Transcriptomic analysis reveals that mTOR pathway can be modulated in macrophage cells by the presence of cryptococcal cells

Abstract

Cryptococcus neoformans and Cryptococcus gattii are the etiological agents of cryptococcosis, a high mortality disease. The development of such disease depends on the interaction of fungal cells with macrophages, in which they can reside and replicate. In order to dissect the molecular mechanisms by which cryptococcal cells modulate the activity of macrophages, a genome-scale comparative analysis of transcriptional changes in macrophages exposed to Cryptococcus spp. was conducted. Altered expression of nearly 40 genes was detected in macrophages exposed to cryptococcal cells. The major processes were associated with the mTOR pathway, whose associated genes exhibited decreased expression in macrophages incubated with cryptococcal cells. Phosphorylation of p70S6K and GSK-3β was also decreased in macrophages incubated with fungal cells. In this way, Cryptococci presence could drive the modulation of mTOR pathway in macrophages possibly to increase the survival of the pathogen.

What’s New in Cryptococcus gattii: From Bench to Bedside and Beyond

“…After inhaled Cryptococcus cells are phagocytosed by alveolar macrophages, they alter the macrophage transcriptome, preventing significant acidification, calcium efflux and protease activity, and thereby allowing intracellular pathogen proliferation [ 51 ].…”

“…Classically activated M1 macrophages that result from the usual Th1 cytokine immune profiles are essential for clearing Cryptococcus, while alternatively activated M2 macrophages resulting from Th2 cytokine stimulation are associated with a higher burden of disease [ 52 , 53 ]. C. gattii can modulate macrophage polarisation to M2, thereby evading immune recognition and clearance [ 51 , 52 , 53 ]. There are observed species-dependent in vitro differences in M1-polarised macrophage transcriptomic gene regulation and subsequent bioprocess modulation.…”

“…Both Cryptococcus species affect the Akt/mTOR pathway and TNF-alpha gene expression, reducing protective M1 macrophage fungicidal activity. Subsequently, there is dysregulation of normal immunologic dendritic cell development, NK cell activation and proliferation, other cellular cytokine profiles and nitric oxide production, leading to the alternative Th2-activated M2 macrophage polarisation [ 51 ]. C. gattii impacts signalling, cell differentiation and regulation of immune system processes, while C. neoformans modulates the cellular response to stimulus, response to DNA damage and cell death [ 51 ].…”

Molecular mechanisms underlying the emergence of polygenetic antifungal drug resistance in msh2 mismatch repair mutants of Cryptococcus

“…TOR signalling in Cryptococcus has recently been shown to modulate the expression of genes required to aid pathogen survival in macrophages during infection. 56 As well as controlling TOR signalling at the vacuole membrane, Vps39 is part of the homotypic fusion and protein sorting (HOPS) complex required for the fusion of vesicles either derived directly from the Golgi, via the alkaline phosphatase (ALP) pathway, or indirectly from the late endosome, via the indirect vacuolar protein sorting (VPS) pathway, to the vacuole. 45 This study has shown that deletion of VPS39 in C. neoformans results in increased susceptibility to fluconazole, suggesting an essential role of membrane trafficking to the vacuole in the tolerance to antifungal drugs.…”