# In vivo mechanisms of brain invasion by Cryptococcus neoformans

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2021 · $377,811

## Abstract

Project Summary
 Cryptococcus neoformans is an encapsulated budding yeast that causes a life-threatening illness in
immunocompromised individuals, especially in AIDS patients. Although the infection starts in the lung,
cryptococcosis commonly presents as meningoencephalitis, which is one of the most common infections of
the central nervous system and a leading cause of death in HIV-infected individuals. Transmigration of C.
neoformans across the blood-brain barrier (BBB) is believed to be one of the most critical steps in the
development of cryptococcal meningoencephalitis. In vitro studies have shown that C. neoformans can
transmigrate across a monolayer of brain microvascular endothelial cells (BMECs) through transcytosis and
“Trojan horse” pathways. However, in vivo the BBB is a complex tissue that consists of BMECs, pericytes,
astrocyte end feet, and a basement membrane in a precise organization, which cannot at present be
recreated in vitro. Questions still remain as to how C. neoformans migrates to the brain across the BBB in
vivo and what is the underlying mechanism(s). Answering these questions is fundamental for understanding
cryptococcal pathogenesis, because brain invasion is the hallmark feature of this disease and
meningoencephalitis is the major and most lethal complication of cryptococcosis. In contrast to previous in
vitro studies that did not account for vascular haemodynamics, we have developed a novel in vivo model
system based on multiple novel approaches to directly investigate the brain invasion by C. neoformans in
vivo. In this project, we will use this in vivo system to study traversal of the BBB by C. neoformans by
addressing the following aims: 1) To characterize the transcytosis of C. neoformans and the mechanism
underlying this pathway in vivo. 2) To investigate the “Trojan horse” pathway and the underlying mechanism
during brain infection in vivo. 3) To characterize the mechanism(s) whereby C. neoformans damages the
BBB in vivo. 4) To determine the relative contribution of each mechanism to brain invasion by C. neoformans.
At the end of the proposed work, we will have identified the in vivo mechanism(s) by which C. neoformans
traverses the BBB. The knowledge created in this study will provide new potential therapeutic targets of
intervention for this disease.

## Key facts

- **NIH application ID:** 10146256
- **Project number:** 5R01AI131905-05
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Meiqing Shi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $377,811
- **Award type:** 5
- **Project period:** 2017-05-22 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146256

## Citation

> US National Institutes of Health, RePORTER application 10146256, In vivo mechanisms of brain invasion by Cryptococcus neoformans (5R01AI131905-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10146256. Licensed CC0.

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