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A Translational Precision-Cut Lung Slice Model for Host-Response and Therapeutic Testing in Pneumocystis Pneumonia

Award Number: R21AI203622
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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A Translational Precision-Cut Lung Slice Model for Host-Response and Therapeutic Testing in Pneumocystis Pneumonia - SUMMARY/ABSTRACT: Pneumocystis jirovecii pneumonia (PJP) remains a major cause of morbidity and mortality in HIV/AIDS1-4. The World Health Organization has classified Pneumocystis jirovecii among its “Fungal Priority Pathogens,” emphasizing the urgent need for novel therapies5. Drug development has been hindered by the organism’s inability to be continuously cultured in vitro, limiting mechanistic studies and systematic drug screening. We have developed a novel ex vivo infection-preserving precision-cut lung slice (PCLS) model derived from immunosuppressed mice with fulminate Pneumocystis pneumonia (PCP). This system retains the infected lung microenvironment, allowing for concurrent quantification of host immune responses and testing of anti-Pneumocystis agents, using far less test agents than in whole animals. Preliminary data demonstrate PCLS maintain viability, and demonstrate reproducible reduction in fungal burden after treatment with pentamidine or the novel anti-fungal agent ISFP106-9, while also exhibiting suppression of inflammatory cytokine responses10-12. We hypothesize this ex vivo infection-preserving PCLS platform will provide standardized and physiologically relevant screening for both anti-Pneumocystis and anti-inflammatory agents during Pneumocystis infection. Aim 1: Standardize and validate an infection-preserving PCP PCLS system for anti-Pneumocystis screening. We will optimize our PCLS model to yield reproducible, quantitative anti-Pneumocystis readouts. We will prepare PCLS (200-300 µM) from Pneumocystis murina-infected lungs derived from AIDS-like CD4+- depleted mice and will assess viability and epithelial integrity13-15. We will also quantify reduced P. murina burden by qPCR16,17 using benchmark anti-Pneumocystis agents (e.g. pentamidine, TMP-SMX), and novel agents (ISFP10)18-20. Aim 2: Integrate multiplexed host-response assessment to enable dual testing of agents for host inflammatory responses and anti-Pneumocystis activity. Our preliminary data indicate that PCP PCLS can recapitulate the antifungal activity of known anti-Pneumocystis drugs (e.g., pentamidine) ex vivo and also measure host immune responses to anti-inflammatory agents 10,21,22,23,24. We will employ cytokine profiling (e.g., IL-6, IL-1β, TNFa, IL-10) via Luminex25, confirmed by qPCR. Furthermore, we will evaluate small-molecule inhibitors targeting novel Pneumocystis-induced host inflammatory signaling pathways10,12,26-30 during PCLS infection9. This approach will provide insight into the progression of infection and host immune responses and will be useful to identify agent that reduce fungal burden while tempering host inflammation. Exploratory Aim 3: Leverage the PCP PCLS model for translational relevance by demonstrating that ex vivo PCP PCLS reliably predicts conserved responses in human lung. We will assess the feasibility of generating human PCLS from surgical tissue and subsequently expose the slices to P. jirovecii derived from BAL28,31-36. We will quantify organism burden and host cytokine responses in the presence or absence of known and novel anti-Pneumocystis and anti-inflammatory compounds in the ex vivo model of human PJP infection.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $242,100 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Allergy and Infectious Diseases Research	000	1	8/25/2026	NEW	$242,100
														Subtotal = $242,100

Grand Total All Awards = $242,100

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A Translational Precision-Cut Lung Slice Model for Host-Response and Therapeutic Testing in Pneumocystis Pneumonia

Award Number: R21AI203622

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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