# BLR&D Research Career Scientist Award Application

> **NIH VA IK6** · CINCINNATI VA MEDICAL CENTER RESEARCH · 2024 · —

## Abstract

Pneumocystis spp. are 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.
Typically, PCP has been associated with patients infected with HIV, however, the fulminate pneumonia, PCP,
and colonization with Pneumocystis jirovecii (the species infecting humans) are emerging clinical problems in
newly susceptible populations in the general and veterans’ populations including bone marrow recipients;
patients receiving immunotherapy for rheumatoid arthritis and other chronic inflammatory diseases; and cancer
chemo- and immunotherapies. The life cycle of Pneumocystis is suggested to contain both an asexual replication
cycle and a sexual cycle involving mating with subsequent formation of asci containing 8 ascospores (1). During
the previous Merit Review, we showed that echinocandin treatment of rodents infected with P. murina and P.
carinii, which target β-1,3-D-glucan synthesis (BG), depleted the asci which contain BG but large numbers of
non-BG expressing life cycle stages remained in the lungs and were unable to proliferate. We further
demonstrated that anidulafungin and caspofungin could prevent infection in a prophylactic model, suggesting
that formation of asci via the sexual cycle may be required for a productive infection (2). Analysis of gene
expression profiles of P. murina in mice treated with anidulafungin, showed strong upregulation of genes
associated with sexual replication, though the resulting infections were devoid of asci, the product of sexual
reproduction, suggesting that P. murina attempted to undergo sexual replication, but could not due to a lack of
BG. Based on these data, we posited that asci, and thus sexual replication, is required to facilitate progression
through the life cycle leading to a productive infection. We further posited that presence of asci is required for
transmission of Pneumocystis infection. In the present Merit Review, we will explore 2 critical but unanswered
questions that will lead to a deeper knowledge of the life cycle of Pneumocystis, and also suggest potential
vulnerabilities for targeted treatment concomitant with anidulafungin therapy: (1) Is sexual replication required
for completion of the life cycle of Pneumocystis? Tracking of the replication status of P. murina during
prolonged treatment with anidulafungin by global gene analysis, BG content, and microscopic methods will reveal
whether the non-BG expressing forms numbers remain: 1) static over time, 2) increase, or 3) decrease;
suggesting: 1) the lack of BG blocks replication; 2) that an asexual or alternative replication phase permits
survival of the fungi; or 3) the lack of sexual replication results in elimination of the infection. (2) Can sexual
replication rebound after cessation of prolonged anidulafungin treatment? Mice will be treated with
anidulafungin for up to 8 weeks, with 2 cessation time points...

## Key facts

- **NIH application ID:** 10881679
- **Project number:** 5IK6BX005232-05
- **Recipient organization:** CINCINNATI VA MEDICAL CENTER RESEARCH
- **Principal Investigator:** Melanie T Cushion
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881679

## Citation

> US National Institutes of Health, RePORTER application 10881679, BLR&D Research Career Scientist Award Application (5IK6BX005232-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10881679. Licensed CC0.

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