Systemic Approach to Virulence Gene Network Analysis for Gaining New Insight into Cryptococcal Virulence.
Cryptococcus neoformansis pathogenic yeast, responsible for highly lethal infections in compromised patients around the globe.C. neoformanstypically initiates infections in mammalian lung tissue and subsequently disseminates to the central nervous system where it causes significant pathologies. Virulence genes ofC. neoformansare 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) ofC. 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,SHO1expression enhancedC. neoformansvirulence 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 inCryptococcusVAFs. Altogether, this study represents a pioneering effort in analysis of the virulence composite network ofC. neoformansusing a systems biology approach.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann ArborMI, USA; VA Ann Arbor Healthcare System Research Service (11R), Ann ArborMI, USA.
Antoni N
AN
Malachowski
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann ArborMI, USA; VA Ann Arbor Healthcare System Research Service (11R), Ann ArborMI, USA; The Regional Center for Mycology and Biotechnology, Al-Azhar UniversityCairo, Egypt.
Mohamed
M
Yosri
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University Seoul, South Korea.
Goun
G
Park
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University Seoul, South Korea.
Yong-Sun
YS
Bahn
Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann ArborMI, USA; Department of Microbiology and Immunology, University of Michigan Medical School, Ann ArborMI, USA; Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann ArborMI, USA.
Yongqun
Y
He
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann ArborMI, USA; VA Ann Arbor Healthcare System Research Service (11R), Ann ArborMI, USA.
Michal A
MA
Olszewski
Cryptococcus neoformans; bioinformatics; curation; data collection; host–pathogen interaction; mouse models; systems biology and network biology; virulence