# Autophagy and Ocular Toxoplasmosis

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $385,880

## Abstract

The intracellular protozoan Toxoplasma gondii is the most common cause of infectious retinitis in
the world. Ocular toxoplasmosis tends to recur and leads to vision loss in 25% of patients, especially
in children with congenital infection, the elderly and the immunosuppressed. Current treatment does
not improve visual function or prevent relapses. A better understanding of the mechanisms that
control ocular toxoplasmosis may result in novel therapeutic approaches against this disease.
 Autophagy is a constitutive process of lysosomal degradation. T. gondii must avoid targeting by
autophagy in order to survive within host cells. We showed that during invasion of host cells, T. gondii
induces EGFR signaling that results in avoidance of initial autophagic targeting. Recently, we found
that T. gondii causes sustained Src signaling that maintains activation of EGFR and Akt (inhibitor of
autophagy). Pharmacologic inhibition of EGFR triggers autophagic killing of T. gondii in previously
infected cells and protects against ocular toxoplasmosis. However, the protection is partial (EGFR
expression is restricted; EGFR is only partially responsible for Akt activation). In contrast, Src is
ubiquitous and low concentrations of a Src inhibitor ablates Akt activation and kills T. gondii. How
autophagosomes selectively target T. gondii (required for effective pathogen elimination) is unknown.
 The objective of this application is to examine the role of Src in avoidance of autophagic killing of
T. gondii, understand how autophagy selectively targets the parasite and determine the relevance of
this mechanism in resistance against ocular toxoplasmosis. The central hypothesis is that inhibition of
Src enables the activation of a specific protein kinase that triggers selective autophagic targeting and
killing of T. gondii promoting protection against ocular toxoplasmosis. In the first aim we will examine
how inhibition of Src triggers activation of this protein kinase in T. gondii-infected cells. This aim will
be pursued using genetic and pharmacologic approaches that block specific signaling pathways. In
the second aim we will examine the role of this kinase in selective vs bulk autophagy in T. gondii-
infected cells. In the third aim, we will examine the molecular events controlled by this protein kinase
that explain how autophagosomes selectively target the parasite. Both aims will be pursued using a
combined approach of confocal microscopy using antibodies against endogenous proteins, live-cell
microscopy using fluorescently-tagged proteins and electron microscopy. In the fourth aim we will use
an animal model of ocular toxoplasmosis and transgenic mice to examine the role of Src, the protein
kinase controlled by Src and autophagy in ocular toxoplasmosis. The proposed work will further our
understanding of how host cell signaling regulates autophagic targeting of T. gondii and the outcome
of the infection, and may lead to adjunctive approaches to improve the treat...

## Key facts

- **NIH application ID:** 9971670
- **Project number:** 2R01EY018341-09
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** CARLOS S SUBAUSTE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,880
- **Award type:** 2
- **Project period:** 2009-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971670

## Citation

> US National Institutes of Health, RePORTER application 9971670, Autophagy and Ocular Toxoplasmosis (2R01EY018341-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9971670. Licensed CC0.

---

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