An Interspecies Regulatory Network Inferred from Simultaneous RNA-seq of Candida albicans Invading Innate Immune Cells

Christian Doppler Laboratory for Infection Biology, Max F. Perutz Laboratories, Medical University of Vienna Vienna, Austria.
Frontiers in Microbiology (Impact Factor: 3.99). 03/2012; 3:85. DOI: 10.3389/fmicb.2012.00085
Source: PubMed


The ability to adapt to diverse micro-environmental challenges encountered within a host is of pivotal importance to the opportunistic fungal pathogen Candida albicans. We have quantified C. albicans and M. musculus gene expression dynamics during phagocytosis by dendritic cells in a genome-wide, time-resolved analysis using simultaneous RNA-seq. A robust network inference map was generated from this dataset using NetGenerator, predicting novel interactions between the host and the pathogen. We experimentally verified predicted interdependent sub-networks comprising Hap3 in C. albicans, and Ptx3 and Mta2 in M. musculus. Remarkably, binding of recombinant Ptx3 to the C. albicans cell wall was found to regulate the expression of fungal Hap3 target genes as predicted by the network inference model. Pre-incubation of C. albicans with recombinant Ptx3 significantly altered the expression of Mta2 target cytokines such as IL-2 and IL-4 in a Hap3-dependent manner, further suggesting a role for Mta2 in host-pathogen interplay as predicted in the network inference model. We propose an integrated model for the functionality of these sub-networks during fungal invasion of immune cells, according to which binding of Ptx3 to the C. albicans cell wall induces remodeling via fungal Hap3 target genes, thereby altering the immune response to the pathogen. We show the applicability of network inference to predict interactions between host-pathogen pairs, demonstrating the usefulness of this systems biology approach to decipher mechanisms of microbial pathogenesis.

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    • "As RNA sequencing costs continue to drop, it will increasingly be feasible to simultaneously study gene expression profiles of multiple categories of socially interacting individuals within social insect colonies, to provide social systems-level insight into the molecular basis of social regulation of the behaviour, physiology, development and fitness of colony members. Such a more systems-level focused strategy of profiling gene expression of multiple interacting organisms simultaneously has already been used to study the molecular mechanisms underlying host–pathogen interactions (Kollmus et al., 2014; Reid and Berriman, 2012; Tierney et al., 2012; Westermann et al., 2012), and this approach is a conceptually straightforward next step to study the molecular mechanisms underlying social interactions (Linksvayer et al., 2012; Vojvodic et al., 2014). Once candidate genes and gene networks are identified in the various classes of interacting individuals , gene-level approaches can be used to experimentally manipulate expression and quantify effects at the individual-and colony-levels. "
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    Advances in insect physiology 12/2015; 48:271-291. DOI:10.1016/bs.aiip.2014.12.003 · 2.71 Impact Factor
    • "Significant insight into the exact nature of the various microenvironments that this fungal pathogen occupies in mammalian hosts can be provided by high-throughput technologies that enable the quantification of fluctuations in the abundance of RNA transcripts (transcriptomic), proteins (proteomic), and other biomolecular components (metabolomic) (Fradin et al., 2003; Tierney et al.; 2012, Reales-Calderón et al., 2014; Muszkieta et al., 2013). These technologies will aid in painting " the big picture " of the battle happening between Sporothrix spp. "
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    • "multi-drugresistancepumpshavebeenpublished(Westerhoff etal.,2000).Alargebodyofliteratureonthemodelingof biofilmformationisavailable(Audretschetal.,2013),though mostlyonbacterialratherthanfungalbiofilms,forareview seeHornandLackner(2014).Moreover,ageneregulatory networkwasinferred(Tierneyetal.,2012).Allofthosemodeling techniquescouldinprinciplebeappliedtoinvestigateC.albicans' interactionswiththehost. "
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