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

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.

Targeting the Immune System with Plant Lectins to Combat Microbial Infections

“…This fact critically reduces the shelf life of antibiotics that are not efficient to combat the emerging multidrug-resistant strains ( Holmes et al, 2016 ; Laxminarayan et al, 2016 ). In addition, pathogens have developed several mechanisms to evade and suppress the host defenses and/or to induce exacerbated inflammation (which may cause host tissue injury) ( Chaves et al, 2016 ; Gomes et al, 2016 ; Ko, 2016 ; Malachowski et al, 2016 ; Sha et al, 2017 ). This scenario encourages the development of new approaches to treat microbial infection, such as those based on the modulation of the host immune system.…”

Sho1 and Msb2 Play Complementary but Distinct Roles in Stress Responses, Sexual Differentiation, and Pathogenicity of Cryptococcus neoformans

“…Previous studies reported that cryptococcal Sho1 contributes to the pulmonary virulence of C. neoformans by its interference with the immune responses (Malachowski et al, 2016). The role of Msb2 and its relationship with Sho1 in virulence during C. neoformans infection remains unknown.…”

“…The role of Msb2 and its relationship with Sho1 in virulence during C. neoformans infection remains unknown. Using our established model of pulmonary cryptococcosis in mice (Malachowski et al, 2016), we compared the virulence of sho1 Δ, msb2 Δ, and sho1 Δ msb2 Δ strains in vivo . The effects of mutations on the fungal growth in the lungs were analyzed on day 3, illustrating the ability for the fungal adaptation to the host environment and on day 7, which reflects the outcomes of the organism’s interaction with building up pulmonary immune defenses (Hoag et al, 1995).…”

“…Furthermore, deletion of yeast Sho1 ortholog (CNAG_05435) in C. neoformans , only weakly decreases thermotolerance but increases C. neoformans capsule production (Kim et al, 2015), which could imply that some or all of these effects might be HOG-independent. Finally, while the sho1 Δ mutant is as virulent as the wild-type (WT) strain in a murine model of systemic cryptococcosis (Kim et al, 2015), Sho1 contributes to the fungal virulence by promoting non-protective Th2 immune response to organism inhaled into the lungs (Malachowski et al, 2016), suggesting a complex relationship between these pathways and virulence. Thus, it remains elusive whether the Sho1-like signaling branch regulates the HOG pathway or else, plays a distinct role in C. neoformans and how these signaling circuits (and their crosstalk) affect cryptococcal fitness and virulence.…”

Corrigendum: Sho1 and Msb2 Play Complementary but Distinct Roles in Stress Responses, Sexual Differentiation, and Pathogenicity of Cryptococcus neoformans

“…Msb2 promotes the acute adaptation to the host environment and seems to be dispensable thereafter. By contrast, Sho1 does not play a substantial role during the acute adaptation but it is required for the optimal fungal growth of fungus in the lungs during the later time points (Figure 9; Malachowski et al, 2016 ) where, as we demonstrated, it interferes with the development of the immune defenses.”…”