# Targeting the Sexual Cycle of Pneumocystis

> **NIH VA I01** · CINCINNATI VA MEDICAL CENTER RESEARCH · 2024 · —

## Abstract

Pneumocystis jirovecii is a fungal pathogen that causes pneumonia (PjP) in immunocompromised patients.
Trimethoprim-sulfamethoxazole (TMP-SMX) is the first line drug for the treatment and prophylaxis of PjP.
However, many patients cannot tolerate TMP-SMX due to severe allergic reactions. Secondary treatments such
as pentamidine are either toxic or not as effective as TMP-SMX. PjP remains refractory to most common
antifungal drugs necessitating novel approaches for new agent discovery.
 Echinocandins, β -1,3 -D-glucan synthase inhibitors, are a newer family of antifungal agents. Reports of the
efficacy of echinocandins for PjP have been contradictory, due in large part to the anecdotal nature of the reports
and combinations with other agents. However, new data from meta-analyses indicate that a combination of
TMP-SMX with echinocandins can lead to a reduction in mortality and improved treatment responses. This new
finding together with the novel insights on the effects of echinocandins on Pneumocystis pneumonia we accrued,
position us to take the next steps in optimizing and understanding this synergy.
 Mouse and rat models of Pneumocystis pneumonia are surrogates for P. jirovecii infection, since no species
of Pneumocystis can be cultivated outside the lung. Fortunately, rodent models are predictive of drug efficacy
in humans. During the tenure of the previous VA Award, we have made several significant discoveries that
we will use to our advantage for the proposed studies, most notably the fact that Pneumocystis spp. are obligated
to undergo sexual replication to survive, grow, and transmit the infection. Treatment with echinocandins interrupt
the sexual cycle, leading to its eventual elimination.
 We will concentrate on the effects of anidulafungin monotherapy (AnM) and combination therapy with TMP-
SMX (AnTS), on the P. carinii sexual cycle and the ability of the host to transmit the infection. We posit that as
sexual obligates, a better understanding of these treatments on the sexual cycle will lead to more efficient
regimens and identify at what point hosts are unable to transmit the infection. Our approaches will employ single
cell RNA-seq and in vivo animal strategies. Typically used to interrogate mammalian cells, application of sc-
RNA-seq to a human fungal pathogen is highly innovative. The aims of this proposal are to:
 Aim 1. Define the perturbations by anidulafungin monotherapy (AnM) and anidulafungin/TMP-SMX
combination therapy (AnTS) on the sexual cycle of Pneumocystis carinii using single cell profiling
(scRNA-seq). We have shown that scRNA-seq can be used to identify clusters of life cycle stages from BALF
of P. carinii-infected rats (Preliminary Data). In the present aim, three groups of P. carinii-infected rats will be
employed to achieve our goals: (i) Untreated, infected, and immunosuppressed rats (Control); (ii) infected,
immunosuppressed treated with AnM; and (iii) infected, immunosuppressed, treated with AnTS. BALF will be
...

## Key facts

- **NIH application ID:** 10693474
- **Project number:** 2I01BX004441-05
- **Recipient organization:** CINCINNATI VA MEDICAL CENTER RESEARCH
- **Principal Investigator:** Melanie T Cushion
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2018-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693474

## Citation

> US National Institutes of Health, RePORTER application 10693474, Targeting the Sexual Cycle of Pneumocystis (2I01BX004441-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10693474. Licensed CC0.

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