# Novel mechanisms of Alveolar Macrophage-Dependent Antifungal Innate Immunity

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2022 · $543,928

## Abstract

Pneumocystis pneumonia (PcP) remains a serious life-threatening respiratory fungal infection of
immunocompromised patients, and one of the most common AIDS-defining illnesses in the US and the
world. PcP-related mortality rates have changed little over the past two decades, likely due to our inability to
adequately treat the infection without exacerbating immunopathogenesis. Adjunctive corticosteroids are used to
suppress inflammatory injury during antibiotic treatment, but the benefit of these broadly acting agents is
uncertain. The mechanisms by which Pc is recognized and cleared from the lung remain incompletely
understood. Alveolar macrophages (AMs) are at the frontline of the host-pathogen interaction, and serve as
important effectors of pulmonary host defense against Pneumocystis. Macrophages possess an array of PRR
that have the potential to recognize Pc, but they are typically ineffective for host defense when CD4+ T cell help
is not available. The reason for this is unknown, but it has been suggested that Pc may actively avoid or suppress
macrophage mediated host defense to insure survival and transmission. Our laboratory has identified an inbred
mouse strain which is unique in its ability to resist Pc infection in the absence of T cells. The resistance phenotype
requires the presence of AMs, and can be overridden by reprogramming the resistant AMs to a susceptible M1
biased phenotype. The identification of resistant and susceptible macrophage phenotypes will provide an
opportunity to explore the divergent host-pathogen interactions associated with either protection or infection. The
overarching hypothesis of this proposal is that differential macrophage polarization, phagocytic processing of Pc,
and antifungal effector production dictates the outcome of the Pc-AM interaction. To test this hypothesis we will
utilize the resistant and susceptible mouse models described in our Preliminary Studies. The identification of
new therapeutic strategies for the treatment of fungal diseases is an active area of drug-discovery research. Our
long-term goal is to understand the mechanisms regulating macrophage mediated innate immunity in the lung
to facilitate the rational design of therapeutic strategies to enhance host defense while limiting
immunopathogenesis. To accomplish this goal we propose Specific Aims that will: 1) define functional differences
in the phagocytic machinery of resistant and susceptible AMs that dictate the outcome of infection; 2) explore
novel antifungal functions for chitinase-like proteins (Chi3l3) and TAM receptors (MerTK); and 3) map the Pc
resistance locus and identify resistance-associated effector molecules that contribute to protective antifungal
innate immunity. Our Preliminary Studies demonstrate that AMs can be programmed for innate protection against
this opportunistic fungal pathogen, and suggest that modifying macrophage function may represent a viable
strategy to enhance antifungal host defense.

## Key facts

- **NIH application ID:** 10311998
- **Project number:** 5R01AI146035-03
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Terry W Wright
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $543,928
- **Award type:** 5
- **Project period:** 2020-01-08 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10311998

## Citation

> US National Institutes of Health, RePORTER application 10311998, Novel mechanisms of Alveolar Macrophage-Dependent Antifungal Innate Immunity (5R01AI146035-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10311998. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*