# The Role of the EphA2 Receptor Kinase Pathway in Pneumocystis Pneumonia (PCP)

> **NIH NIH R21** · MAYO CLINIC ROCHESTER · 2024 · $242,100

## Abstract

Summary/Abstract
The overall goal of this proposal is to better understand the role of the tyrosine kinase receptor EphA2 signaling
pathway in alveolar macrophages during Pneumocystis pneumonia (PCP). Pneumocystis jirovecii pneumonia
(PJP) remains a significant cause of morbidity and mortality in AIDS1,2. During AIDS and other
immunosuppressive states, the absence of CD4 lymphocytic immunity results in exuberant and often fatal PJP3,4.
Myeloid cells, particularly alveolar macrophages (AMs) are crucial for anti-PJP innate immunity5-8. The binding
of Pneumocystis to alveolar macrophages mediates early host immune response to the fungus9,10. AMs further
promote killing and clearance of organisms but are also major sources of proinflammatory mediators contributing
to profound pulmonary inflammation and lung injury during PJP11-13.
 To date, extremely little is known regarding the role of EphA2 receptor and Pneumocystis engagement
in mediating subsequent effects on the host immune response and fungal killing during Pneumocystis pneumonia
(PCP). We have previously shown the importance of the β-glucan receptor EphA2 in Pneumocystis organism
attachment to lung epithelial cells14. Furthermore, we demonstrated that following EphA2 receptor-ligand
engagement with Pneumocystis β-glucan carbohydrates, the tyrosine kinase receptor is activated in epithelial
cells14. Now, our preliminary studies further indicate the importance of the EphA2 receptors on AMs in
inflammatory responses to Pneumocystis. To date, there are no published descriptions of the potential roles of
EphA2 on AMs during fungal infection pathogenesis. We now provide exciting new initial in vivo data
demonstrating that EphA2-deficient mice have significantly less proinflammatory responses and significantly
greater organism burden in both immunocompromised and immunocompetent mouse models of PCP.
 We therefore hypothesize that EphA2 receptors signal following Pneumocystis binding to alveolar
macrophages mediating early host immune recognition and response to the organism. In addition, based on our
preliminary in vivo PCP model data, we further hypothesize that EphA2-receptor signaling in AMs is critical for
mounting proper lung inflammation and organism control during PCP. Two Specific Aims are proposed.
 Aim 1: We will characterize the function of EphA2 signaling pathways in AMs following in vitro organism
attachment. We will specifically study the resulting cytokine response in AMs, as well as subsequent
organism killing by AMs. To address this, we will examine the function of EphA2 in AMs derived from EphA2
(EphA2-/-) receptor knockout and wildtype mice challenged with mouse derived Pneumocystis murina.
Specifically, we will study the binding kinetics and inflammatory responses following P. murina interactions with
AMs. Initial data from our lab suggests significantly less inflammatory cytokine responses in macrophages from
EphA2-/- versus wildtype controls. Furthermore, we will analyze the up...

## Key facts

- **NIH application ID:** 10828237
- **Project number:** 1R21AI181542-01
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** ANDREW H LIMPER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $242,100
- **Award type:** 1
- **Project period:** 2023-11-16 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828237

## Citation

> US National Institutes of Health, RePORTER application 10828237, The Role of the EphA2 Receptor Kinase Pathway in Pneumocystis Pneumonia (PCP) (1R21AI181542-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10828237. Licensed CC0.

---

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