Comparative host transcriptome in response to pathogenic fungi identifies common and species-specific transcriptional antifungal host response pathways.

Mariolina Bruno,Yang Li,Rob Ter Horst,Intan M.W Dewi,Mihai G Netea,Frank L Van De Veerdonk,Mark S Gresnigt,Berenice Rösler,Marina Pekmezovic,Jean-Paul Latgé,Vicky Matzaraki,Rutger J Röring,Vinod Kumar,Laszlo Groh,Agostinho Carvalho

doi:10.1016/j.csbj.2020.12.036

Abstract

Candidiasis, aspergillosis, and mucormycosis cause the majority of nosocomial fungal infections in immunocompromised patients. Using an unbiased transcriptional profiling in PBMCs exposed to the fungal species causing these infections, we found a core host response in healthy individuals that may govern effective fungal clearance: it consists of 156 transcripts, involving canonical and non-canonical immune pathways. Systematic investigation of key steps in antifungal host defense revealed fungal-specific signatures. As previously demonstrated, Candida albicans induced type I and Type II interferon-related pathways. In contrast, central pattern recognition receptor, reactive oxygen species production, and host glycolytic pathways were down-regulated in response to Rhizopus oryzae, which was associated with an ER-stress response. TLR5 was identified to be uniquely regulated by Aspergillus fumigatus and to control cytokine release in response to this fungus. In conclusion, our data reveals the transcriptional profiles induced by C. albicans, A. fumigatus, and R. oryzae, and describes both the common and specific antifungal host responses that could be exploited for novel therapeutic strategies.

Highlights

Unstimulated peripheral blood mononuclear cells (PBMCs) served as reference, and the transcriptional profile was assessed after 4 h (4 h) and 24 h (24 h) of stimulation with inactivated yeast and conidia of the three fungal species
Unsupervised hierarchical clustering revealed that the transcriptional response of PBMCs from various donors show stimulus dependent clustering at both the 4 h and 24 h time points (Fig. 1C, D)
Principle component analysis (PCA) revealed that the majority of the variance in transcription was stimulus-dependent, as demonstrated by the three distinct clusters corresponding to the three different fungal species

Summary

Introduction

The number of immunocompromised patients is steadily increasing [19,35] due to evolving medical care with more invasive procedures, increased use of immunosuppressive drugs [26,75], and growing numbers of ICU admissions These factors mutually contribute to the increasing incidence of aspergillosis, candidiasis, and mucormycosis. Speciesspecific host defense pathways in terms of pathogen recognition, cytokine release, and metabolism may be activated depending on the particular fungal species encountered by the immune system. The knowledge of these mechanisms will provide valuable insights for the selection of immunotherapies adapted against each species.

Objectives

Methods

Results

Conclusion