogens. Despite the well-defined role of lung macrophages
as crucial initiators of immunity to diverse sets of pathogens, our understanding of how previous infection history
shapes subsequent macrophage responses to fungal infection in the lung remain poorly defined. Moreover, an
emerging body of literature has now revealed that macrophage populations in the lung are more heterogeneous
than originally appreciated and can undergo innate training; an enhanced response to diverse secondary
challenges. It is now also understood that alveolar macrophages present in the lung can originate from embryonic
precursors (tissue-derived alveolar macrophages-TD-AMs) or from blood monocytes (monocyte-derived alveolar
macrophages-Mo-AMs). Whether TD-AM and Mo-AM are equally capable of undergoing innate training is
currently unclear. It is also unknown whether innate training is a conserved response to any infectious stimuli or
regulated by specific pathways. In preliminary studies, we uncovered that priming with an immunogenic strain of
Cn (HK-fbp1) could confer heterologous protection against infection with Af even in the context of drug-induced
immunosuppression and in a T cell-independent manner. Preliminary data gathered, suggest that neutrophils
and STAT1-dependent signals are important regulators of antifungal monocytes and their differentiation into
monocyte-derived cells. Based on our aggregate observations, the central hypothesis of this project is that:
CCR2+mo are critical mediators of antifungal immunity and can be instructed by HK-fbp1 into trained mo-AM via
the coordinated actions of neutrophils and an interferon (IFN) cascade. We will address two related but
independent aims: Aim 1: Investigate the impact of HK-fbp1 immunization to pulmonary innate cell priming and
training to promote antifungal immunity; Aim 2: Decipher the contributions of neutrophils in the regulation of
antifungal trained immunity.

## Key facts

- **NIH application ID:** 10466617
- **Project number:** 1R01AI169769-01
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Amariliz Rivera
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $635,850
- **Award type:** 1
- **Project period:** 2022-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466617

## Citation

> US National Institutes of Health, RePORTER application 10466617, Trained immunity and the regulation of anti-fungal defense (1R01AI169769-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10466617. Licensed CC0.

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