# The role of sex in the life cycle and transmission of Pneumocystis

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2020 · $477,062

## Abstract

Pneumocystis spp. are host obligate fungal pathogens that cause a fatal pneumonia (PCP) in
immunocompromised hosts. Few drugs are effective against PCP and there have been no new therapies for its
treatment in decades. PCP remains a problem in HIV-infected patients and is emerging as a clinical concern in
newly susceptible populations including patients receiving immunotherapy for chronic conditions.
 We recently reported that treatment of PCP in murine models with the echinocandins, anti-fungal agents that
target β-1,3-D-glucan synthesis (BG), depleted the asci which contain BG, but large numbers of forms that do
not express BG remained in the infected lungs and were apparently unable to proliferate. Notably, the treated
mice could not transmit the infection without asci. The echinocandins prevented PCP when administered
prophylactically at higher doses, suggesting that formation of asci via the sexual cycle may be required for a
productive infection. Genes associated with sexual replication and cell cycle perturbation comprised the
strongest up-regulated signals in P. murina from anidulafungin treated mice. These infections were devoid of
asci, suggesting that P. murina attempted to undergo sexual replication, but could not due to a lack of BG.
Based on these data, we posit that asci, and thus sexual replication, is required for progression through
the Pneumocystis life cycle. The importance of the sexual cycle for survival of Pneumocystis will be
investigated using the anidulafungin treatment and prophylactic models. The specific aims address 2 major
questions we propose to pursue: Question 1: Is sexual replication required for completion of the life cycle
of Pneumocystis? 3 aims will be used to address this question. The first will be to assess the replication
competency of P. murina treated with anidulafungin by transferring them to new hosts. Replication will be
determined by a combination of microscopic methods, BG measurement, and quantitative PCR. The second
aim will use the prophylactic model to allow low level replication to ask whether replication occurs via the sexual
cycle, using the same methods. The third aim will determine whether P. murina can survive during prolonged
anidulafungin treatment in the same hosts without proceeding through the sexual cycle or if it is eventually
cleared. Question 2: At what point in the Pneumocystis life cycle can the infection be transmitted? The
sexual cycle returns after withdrawal of anidulafungin. During 10 days to 4 weeks post-cessation, we will track
the emergence of the sexual cycle and identify gene signatures, biomarkers and numbers of asci prior to
exposing these mice to naïve recipients. Using these data, we will determine at what point in the life cycle
transmission takes place and the thresholds necessary for transmission. Selected proteins based on gene
expression data will be validated by proteomics as potential biomarkers associated with return of the sexual
cycle and transmission. ...

## Key facts

- **NIH application ID:** 9851431
- **Project number:** 5R01HL146266-02
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Melanie T Cushion
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $477,062
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851431

## Citation

> US National Institutes of Health, RePORTER application 9851431, The role of sex in the life cycle and transmission of Pneumocystis (5R01HL146266-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851431. Licensed CC0.

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