Systemic Approach to Virulence Gene Network Analysis for Gaining New Insight into Cryptococcal Virulence.

Antoni N Malachowski,Goun Park,Michal A Olszewski,Mohamed Yosri,Yongqun He,Yong-Sun Bahn

doi:10.3389/fmicb.2016.01652

Abstract

Cryptococcus neoformans is pathogenic yeast, responsible for highly lethal infections in compromised patients around the globe. C. neoformans typically initiates infections in mammalian lung tissue and subsequently disseminates to the central nervous system where it causes significant pathologies. Virulence genes of C. neoformans are being characterized at an increasing rate, however, we are far from a comprehensive understanding of their roles and genetic interactions. Some of these reported virulence genes are scattered throughout different databases, while others are not yet included. This study gathered and analyzed 150 reported virulence associated factors (VAFs) of C. neoformans. Using the web resource STRING database, our study identified different interactions between the total VAFs and those involved specifically in lung and brain infections and identified a new strain specific virulence gene, SHO1, involved in the mitogen-activated protein kinase signaling pathway. As predicted by our analysis, SHO1 expression enhanced C. neoformans virulence in a mouse model of pulmonary infection, contributing to enhanced non-protective immune Th2 bias and progressively enhancing fungal growth in the infected lungs. Sequence analysis indicated 77.4% (116) of total studied VAFs are soluble proteins, and 22.7% (34) are transmembrane proteins. Motifs involved in regulation and signaling such as protein kinases and transcription factors are highly enriched in Cryptococcus VAFs. Altogether, this study represents a pioneering effort in analysis of the virulence composite network of C. neoformans using a systems biology approach.

Highlights

Cryptococcus neoformans, a basidiomycetous pathogenic yeast, is a leading cause of fatal mycosis in AIDS patients (Chuck and Sande, 1989) and a major cause of fungal meningoencephalitis and central nervous system (CNS)-related mortality around the world (Jarvis and Harrison, 2007)
A motif analysis was conducted to identify all motifs in each virulence associated factors (VAFs) and motifs shared by different VAFs. Our application of these three methods of sequence-based prediction identified specific patterns in different strains of Cryptococcus VAFs; and apart from already known pathways, our study identified virulence function of a new strain-specific gene, SHO1, likely to be involved in the Hog1 mitogen-activated protein kinase (MAPK) signaling pathway
We defined comprehensive interactions among these VAFs based on their reported roles in different pathogenicity pathways, as well as their involvement in pathogenesis of both lungs and the CNS infections

Summary

Introduction

Cryptococcus neoformans, a basidiomycetous pathogenic yeast, is a leading cause of fatal mycosis in AIDS patients (Chuck and Sande, 1989) and a major cause of fungal meningoencephalitis and central nervous system (CNS)-related mortality around the world (Jarvis and Harrison, 2007). Systemic Virulence Network Analysis of C. neoformans organs, most critically, the CNS (Tripathi et al, 2012). Cryptococcal strains display different levels of virulence, ranging from extremely virulent strains that can infect non-immunocompromised individuals to completely avirulent. These levels of virulence are associated with differential expression levels of virulence-associated genes, of which most have been identified and studied by functional genetic analysis of a mutant or using a large-scale mutant screening

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Conclusion