Is Ferroptosis a Future Direction in Exploring Cryptococcal Meningitis?

Abstract

Cryptococcal meningitis (CM) is the leading cause of mortality among patients infected with human immunodeficiency virus (HIV). Although treatment strategies for CM are continually being developed, the mortality rate is still high. Therefore, we need to explore more therapeutic strategies that are aimed at hindering its pathogenic mechanism. In the field of CM, several studies have observed rapid iron accumulation and lipid peroxidation within the brain, all of which are hallmarks of ferroptosis, which is a type of programmed cell death that is characterized by iron dependence and lipid peroxidation. In recent years, many studies have confirmed the involvement of ferroptosis in many diseases, including infectious diseases such as Mycobacterium tuberculosis infection and coronavirus disease-2019 (COVID-19). Furthermore, ferroptosis is considered as immunogenic and pro-inflammatory as the ferroptotic cells release damage-associated molecular pattern molecules (DAMPs) and alarmin, both of which regulate immunity and pro-inflammatory activity. Hence, we hypothesize that there might be a relationship between this unique cell death modality and CM. Herein, we review the evidence of ferroptosis in CM and consider the hypothesis that ferroptotic cell death may be involved in the cell death of CM.

Identification of a ferroptosis-related gene pair biomarker with immune infiltration landscapes in ischemic stroke: a bioinformatics-based comprehensive study

“…A plethora of data has indicated the participation of ferroptosis in immunity [ 5 , 59 ]. Ferroptotic cells can activate innate immunity and release pro-inflammatory factors in various diseases (including myocardial I/R injury, and glioma), recruiting lots of immune cells [ 60 ].…”

Diffuse Adrenal Gland and Pancreas Necrosis in a Patient with Disseminated Cryptococcosis—Case Report

“…Additionally, host sphingolipids have been shown to alter granuloma formation and contribute to melanin production, and can alter microbial uptake via macrophages, phagocytic cell response, and neutrophil’s killing ability in Cryptococcal infection [ 43 ]. Besides, ferroptosis has been described in cryptococcal meningitis, involving rapid iron accumulation and lipid peroxidation [ 44 ]. Taken together, these may explain why Cryptococci have tropism to organs high in lipids, or with a significant amount of peri-organ fat; as in our patient’s case.…”

The Molecular Mechanisms of Ferroptosis and Its Role in Blood-Brain Barrier Dysfunction

“…System X C – transports cystine into the cell and glutamate or cysteine out of the cell in a 1:1 exchange ratio ( Stockwell et al, 2017 ). GSH, a tripeptide antioxidant, is then used as a cofactor for glutathion peroxidase 4 (GPX4), which reduces oxidative stress, maintains the intracellular redox balance and inhibits ferroptosis ( Xu et al, 2021 ). The synthesis of GSH depends on the availability of cysteine (generated from its precursor cystine), the level of sulfur amino acid precursors and the activity of glutamate-cysteine ligase (GCL) ( Kuang et al, 2020 ).…”